List of references Genetics and JIA (December 2001)
BADILLA A, ROJAS C: [Familial gout and nephropathy in a young woman. Report of one case]. Rev.Med.Chil. 2001, 129:666-670. Organism:Departamento de Reumatologia Hospital San Juan de Dios, Santiago de Chile rbadilla@rdccl Abstract: We report a 29 years old woman with a chronic tophaceous gout, whose disease started at the age of 18. On clinical examination, the blood pressure was elevated. The laboratory assessment showed a serum uric acid of 15 mg/dl, a urinary uric acid of 155 mg/24 h, a creatinine clearance of 59 ml/min/1.73 m2 and a uric acid excretion fraction off 1.3% (normal 7 to 12%). The clinical and laboratory features of this patient suggest the diagnosis of a familial juvenile gouty nephropathy Internet : PM:11510209
BLANCHONG CA, OLSHEFSKI R, KAHWASH S: Large Granular Lymphocyte Leukemia: Case Report of Chronic Neutropenia and Rheumatoid Arthritis-like Symptoms in a Child. Pediatr.Dev.Pathol. 2001, 3:94-99. Organism:Division of Hematology/Oncology, Columbus Children's Hospital, the Ohio State University, 700 Children's Drive, Columbus, OH 43205, USA Abstract: Lymphoproliferative disorders of large granular lymphocytes (LGL) are heterogeneous, with a clinical/pathologic spectrum ranging from a benign polyclonal expansion to an aggressive clonal disease. Often these lymphoproliferative disorders are associated with autoimmune disease. The clonal form of the disorder, LGL leukemia, typically occurs in older adults with a median age of 55 years at diagnosis. Pediatric cases are referred to in review articles; however, no detailed reports of T-cell LGL leukemia in children exist. This report illustrates a case of a child who presented initially at age 2 and 1/2 years with psoriasis, juvenile rheumatoid arthritis-like symptoms, and neutropenia. Bone marrow examinations obtained throughout his course have demonstrated progressive hypercellularity with increased reticulin fibers and replacement of the normal marrow elements by lymphocytes, which were later identified as large granular lymphocytes. Further testing with immunophenotyping by flow cytometry and T-cell receptor gene rearrangement studies revealed a monoclonal proliferation of large granular lymphocytes and confirmed a diagnosis of LGL leukemia. Although rare, large granular lymphocyte leukemia should be included in the differential diagnosis of chronic neutropenia in children Internet : PM:11116299
BROPHY S, CALIN A: Ankylosing spondylitis: Interaction between genes, joints, age at onset, and disease expression. Rinsho Ganka 2001, 28:2283-2288. Organism:Dr. A. Calin, Royal National Hosp. Rheum. Dis., Upper Borough Walls, Bath BA1 1RL Abstract: Objective. Ankylosing spondylitis (AS) is a chronic inflammatory disorder with symptom onset generally occurring in the late teens/mid-twenties. In women, a younger age at onset enhances disease susceptibility in the next generation. We examined the influence of age at symptom onset on phenotypic expression. Methods. Patients were divided into cohorts according to age of symptom onset. The primary outcome measure was radiological progression (by Bath AS Radiology Index, BASRI). Secondary measures were disease activity (Bath AS Disease Activity Index, BASDAI), function (Bath AS Functional Index, BASFI), numbers undergoing AS related surgery, and percentage with secondary disorders. Results. Age at onset had no significant effect on radiological progression (young onset vs late onset, 8.0, 8.6, respectively) disease activity (young vs late, 4.4, 4.4), need for non-hip surgical intervention (9%, 8%, respectively), or prevalence of secondary disorders (iritis, 40%, 41%; psoriasis, 20%, 19%; inflammatory bowel disease, 7.5%, 8.9%). By contrast, there was a striking increase in prevalence of total hip replacement in those with juvenile onset (18%, 8%, respectively; p<0.001). Regardless of age at onset, spinal progression determined radiologically was greater in those with hip arthritis compared to those without [young onset hip involvement vs non-hip involvement, 9.7 (2.4), 7.2 (3.0) (p<0.001); late onset hip involvement vs non-hip involvement, 10.1 (2.5), 7.1 (3.0), respectively]. Function deteriorates with age (young onset vs late onset, 3.7, 4.5, respectively; p<0.01). Conclusion. (1) Hip disease (young or late onset) is a major prognostic marker for longterm severe disease (patients with hip disease have a spinal score increased by 2.5-3 points or 35-40% more change). (2) Hip involvement is more prevalent among patients with young age at onset. (3) Young onset patients without hip involvement do not have more severe disease. Thus, age at onset, itself, does not influence disease severity. (4) Since hip involvement and not age at onset is associated with worse outcome, patients with a young age at onset may be assumed to have an increased susceptibility load (i.e., genetic component or environmental trigger) rather than more severity genes. The lack of association between severity and age at onset implies that the determinants of susceptibility and severity are independent Internet : andrei.calin@virgin.net
CAVET J, DICKINSON AM, NORDEN J, TAYLOR PR, JACKSON GH, MIDDLETON PG: Interferon-gamma and interleukin-6 gene polymorphisms associate with graft-versus-host disease in HLA-matched sibling bone marrow transplantation. Blood 2001, 98:1594-1600. Organism:University Department of Haematology, School of Clinical and Laboratory Sciences, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom jamescavet@nclacuk Abstract: Proinflammatory cytokines including interferon-gamma (IFNgamma), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFalpha) are implicated in the pathogenesis of acute graft-versus-host disease (aGVHD). Cytokine gene polymorphism is associated with functional differences in cytokine regulation and altered clinical performance in a variety of diseases. Polymorphism in the IFNgammaIntron1 microsatellite (CA)n repeat has been linked with in vitro IFNgamma production and renal transplant rejection. The IL-6(-174)(G/C) single nucleotide polymorphism has been linked to in vitro and in vivo IL-6 production, juvenile chronic arthritis, and renal transplant rejection. This study examined the potential association of GVHD with IFNgamma and IL-6 polymorphisms in 80 sibling bone marrow transplant (BMT) donor/recipient pairs. Patients homozygous for the IFNgammaIntron1 allele 3 had more severe (grade III-IV) aGVHD. Patients possessing the IL-6(-174)G allele had a trend toward higher grades of aGVHD, and those homozygous for the IL-6(-174)G allele were more likely to develop chronic GVHD (cGVHD). The associations of previously identified aGVHD severity-associated cytokine gene polymorphisms (TNFd and IL-10(-1064)) with severe aGVHD were reconfirmed. Logistic regression analysis confirmed the association of severe aGVHD with recipient genotype at IFNgammaIntron1 (odds ratio [OR] 3.92; P =.02), IL-10(-1064) (OR 4.61; P =.026) and TNFd (OR 3.29; P =.039), and that of cGVHD with recipient IL-6(-174) genotype (OR 4.25; P =.007), in addition to age, gender mismatch, and underlying disease. Assessment of cytokine genotype may potentially allow more accurate prediction of GVHD and appropriate adjustment of GVHD prophylaxis, as well as indicating novel areas for future studies of GVHD pathogenesis Internet : PM:11520812
CRAWLEY E, KON S, WOO P: Hereditary predisposition to low interleukin-10 production in children with extended oligoarticular juvenile idiopathic arthritis. Rheumatology (Oxford) 2001, 40:574-578. Organism:Department of Molecular Pathology, University College London Medical School, 46 Cleveland Street, London W1T 4JF, UK Abstract: OBJECTIVE: To determine whether children with extended oligoarticular juvenile idiopathic arthritis (JIA) produce less of the anti-inflammatory cytokine interleukin-10 (IL-10) than those with persistent oligoarticular JIA. METHODS: We measured IL-10 production in the parents of children with oligoarticular or extended oligoarticular JIA, from whole-blood cultures stimulated with lipopolysaccharide. RESULTS: IL-10 production was lower in the parents of children with extended oligoarticular JIA compared with those of children with oligoarticular JIA (P=0.034). There was an increase in the percentage of ATA-containing genotypes (i.e. genotypes ATA/ATA, ATA/ACC or ATA/GCC) in the parents of children with extended oligoarticular JIA compared with healthy controls (P<0.02) but not in the parents of children with oligoarticular JIA. CONCLUSIONS: As approximately 84% of the variation in IL-10 production is thought to be genetically regulated, these results suggest that stimulated IL-10 production would be lower in children with extended oligoarticular JIA. Because IL-10 is an anti-inflammatory cytokine, this may partly explain why this group of children has more severe disease Internet : PM:11371669
DONN RP, SHELLEY E, OLLIER WE, THOMSON W: A novel 5'-flanking region polymorphism of macrophage migration inhibitory factor is associated with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2001, 44:1782-1785. Organism:Epidemiology Unit, Arthritis Research Campaign, Manchester, UK Abstract: OBJECTIVE: To determine if polymorphisms of the macrophage migration inhibitory factor (MIF) gene are associated with systemic-onset juvenile idiopathic arthritis (JIA). METHODS: Denaturing high-performance liquid chromatography was used to screen for the MIF gene in 32 healthy Caucasian subjects. One hundred seventeen UK Caucasian patients with systemic-onset JIA and 172 unrelated healthy UK Caucasian controls were genotyped for a single-nucleotide polymorphism (SNP) identified in the 5'-flanking region of the gene, using polymerase chain reaction-restriction fragment length analysis. RESULTS: A G-to-C transition was identified at position -173 of the MIF gene. The presence of a C at -173 creates an activator protein 4 transcription factor binding site. Allele and genotype frequencies differed significantly between the patients and controls for the MIF-173 polymorphism. Individuals possessing a MIF-173*C allele have an increased risk of systemic-onset JIA (36.8% versus 20.3%) (odds ratio 2.3, 95% confidence interval 1.34-3.86; P = 0.0005). CONCLUSION: This is the first report of a SNP in the MIF gene. This polymorphism is associated with systemic-onset JIA Internet : PM:11508429
DONN RP, BARRETT JH, FARHAN A, STOPFORD A, PEPPER L, SHELLEY E, DAVIES N, OLLIER WE, THOMSON W: Cytokine gene polymorphisms and susceptibility to juvenile idiopathic arthritis. British Paediatric Rheumatology Study Group. Arthritis Rheum. 2001, 44:802-810. Organism:Arthritis Research Campaign Epidemiology Unit, Manchester, UK Abstract: OBJECTIVE: To investigate the involvement of candidate cytokine genes in the pathogenesis of juvenile idiopathic arthritis (JIA). METHODS: Single nucleotide polymorphisms and intragenic microsatellite markers within 8 candidate cytokine genes (interleukin-1alpha [IL-1alpha], IL-2, IL-4, IL-6, IL-10, interferon-alpha1 [IFNA1], interferon-gamma [IFNG], and interferon regulatory factor 1 [IRF-1]) were investigated in 417 Caucasian patients with clinically characterized JIA and a panel of 276 unrelated, healthy Caucasian controls, all from the United Kingdom. RESULTS: A novel 3'-untranslated region (3'UTR) polymorphism in IRF-1 was found to be associated with susceptibility to JIA (corrected P = 0.002). No significant association with IL-1alpha, IL-2, IL-4, IL-6, IL-10, IFNA1, or IFNG was observed. CONCLUSION: An association between JIA and a previously unreported 3'UTR polymorphism of IRF-1 was observed. This association was not found to be specific to any particular JIA subgroup. This suggests that IRF-1 may contribute to a common pathogenesis shared by all JIA patients, regardless of clinical phenotype. This is most likely to be a genetic contribution to the chronic inflammatory process that underlies JIA pathology Internet : PM:11315919
KOGA Y, KUROMARU R, TAKADA H, HARA T: Juvenile idiopathic arthritis associated with autoimmune thyroid disorders and autoimmune cholangitis. Rheumatology (Oxford) 2001, 40:942-943. Internet : PM:11511767
MCGEER PL, MCGEER EG: Polymorphisms in inflammatory genes and the risk of Alzheimer disease. Arch.Neurol. 2001, 58:1790-1792. Organism:Department of Psychiatry, University of British Columbia, Vancouver, Canada mcgeerpl@interchangeubcca Abstract: The concept of inflammation as a major factor in Alzheimer disease (AD) has heretofore been based on postmortem findings of autodestructive changes associated with the lesions coupled with epidemiological evidence of a protective effect of anti-inflammatory agents. Now there is evidence that the risk of AD is substantially influenced by a total of 10 polymorphisms in the inflammatory agents interleukin 1alpha, interleukin 1beta, interleukin 6, tumor necrosis factor alpha, alpha(2)-macroglobulin, and alpha(1)-antichymotrypsin. The polymorphisms are all common ones in the general population, so there is a strong likelihood that any given individual will inherit 1 or more of the high-risk alleles. The overall chances of an individual developing AD might be profoundly affected by a "susceptibility profile" reflecting the combined influence of inheriting multiple high-risk alleles. Since some of the polymorphisms in question have already been linked to peripheral inflammatory disorders, such as juvenile rheumatoid arthritis, myasthenia gravis, and periodontitis, associations between AD and several chronic degenerative diseases may eventually be demonstrated. Such information could lead to strategies for therapeutic intervention in the early stages of such disorders Internet : PM:11708985
MYERS LK, HIGGINS GC, FINKEL TH, REED AM, THOMPSON JW, WALTON RC, HENDRICKSON J, KERR NC, PANDYA-LIPMAN RK, SHLOPOV BV, STASTNY P, POSTLETHWAITE AE, KANG AH: Juvenile arthritis and autoimmunity to type II collagen. Arthritis Rheum. 2001, 44:1775-1781. Organism:University of Tennessee, Memphis, USA Abstract: OBJECTIVE: Joint inflammation in juvenile rheumatoid arthritis (JRA) is sometimes associated with an autoimmune response to type II collagen (CII), a cartilage-specific protein. To test the hypothesis that down-regulation of autoimmunity to CII can be accomplished in JRA by oral administration of CII, an open-label study of CII was performed in 9 patients with JRA. METHODS: Seven rheumatoid factor-negative JRA patients with polyarticular disease and 2 JRA patients with pauciarticular disease (1 with early onset and 1 with late onset) were treated for 3 months with oral bovine CII. Patients were examined for disease activity and underwent routine laboratory testing at monthly intervals. Two of the patients had flares of disease when treatment was discontinued, and these patients were re-treated for an additional 3 months. To test the hypothesis that oral tolerance induces an immune deviation of T cells, peripheral blood mononuclear cells from patients were collected before and after treatment and cultured with CII. Supernatants and RNA were collected and analyzed for the presence of various cytokines. RESULTS: Eight patient trials met the criteria for clinical improvement outlined by Giannini and coworkers in 1997. None of the patients had any side effects from the treatment. In 6 of the 8 patients who improved, interferon-gamma production decreased after oral CII therapy, correlating with clinical improvement, while 6 patients had increases in levels of transforming growth factor beta3. CONCLUSION: These results are encouraging. The possible beneficial effect of oral CII in JRA merits further investigation Internet : PM:11508428
SAILA H, KOTANIEMI K, SAVOLAINEN A, KAUTIAINEN H, LEIRISALO-REPO M, AHO K: Uveitis in sibling pairs with juvenile idiopathic arthritis. Rheumatology (Oxford) 2001, 40:221-224. Organism:Rheumatism Foundation Hospital, Heinola, Finland Abstract: OBJECTIVE: To ascertain the occurrence and characteristics of uveitis in sibling pairs affected with juvenile idiopathic arthritis (JIA). METHODS: The sibling series comprised 80 JIA patients from 37 families with two or three JIA children, seen at the paediatric department of the Rheumatism Foundation Hospital in Heinola, Finland. An ophthalmologist examined the children for uveitis two to four times a year and the course of the condition was recorded during the follow-up. RESULTS: Uveitis was diagnosed in 21 of the 80 patients (26%). Three pairs (3.4 pairs expected) were concordant for the presence of asymptomatic uveitis. Two patients with enthesitis-related arthritis had acute unilateral uveitis. Among the remaining cases, uveitis was chronic and continuously active at the end of follow-up in 13 instances, but in spite of this only one patient had impaired vision. HLA allele B27 occurred more frequently in patients with uveitis than in those without uveitis (52 vs 30%, P=0.073) and all six subjects in the pairs concordant for chronic uveitis carried this allele. CONCLUSIONS: The observed concordance rate for uveitis did not differ from that expected. Although the uveitis was chronic in most instances, its course was usually mild Internet : PM:11257162
SCOLA MP, IMAGAWA T, BOIVIN GP, GIANNINI EH, GLASS DN, HIRSCH R, GROM AA: Expression of angiogenic factors in juvenile rheumatoid arthritis: correlation with revascularization of human synovium engrafted into SCID mice. Arthritis Rheum. 2001, 44:794-801. Organism:Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA Abstract: OBJECTIVE: Although increased vascularity was noted in early histopathologic studies of juvenile rheumatoid arthritis (JRA) synovium, the available data on angiogenesis in JRA are very limited. The main purposes of this study were to assess expression of the key angiogenic factors in JRA synovium, and to evaluate a SCID mouse model of JRA as an approach to study in vivo regulation of the expression of these factors in JRA. METHODS: RNase protection assay was used to assess the expression of the key angiogenic factors in fresh JRA synovium and in JRA synovial tissue fragments that had been minced and then implanted into SCID mice. Vascularity of the samples was assessed by immunohistochemical staining for von Willebrand factor. Synovial specimens obtained from patients with osteoarthritis (OA) or other noninflammatory arthropathies were used as controls. RESULTS: Detectable levels of messenger RNA for vascular endothelial growth factor and angiopoietin 1 and their respective receptors, as well as endoglin and thrombin receptors, were present in all JRA tissue specimens studied. The levels of expression of these factors in JRA tissues were significantly higher than those in tissues obtained from patients with OA or other noninflammatory arthropathies. Furthermore, increased expression of the key angiogenic factors in the fresh JRA tissues correlated with the exuberant revascularization of JRA minced tissue fragments implanted into SCID mice. This was in sharp contrast to the poor revascularization of implanted OA tissues. CONCLUSION: JRA synovium is characterized by high angiogenic activity. SCID mouse-human JRA synovium chimeras may provide a good approach to study the in vivo regulation of angiogenesis in JRA Internet : PM:11315918
VENCOVSKY J, JAROSOVA K, RUZICKOVA S, NEMCOVA D, NIEDERLOVA J, OZEN S, ALIKASIFOGLU M, BAKKALOGLU A, OLLIER WE, MAGEED RA: Higher frequency of allele 2 of the interleukin-1 receptor antagonist gene in patients with juvenile idiopathic arthritis. Arthritis Rheum. 2001, 44:2387-2391. Organism:Institute of Rheumatology, Prague, Czech Republic venc@revmacz Abstract: OBJECTIVE: An increased incidence of allele 2 of the interleukin-1 receptor antagonist gene (IL1RN*2) in several inflammatory diseases has recently been reported. The aim of this study was to examine a variable number tandem repeat (VNTR) polymorphism of the IL1RN gene in patients with juvenile idiopathic arthritis (JIA). METHODS: Findings in 185 Czech patients with JIA were compared with those in 168 Czech controls, 50 JIA patients and 52 controls of Turkish origin, and 79 controls from central England. VNTR polymorphism analysis of IL1RN was performed by polymerase chain reaction using 2 flanking primers to amplify an 86-bp tandem repeat region in intron 2. RESULTS: The frequency and carriage rate of IL1RN*2 were significantly increased in Czech JIA patients compared with the Czech controls (frequency 27.6% versus 15.8%; carriage rate 44.3% versus 26.2%). Increased frequency and carriage rate of IL1RN*2 were found in 23.3% and 40.0% of Turkish JIA patients and in 17.3% and 34.6% of ethnically matched controls. The high representation of IL1RN*2 in 52.3% of the 22 patients with extended oligoarthritis, 31.3% of the 56 patients with enthesitis-related arthritis, and 42.9% of the 14 patients with other arthritis was particularly responsible for the increased frequency of IL1RN*2 in the Czech JIA patients. We found no association of IL1RN*2 with disease activity or severity parameters. CONCLUSION: Inheritance of IL1RN*2 may contribute to genetic susceptibility in several forms of autoimmune diseases, including JIA. The IL1RN*2 allele may be useful as a prognostic indicator of the evolution of an extended oligoarticular course of JIA Internet : PM:11665981
Anonymous36th Workshop for Pediatric Research, Goettingen, Germany, February 17-18, 2000. European Journal Of Pediatrics 2000, 159:R2-R10 Abstract: This meeting contains abstracts of 36 papers, written in English, covering topics in pediatric research, including hyperinsulinism, endocrine deficiencies, gene mutations, growth disturbance, cardiomyopathy, familial hypomagnesemia, Fanconi anemia, acute lymphoblastic leukemia, Ewing's sarcoma and other pediatric tumors, cytodifferentiation, respiratory syncytial virus, juvenile rheumatoid arthritis, tuberculosis, cystic fibrosis, congenital heart defect, preterm birth, Down syndrome, autism, microdialysis, therapeutic drug monitoring in human children and experimental animal models
CARRENO PL, GONZALEZ FERNANDEZ CM, LOPEZ LONGO FJ, MONTEAGUDO S, I: [Juvenile chronic arthritis]. Rev.Clin.Esp. 2000, 200 Monog 1:64-68. Organism:Servicio de Reumatologia, Hospital General Universitario Gregorio Maranon, Madrid Internet : PM:0010901028
CUESTA IA, MOORE EC, RABAH R, BAWLE EV: Blau syndrome (familial granulomatous arthritis, iritis, and rash) in an African-American family. Journal of Clinical Rheumatology 2000, 6:30-34. Organism:Dr. I.A. Cuesta, Division of Immunology/Rheumatology, Children's Hospital of Michigan, 3901 Beaubien Blvd., Detroit, MI 48201 Abstract: Blau syndrome (familial granulomatous arthritis, iritis, and rash) was originally described in 1985, in 11 members of a family of Dutch ancestry. Inheritance is autosomal dominant. Several more Caucasian families have been described since. Skin and synovial biopsy specimens show noncaseating sarcoid like granulomas, but the lung is not involved as in classic sarcoidosis. This report describes 3 members of an African American family with Blau syndrome. It is important to differentiate this genetic disorder from other childhood arthritides, such as, juvenile rheumatoid arthritis, juvenile spondyloarthropathies, and early-onset sarcoidosis, because of the need for genetic counseling, treatment and differing potential for selective involvement of other organs (eye, skin, and tendons/joints). All children of an affected individual have a 50% chance of inheriting the disease. Unaffected children do not have to be concerned about subsequent generations being affected. The response to conventional treatments used in juvenile rheumatoid arthritis and to etanercept in our patients has not been satisfactory. Joint disease responds to corticosteroids, but these agents are not suitable for a disease that is lifelong. The eye involvement is aggressive and can lead to blindness. These patients need close follow-up by an ophthalmologist
CZAKO M, RIEGEL M, MORAVA_(A), KOSZTOLANYI G: Familial whole arm translocation between chromosomes 18 and 20 resulting in a deletion/duplication syndrome with immune disorder in the offspring. European Journal of Human Genetics 2000, 8:93 Organism:University of Pecs, Pecs Hungary
FALCINI F, CIMAZ R: Juvenile rheumatoid arthritis. Current Opinion in Rheumatology 2000, 12:415-419. Organism:Dr. F. Falcini, Department of Pediatrics, Rheumatology Unit, Universita di Firenze, Via Luca Giordano 13, 50132 Firenze Abstract: A satisfactory classification of arthritis in childhood has still to be defined, and a system that can facilitate communication among physicians has been proposed by an international committee. The immunopathogenesis of the diseases that are encompassed by the term juvenile rheumatoid arthritis is complex, and many studies have investigated the role of genetic and cytokine balance abnormalities. HLA associations have been confirmed in multiple series, and there is evidence that non-major histocompatibility complex genes might also contribute to disease pathogenesis. Recent studies have added knowledge to the diverse clinical features of the disease, including joint distribution at presentation, association with Turner syndrome, presence of arthritis mutilans, and alterations in mandibulofacial development. Medical treatment remains a challenge. For cases recalcitrant to conventional therapy autologous hemopoietic stem-cell transplantation has been attempted; the risks of this procedure must however be carefully balanced in individual patients. (C) 2000 Lippincott Williams and Wilkins, Inc Internet : falcini@cesit1.unifi.it
FALCINI F, CIMAZ R: Juvenile rheumatoid arthritis [In Process Citation]. Curr Opin Rheumatol 2000, 12:415-419. Organism:Department of Pediatric Rheumatology Unit, University of Florence, Faculty of Medicine, Firenze, Italy falcini@cesit1unifiit Abstract: A satisfactory classification of arthritis in childhood has still to be defined, and a system that can facilitate communication among physicians has been proposed by an international committee. The immunopathogenesis of the diseases that are encompassed by the term juvenile rheumatoid arthritis is complex, and many studies have investigated the role of genetic and cytokine balance abnormalities. HLA associations have been confirmed in multiple series, and there is evidence that non-major histocompatibility complex genes might also contribute to disease pathogenesis. Recent studies have added knowledge to the diverse clinical features of the disease, including joint distribution at presentation, association with Turner syndrome, presence of arthritis mutilans, and alterations in mandibulofacial development. Medical treatment remains a challenge. For cases recalcitrant to conventional therapy autologous hemopoietic stem-cell transplantation has been attempted; the risks of this procedure must however be carefully balanced in individual patients Internet : PM:0010990178
GILLUM JD, BENNETT LB, PASCUAL V, BOWCOCK AM, LOVETT M, WISE CA: Localization of a novel form of juvenile rheumatoid arthritis (familial recurrent arthritis) to human chromosome 15q. Am.J.Hum.Genet. 2000, 67:384 Organism:Research, Texas Scottish Rite Hosp., Dallas, TX USA
JOHNSON S, SIDEBOTTOM D, BRUCKNER F, COLLINS D: Identification of Mycoplasma fermentans in synovial fluid samples from arthritis patients with inflammatory disease. J Clin.Microbiol. 2000, 38:90-93. Organism:St George's Hospital and Medical School, Cranmer Terrace, London SW17 0RE, United Kingdom sjohnson@sghmsacuk Abstract: Since 1970 Mycoplasma fermentans has been suspected of being associated with rheumatoid arthritis. However, this association has been difficult to prove, and this has been our goal. The distribution of M. fermentans was studied in the synovial fluid of patients suffering from different arthritides. Samples of synovial fluid were taken from patients with well-defined disease and a clear diagnosis. After removal of the inflammatory cells and hyaluran, they were treated with proteinase K and tested by a single or fully nested PCR with primers directed against part of the two 16S rRNA genes of M. fermentans. The product was sequenced automatically, by using an ALF Express automatic sequencer, to confirm the mycoplasma species and to identify the strain since the two genes were usually found to be polymorphic. This was also true of the type strain, strain PG18. M. fermentans was detected in 23 of 26 (88%) rheumatoid arthritis patients, and four different strains were found. It was also found in 7 of 8 (88%) of the nonrheumatoid inflammatory arthritis patient group, which consisted of one patient with reactive arthritis, one patient with pauciarticular juvenile chronic arthritis, two patients with gout, two patients with ankylosing spondylitis, and two patients with psoriatic arthritis, only one of whom was infected with M. fermentans. It was not detected in any of the 10 osteoarthritis patients. M. fermentans was therefore found to be a variable and very common organism in arthritic patients with inflammatory joint exudates and may well prove to be important in the etiology of the diseases Internet : PM:0010618069
KAMATANI N, MORITANI M, YAMANAKA H, TAKEUCHI F, HOSOYA T, ITAKURA M: Localization of a gene for familial juvenile hyperuricemic nephropathy causing underexcretion-type gout to 16p12 by genome-wide linkage analysis of a large family. Arthritis Rheum 2000, 43:925-929. Organism:Institute of Rheumatology, Tokyo Women's Medical University, Japan Abstract: OBJECTIVE: Familial juvenile hyperuricemic nephropathy (FJHN, MIM 162000) is an autosomal-dominant disease characterized by underexcretion-type hyperuricemia, gout, and chronic renal failure. No loci responsible for this disease or any underexcretion-type hyperuricemia/gout have ever been identified. The aim of the study was to localize a gene responsible for FJHN by linkage analysis. METHODS: A single large family with at least 20 affected members was analyzed. DNA was obtained from 13 affected and 18 non-affected members after lymphoblastoid cell lines were established. Initially, polymorphic data were obtained for 343 microsatellite loci covering all chromosomes except the X chromosome. Parametric linkage analysis was performed using the obtained data with LINKAGE package software. RESULTS: Following a genome-wide search using a set of highly polymorphic microsatellite markers, initial evidence for linkage was obtained for a marker on chromosome 16p. We subsequently genotyped the same subjects for 12 additional markers spanning approximately 30 cM on the short arm of chromosome 16. We obtained a maximum 2-point logarithm of odds (LOD) score of 6.04 at theta = 0 with the marker D16S401; multipoint linkage analysis yielded a maximum LOD score of 6.14 with markers D16S401 and D16S3113, and established a minimum candidate interval of approximately 9 cM. CONCLUSION: A gene for FJHN was localized to a candidate interval of approximately 9 cM at 16p12. These findings will be useful for the presymptomatic diagnosis of FJHN in some families and for testing genetic heterogeneity of FJHN in general Internet : PM:0010765940
LONDINO AV, ROTHMAN D, ROBBINS PD, EVANS CH: Gene therapy for juvenile rheumatoid arthritis? [In Process Citation]. J Rheumatol 2000, 27 Suppl 58:53-55. Organism:Department of Medicine, Children's Hospital of Pittsburgh and University of Pittsburgh School of Medicine, Pennsylvania, USA Abstract: Gene therapy shows promise as a means of improving the treatment of a number of rheumatic diseases, including adult rheumatoid arthritis (RA). We summarize these developments and discuss the merits of extending such approaches to the treatment of juvenile RA. The special issues that arise when treating children by experimental new procedures predicate a cautious approach using strategies first shown to be safe in adults. Patients with severe, erosive, nonremitting pauciarticular juvenile RA might be suitable first candidates for gene therapy Internet : PM:0010782858
MCGARVEY T, ROSONINA E, MCCRACKEN S, LI Q, ARNAOUT R, MIENTJES E, NICKERSON JA, AWREY D, GREENBLATT J, GROSVELD G, BLENCOWE BJ: The acute myeloid leukemia-associated protein, DEK, forms a splicing- dependent interaction with exon-product complexes. Journal of Cell Biology 2000, 150:309-320. Organism:B.J. Blencowe, Banting and Best Dept. of Med. Res., C.H. Best Institute, University of Toronto, 112 College Street, Toronto, Ont. M5G 1L6 Abstract: DEK is an ~45-kD phosphoprotein that is fused to the nucleoporin CAN as a result of a (6;9) chromosomal translocation in a subset of acute myeloid leukemias (AMLs). It has also been identified as an autoimmune antigen in juvenile rheumatoid arthritis and other rheumatic diseases. Despite the association of DEK with several human diseases, its function is not known. In this study, we demonstrate that DEK, together with SR proteins, associates with the SRm160 splicing coactivator in vitro. DEK is recruited to splicing factor-containing nuclear speckles upon concentration of SRm160 in these structures, indicating that DEK and SRm160 associate in vivo. We further demonstrate that DEK associates with splicing complexes through interactions mediated by SR proteins. Significantly, DEK remains bound to the exon-product RNA after splicing, and this association requires the prior formation of a spliceosome. Thus, DEK is a candidate factor for controlling postsplicing steps in gene expression that are influenced by the prior removal of an intron from pre-mRNA Internet : b.blencowe@utoronto.ca
SANJEEVI CB, MILLER EN, DABADGHAO P, RUMBA I, SHTAUVERE A, DENISOVA A, CLAYTON D, BLACKWELL JM: Polymorphism at NRAMP1 and D2S1471 loci associated with juvenile rheumatoid arthritis. Arthritis Rheum 2000, 43:1397-1404. Organism:University of Cambridge School of Clinical Medicine, UK Abstract: OBJECTIVE: To examine the role of NRAMP1 in susceptibility to juvenile rheumatoid arthritis (JRA). METHODS: DNA from 119 JRA patients (72 pauciarticular, 47 polyarticular) and 111 healthy controls from Latvia was genotyped for a functional repeat polymorphism in the promoter of NRAMP1 and a linked (<150 kb) microsatellite D2S1471. The findings were compared with those from HLA-DQ alleles typed previously. Chi-square analyses were performed using the Mantel-Haenszel test and stratification according to pure Latvian or pure Russian descent. Haplotype analysis was performed using the Associate program to implement the expectation-maximization algorithm based on the gene-counting technique. RESULTS: Allele 3 at NRAMP1 conferred increased risk (odds ratios [ORs] 2.26, 2.31, and 2.19; P = 0.0006, 0.003, and 0.019) of disease in the JRA, pauciarticular, and polyarticular patient groups, respectively. Allele 2 conferred protection (OR 0.44, 0.43, and 0.46). Alleles at D2S1471 that conferred susceptibility (6 and 12) or protection (11) did so only when on a haplotype with alleles 3 or 2, respectively, at NRAMP1. Allele 3 at NRAMP1 was additive with HLA-DQ7 for susceptibility (OR 3.71, 3.71, and 4.02), and allele 2 at NRAMP1 was additive with HLA-DQ5 for protection (OR 0.19, 0.08, and 0.12). CONCLUSION: The NRAMP1 allele conferring susceptibility to JRA drives high levels of NRAMP1 expression, while the allele associated with protection drives low levels. These 2 alleles are inversely associated with susceptibility to infectious disease, consistent with their maintenance in populations through balancing selection Internet : PM:0010857800
THOMAS E, BARRETT JH, DONN RP, THOMSON W, SOUTHWOOD TR: Subtyping of juvenile idiopathic arthritis using latent class analysis. Arthritis And Rheumatism 2000, 43:1496-1503. Organism:Dr. E. Thomas, Industrial/Community Hlth. Res. Ctr., School of Postgraduatc Medicine, Keele University, Hartshill Road, Stoke-on-Trent ST4 7NY Abstract: Objective. To use statistical techniques to identify underlying subtypes of juvenile idiopathic arthritis (JIA) that best explain the observed relationships of clinical and laboratory variables, and to compare the statistically derived subtypes with those defined by the International League of Associations for Rheumatology (ILAR) criteria and examine them for HLA associations. Methods. Information on 572 patients diagnosed as having JIA was summarized by 10 clinical and laboratory categorical variables (age at onset, large joint involvement, small joint involvement, polyarthritis, symmetric arthritis, spinal pain, fever, psoriasis, antinuclear antibodies [ANA], and rheumatoid factor). Latent class analysis (LCA) was used to identify underlying ('latent') classes that explained the relationships among the observed variables. Statistical models incorporating 5-8 latent classes were applied to the data. Results. The 7-class model was the most appropriate. Patterns of joint involvement and the presence of ANA were influential in determining latent classes. There was some correspondence between the latent classes and the ILAR categories, but they did not coincide completely. Significant differences between the latent classes were seen for 3 HLA haplotypes (DRB1*04-DQA1*03-DQB1*03, DRB1*13-DQA1*01-DQB1*06, and DRB1*08-DQA1*0401-DQB1*0402). Conclusion. LCA provides a novel approach to the task of identifying homogeneous subtypes within the umbrella of JIA. In further work, the identified latent classes will be examined for associations with other candidate genes and for differences in outcome
WEDDERBURN LR, ROBINSON N, PATEL A, VARSANI H, WOO P: Selective recruitment of polarized T cells expressing CCR5 and CXCR3 to the inflamed joints of children with juvenile idiopathic arthritis. Arthritis Rheum 2000, 43:765-774. Organism:Department of Molecular Pathology, University College, London, UK Abstract: OBJECTIVE: To study the expression of chemokine receptors CCR5 and CXCR3 and the Th1/Th2 cytokine balance in children with oligoarticular or polyarticular juvenile idiopathic arthritis (JIA). METHODS: Using 3-color immunofluorescence, we studied the expression of CCR5 and CXCR3 on, and T cell cytokine production by, paired samples of synovial fluid (SF) and peripheral blood (PB) T cells from 20 patients with oligoartic
BLACKWELL JM, SEARLE S: Genetic regulation of macrophage activation: understanding the function of Nramp1 (+AD0-Ity/Lsh/Bcg). Immunol Lett 1999, 65:73-80. Organism:Department of Medicine, University of Cambridge School of Clinical Medicine, UK. jmb37+AEA-cus.cam.ac.uk Abstract: The Nramp1 gene was originally described as Ity/Lsh/Bcg, a single gene controlling resistance and susceptibility of inbred mice to a range of intramacrophage pathogens. Functional studies demonstrated that Ity/Lsh/Bcg had multiple pleiotropic effects on macrophage activation pathways, broadening interest in the gene to include its candidacy as an autoimmune disease susceptibility gene. In 1993 the gene was positionally cloned and found to encode a polytopic integral membrane protein of unknown function. Subsequent studies have localized the protein to late endosomal and lysosomal compartments, and demonstrated that it functions as an iron transporter. Precisely how this function influences macrophage activation pathways is still under investigation, but is likely to include direct effects on pathogen survival in the endosomal/lysosomal compartment as well as influences on intracellular signalling pathways and in regulating mRNA stability. Several studies now provide evidence for a role for NRAMP1 in determining human susceptibility to autoimmune (rheumatoid arthritis. juvenile rheumatoid arthritis, diabetes, Crohn's disease) and infectious (tuberculosis, leprosy) diseases. Amongst these. data are accumulating to support the hypothesis that a functional Z-DNA forming repeat polymorphism in the promoter region of human NRAMP1 contributes directly to disease susceptibility. Four alleles have been observed, alleles 1 and 4 are rare (gene frequencies approximately equal to 0.001), alleles 2 and 3 occur at gene frequencies approximately 0.25 and approximately 0.75, respectively. In the absence of exogenous stimuli, alleles 1, 2 and 4 are poor promoters of gene expression in a luciferase reporter gene system+ADs- allele 3 drives high expression. Allele 3 shows allelic association with autoimmune disease susceptibility, allele 2 with infectious disease susceptibility. Hence, balancing selection is likely to be maintaining these two alleles in human populations. Although the association of NRAMP1 with autoimmune disease susceptibility may be related to any one of the multiple pleiotropic effects associated with macrophage activation, the function of NRAMP1 as an iron transporter now prompts more interesting speculation that regulation of iron transport may contribute directly to the disease phenotype in arthritic disease. Patients suffering from rheumatoid arthritis show increased deposition of iron in the synovial membrane, which may contribute to free radical generation and local inflammation. Further analysis of NRAMP1 function will continue to be of importance in understanding the molecular basis to autoimmune and infectious disease susceptibility Type: JOURNAL ARTICLE Internet :
CALLARD R, GEORGE AJT, STARK J: Cytokines, chaos, and complexity. Immunity 1999, 11:507-513. Organism:R. Callard, COMPLEX, University College London, Gower Street, London WC1E 6BT Internet : rcallard@ich.ucl.ac.uk
CRAWLEY E, KAY R, SILLIBOURNE J, PATEL P, HUTCHINSON I, WOO P: Polymorphic haplotypes of the interleukin-10 5' flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. Arthritis Rheum 1999, 42:1101-1108. Organism:University College , London Medical School, UK. Abstract: OBJECTIVE: To determine the distribution of the interleukin-10 (IL-10) 5' flanking region haplotypes in children with arthritis and in controls, and to investigate the functional significance of each haplotype. METHODS: Sequence-specific oligonucleotide probing was used to determine haplotype frequency. Transient transfection studies were used to investigate the transcription of reporter genes driven by each haplotype. Whole blood cultures were performed to assess IL-10 production by each genotype. RESULTS: Patients with arthritis involving +AD4-4 joints were more likely to have a genotype with an ATA haplotype than those whose arthritis remained restricted to +ADw-4 joints. This ATA haplotype was associated with lower transcriptional activity than the GCC haplotype (P +AD0- 0.02), and the ATA/ATA genotype was associated with lower IL-10 production under lipopolysaccharide stimulation than other genotypes (P +ADw- 0.02). CONCLUSION: The results of this study demonstrate the functional significance of the ATA haplotype and reveal a significant association of genotypes containing this haplotype with extended oligoarthritis Type: JOURNAL ARTICLE
DATE Y, KAMIZONO S, KAMIZONO S, HIGUSHI T, HIRATA T, MIYATA K, TATSUZAWA O, TATSUZAWA O, YOKOTA S, UEDA K, UEDA K, SASAZUKI T, KIMURA A, ITOH K, KATO T: Identification of a genetic risk factor for systemic juvenile rheumatoid arthritis in the 5'-flanking region of the TNFalpha gene and HLA genes.Arthritis And Rheumatism 1999, 42:2577-2582. Organism:Kurume University, Japan. Abstract: OBJECTIVE: To study polymorphisms in the 5'-flanking promoter/enhancer region of the tumor necrosis factor alpha (TNFalpha) gene and in the coding regions of HLA class I and class II genes, in order to better understand the genetic background of juvenile rheumatoid arthritis (JRA).
METHODS: One hundred eleven Japanese JRA patients (50 with systemic disease, 29 with pauciarticular disease, and 32 with polyarticular disease) and 575 healthy Japanese subjects were examined for the allele frequencies of the TNFalpha, HLA-A, and HLA class II (DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, DPA1, and DPB1) genes, by DNA typing using the polymerase chain reaction-sequence-specific oligonucleotide probe method.
RESULTS: The frequencies of the polymorphic allele at positions -1,031 (T to C substitution, termed -1,031C), -863 (C to A, termed -863A), and -857 (C to T, termed -857T) of the TNFalpha gene in patients with systemic JRA, but not in those with polyarticular or pauciarticular JRA, were significantly higher than in the healthy controls. The allele frequencies of DRB1*0405 and DQB1*0401 in systemic JRA, but not in the other JRA types, were significantly higher than in controls. Linkage analysis showed that the presence of both the TNFalpha -857T allele and DRB1*0405 yielded a significantly increased odds ratio (3.84), while the presence of only 1 of them did not yield a high odds ratio (0.87 and 1.58).
CONCLUSION: The -1,031C/-863A allele and the -857T allele of the TNFalpha gene, both of which are related to high production of tumor necrosis factor alpha, are associated with systemic JRA. The -857T allele may enhance the effect of the DRB1*0405/DQB1*0401 haplotype in predisposing to development of systemic JRA. PMID: 10616003, UI: 20081749
HARJACEK M: Immunopathology of juvenile idiopathic arthritis: The role of cytokines and defective apoptosis. Periodicum Biologorum 1999, 101:303-310. Organism:M. Harjacek, Department of Pediatrics, Children's Hospital Zagreb, Klaiceva 16, 10 000 Zagreb Abstract: Objective: Juvenile idiopathic arthritis (JIA) encompasses a heterogeneous group of chronic inflammatory diseases of unknown etiology. The aim of the present paper was to evaluate the possible role of the cytokines and defective mononuclear cells apoptosis in a immunopathogenesis of the chronic synovitis in JIA patients. Patients and methods: Author's own experimental data on various cytokine mRNA expression in the synovial tissue of JIA patients using in situ hybridization (ISH), as well as all published studies of the subject were discussed. In addition, on the similar patient population, the rate of proliferation and apoptosis of the infiltrating mononuclear cells was evaluated using slide cytometry immunohistochemistry and the in situ end-labeling hybridization (ISEL). Results: The results of our study and those found in literature, suggest that the production of pro-inflammatory cytokines (Type 1) by inflammatory cells in the synovium of patients with JIA, in addition to the lack of IL-4 production and/or insufficient IL-10 production, might contribute to the ongoing, active inflammation in JIA patients. We have also found that low apoptotic indexes and low lymphocytic proliferation were general characteristics of patients with chronic JIA. Patients with pauciarticular JIA showed only minimal apoptosis, as detected by ISEL, and the highest bcl-2 expression. Patients with systemic-onset JIA, on the other hand, had either normal or high lymphocytic proliferation with normal apoptotic indexes and very low bcl-2 expression. Similarly to patients with polyarticular JIA, lymphocytic proliferation was very low. Conclusions: It is now generally accepted that several pro-inflammatory cytokines (IL-1beta, TNF-alpha, IL-6, IFN-gamma, etc.), and defective expression of anti-inflammatory cytokines (e.g. IL-4, IL-10) are strongly involved in the induction and perpetuation of the chronic inflammatory process in joints. Furthermore, it seems that mononuclear infiltrates in chronically inflammed synovia arise not only as a result of continuos site-specific recruitment but also because those cells are actively prevented from dying (e.g. have defective apoptosis) by abnormal synovial microenvironment. Despite our 'aggressive' treatment patients with long-lasting juvenile arthritis continue to have chronic inflammation; inflammatory mononuclear cells are activated, non-proliferative, have defective apoptosis and produce a different cytokine profiles than that found in patients with early juvenile arthritis. The concept of reestablishing cytokine balance in chronic synovitis is appealing since it would enable treatment even if the cause of the disease cannot be identified. This implies early treatment before joint destruction in patients with high risk. The genetic (HLA, TCR genes, and cytokine gene polymorphism), and neuroendocrine background are obviously linked to juvenile arthritis severity and therefore should be seriously taken into account
KAWAME H, ADACHI M, TACHIBANA K, MASUNO M, KUROSAWA K, OCHIAI Y, ITO F, ETO Y: Graves disease in patients with microdeletion 22q11.2: Possible predisposition to autoimmune disorders. Am.J.Hum.Genet. 1999, 65:A154 Organism:Dep of Pediatrics, Tokyo Metropolitan Kita Med and Rehabilitation Ctr, Tokyo Japan
KINANE DF, HODGE P, ESKDALE J, ELLIS R, GALLAGHER G: Analysis of genetic polymorphisms at the interleukin-10 and tumour necrosis factor loci in early-onset periodontitis. J Periodontal Res 1999, 34:379-386. Organism:Glasgow Dental Hospital and School, UK dkinane@dentalglaacuk Abstract: Early onset periodontitis (EOP) is considered to have a substantial genetic basis, although the gene or genes involved have not been elucidated. The aim of the present study was to investigate possible links between generalized EOP (GEOP) and genes regulating expression of the cytokines tumour necrosis factor (TNF) and interleukin-10 (IL-10). Microsatellite marker DNA sequences corresponding to phenotypic variations in cytokine response were analysed. Genotypic variations in cytokine response have been shown in vitro for TNF and IL-10, and specific alleles are implicated in diseases such as systemic lupus erythmatosus (SLE) and rheumatoid arthritis (RA). Two microsatellites at the IL-10 locus, IL10.R and IL10.G, and 1 microsatellite at the TNF locus, TNFa, were typed for 77 GEOP patients in the West of Scotland. Due to the highly polymorphic nature of the microsatellite loci, a statistical comparison with ethnically matched healthy controls (TNFa, n = 91, IL10.R, n = 94, IL10.G, n = 102) was conducted using a Monte Carlo simulation for each marker. No significant differences were observed for any of the 3 markers, although there were possible indications of trends similar to those observed in SLE for the IL10.G marker. In conclusion, no links were found between GEOP and microsatellites at TNFa, IL10.R or IL10.G loci
MCCURDY D: Genetic susceptibility to the connective tissue diseases. Curr.Opin.Rheumatol. 1999, 11:399-407. Organism:Dr. D. McCurdy, Children's Hospital of Orange County, Department of Rheumatology, 455 South Main Street, Orange, CA 92868 Abstract: Genes important in the connective tissue diseases are being recognized in two basic ways: association studies and linkage analysis. Traditionally, association studies have confirmed a genetic influence in disease pathogenesis, especially in systemic lupus erythematosus, rheumatoid arthritis, juvenile rheumatoid arthritis, and the spondyloarthropathies. One of the strongest associations is with the HLA region. As techniques improve, genome scan studies suggest that multiple genes are involved in each of the connective tissue diseases, with some genes in common that confer an autoimmune susceptibility. Linkage analysis is identifying new candidate genes that will help to explain the etiology of connective tissue diseases Internet : dmccurdy@choc.org
MURRAY KJ, MOROLDO MB, DONNELLY P, PRAHALAD SP, PASSO MH, GIANNINI EH, GLASS DN: Age-Specific Effects of Juvenile Rheumatoid Arthritis-Associated HLA Alleles. Arthritis Rheum 1999, 42:1843-1853. Abstract: Objective: To define the onset and duration of effect of the HLA alleles that are associated with disease susceptibility and protection in juvenile rheumatoid arthritis (JRA) and 2 of its subtypes. Methods: We typed 680 patients with JRA and 254 ethnically matched unrelated controls for HLA class I and II genes. The frequency of each allele was calculated for each of the age-at-onset, onset type, and sex categories and plotted against the allele frequency in the control population. Survival analysis (with onset of disease as the terminating event) was used to calculate the age by which 50% (St0.5) and 80% (St0.2) of the children with particular alleles and combinations of alleles develop disease. This allele-specific survival analysis also allowed for the comparison of the overall survival functions for the various JRA subtype and sex categories. Results: Certain alleles are strongly associated with early susceptibility to pauciarticular JRA, including HLA-A2, DR8, DR5, and DPB1*0201. Fifty percent of the children carrying at least 1 of these alleles had disease onset prior to their third birthday. Among children who carried HLA-A2 and any 2 HLA-DR alleles (DR3, DR5, DR6, or DR8), the median age at the onset of pauciarticular disease was 2.7 years. Combinations of A2 and DPB1*0201 and one DR allele narrowed the window further to a median age at onset of 2.4 years. B27 and DR4 were associated with protection early in life but with increased risk later in childhood, with St0.5 values of 7.3 and 6.6 years, respectively, for pauciarticular JRA and St0.5 values of 10.2 and 10.7 years, respectively, for polyarticular JRA. Sex strongly influenced the age at which many of the alleles have their effect. Conclusion: These data define at what age and for how long various HLA alleles influence susceptibility and protection (window-of-effect) in patients with JRA. In addition, these data establish more clearly the boundaries of ages-at-onset for 2 of the subtypes of the disease
POOLE TRG, GRAHAM EM: Ocular manifestations of rheumatologic disorders. Current Opinion in Ophthalmology 1999, 10:458-463. Organism:E.M. Graham, Medical Eye Unit, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH Abstract: In the past year, advances have been made in our understanding of the genetics of Behcet disease. Indocyanine green angiography has allowed us to look at the pathologic changes seen in Behcet disease and sarcoidosis in more detail. New steroid-sparing treatment strategies for the control of ocular inflammatory disease are becoming better understood and better used, and their applications in sarcoidosis and juvenile chronic arthritis are reviewed here. The role of antiphospholipid antibodies in ocular disease has received attention, particularly in the context of systemic lupus erythematosus. Outcomes in HLA-B27-positive patients with uveitis and in ocular disease associated with the systemic vasculitides are discussed here, and scalp necrosis in giant-cell arteritis is reviewed
RUPERT KL, RENNEBOHM RM, YU CY: An unequal crossover between the RCCX modules of the human MHC leading to the presence of a CYP21B gene and a tenascin TNXB/TNXA-RP2 recombinant between C4A and C4B genes in a patient with juvenile rheumatoid arthritis. Exp Clin Immunogenet 1999, 16:81-97. Organism:Children's Hospital Research Foundation, Columbus, Ohio, USA. Abstract: The RCCX module of the human MHC class III region is comprised of four genes arranged in tandem: RP, complement C4, steroid 21-hydroxylase (CYP21), and tenascin X (TNX). Variations in the number and genes of the RCCX modules may lead to genetic and/or autoimmune diseases. Restriction fragment length polymorphism (RFLP) analysis was utilized to determine the RCCX modular variation in patients with juvenile rheumatoid arthritis (JRA). In JRA patient L1, RFLP analysis suggested the presence of a bimodular RCCX structure containing both C4A long and C4B short genes, yet missing the markers for the CYP21A and TNXA genes usually located between the C4A and C4B genes. The 7.5-kb genomic fragment spanning the CYP21-TNX-RP2 genes was cloned and sequenced, revealing that a genetic recombination occurred between TNXA of a bimodular RCCX chromosome and TNXB of a monomodular RCCX chromosome. This recombination results in a new MHC haplotype with a CYP21B gene and a TNXB/TNXA-RP2 recombinant between the two C4 genes. Elucidation of the breakpoint region provides further evidence for the instability of the MHC class III gene region as a result of the RCCX modular variation Type: JOURNAL ARTICLE
YANG Z, MENDOZA AR, WELCH TR, ZIPF WB, YU CY: Modular variations of the human major histocompatibility complex class III genes for serine/threonine kinase RP, complement component C4, steroid 21-hydroxylase CYP21, and tenascin TNX (the RCCX module). A mechanism for gene deletions and disease associations. J Biol Chem 1999, 274:12147-12156. Organism:Children's Hospital Research Foundation, Columbus, Ohio 43205, USA. Abstract: The frequent variations of human complement component C4 gene size and gene numbers, plus the extensive polymorphism of the proteins, render C4 an excellent marker for major histocompatibility complex disease associations. As shown by definitive RFLPs, the tandemly arranged genes RP, C4, CYP21, and TNX are duplicated together as a discrete genetic unit termed the RCCX module. Duplications of the RCCX modules occurred by the addition of genomic fragments containing a long (L) or a short (S) C4 gene, a CYP21A or a CYP21B gene, and the gene fragments TNXA and RP2. Four major RCCX structures with bimodular L-L, bimodular L-S, monomodular L, and monomodular S are present in the Caucasian population. These modules are readily detectable by TaqI RFLPs. The RCCX modular variations appear to be a root cause for the acquisition of deleterious mutations from pseudogenes or gene segments in the RCCX to their corresponding functional genes. In a patient with congenital adrenal hyperplasia, we discovered a TNXB-TNXA recombinant with the deletion of RP2-C4B-CYP21B. Elucidation of the DNA sequence for the recombination breakpoint region and sequence analyses yielded definitive proof for an unequal crossover between TNXA from a bimodular chromosome and TNXB from a monomodular chromosome Type: JOURNAL ARTICLE
AREND WP, MALYAK M, GUTHRIDGE CJ, GABAY C: Interleukin-1 receptor antagonist: Role in biology. Annu.Rev.Immunol. 1998, 16:27-55. Organism:UNIV COLORADO,HLTH SCI CTR, DEPT MED, DIV RHEUMATOL/DENVER//CO/80262 (REPRINT) Abstract: The interleukin-l receptor antagonist (IL-1Ra) is a member of the IL-1 family that binds to IL-1 receptors but does not induce any intracellular response. Two structural variants of IL-1Ra have previously been described: a 17-kDa form that is secreted from monocytes, macrophages, neutrophils, and other cells (sIL-1Ra) and an 18-kDa form that remains in the cytoplasm of keratinocytes and other epithelial cells, monocytes, and fibroblasts (icIL-1Ra). An additional 16-kDa intracellular isoform of IL-1Ra has recently been described in neutrophils, monocytes, and hepatic cells. Both of the major isoforms of IL-1Ra are transcribed from the same gene through the use of alternative first exons. The two promoters regulating transcription of the secreted and intracellular forms have been cloned, and some of the functional cis-acting DNA regions have been characterized. The production of IL-1Ra is stimulated by many substances including adherent IgG, other cytokines, and bacterial or viral components. The tissue distribution of IL-1Ra in mice indicates that sIL-1Ra is found predominantly in peripheral blood cells, lungs, spleen, and liver, while icIL-1Ra is found in large amounts in skin. Studies in transgenic and knockout mice indicate that IL-1Ra is important in host defense against endotoxin-induced injury. IL-1Ra is produced by hepatic cells with the characteristics of an acute phase protein. Endogenous IL-1Ra is produced in numerous experimental animal models of disease as well as in human autoimmune and chronic inflammatory diseases. The use of neutralizing anti-IL-1Ra antibodies has demonstrated that endogenous IL-1Ra is an important natural antiinflammatory protein in arthritis, colitis, and granulomatous pulmonary disease. Treatment of human diseases with recombinant human IL-1Ra showed an absence of benefit in sepsis syndrome. However, patients with rheumatoid arthritis treated with IL-1Ra for six months exhibited improvements in clinical parameters and in radiographic evidence of joint damage
BAHABRI SA, SUWAIRI WM, LAXER RM, POLINKOVSKY A, DALAAN AA, WARMAN ML: The camptodactyly-arthropathy-coxa vara-pericarditis syndrome: clinical features and genetic mapping to human chromosome 1. Arthritis Rheum 1998, 41:730-735. Organism:King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. Abstract: OBJECTIVE: To delineate the clinical features in patients with the autosomal recessive camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) and to determine the location of the involved gene. METHODS: Eight affected individuals (ages 2-15 years) with CACP from 4 consanguineous kindreds were clinically evaluated. Four patients are newly described and 4 have been reported previously. Findings were compared with those in 21 other previously reported cases. DNA obtained from the 8 affected patients and their available siblings and parents was used in a genome-wide search for linkage. RESULTS: Congenital camptodactyly and childhood-onset noninflammatory arthropathy were present in all affected patients. Seven patients developed bilateral coxa vara deformity, and 1 developed coxa magna with cystic erosions. Two of the patients also had symptoms or signs of pericarditis. A genome-wide search for linkage identified homozygosity for a series of genetic markers on human chromosome 1q in all affected patients. The marker D1S191 yielded a maximum logarithm of the odds ratio (LOD score) of 3.3 at theta = 0. The CACP gene lies within a 1.9-cM candidate interval defined by the markers D1S2107 and D1S222. CONCLUSION: The principal features of the CACP syndrome are congenital or early-onset camptodactyly and childhood-onset noninflammatory arthropathy. Coxa vara deformity or other dysplasia associated with progressive hip disease may develop over time. Clinical pericarditis may also occur. A locus responsible for causing CACP syndrome is assigned to a 1.9-cM interval on human chromosome 1q25-31 by homozygosity mapping. This now facilitates the identification of the responsible gene and permits testing for locus homogeneity in other CACP kindreds Type: JOURNAL ARTICLE
BROWN MA, RUDWALEIT M, PILE KD, KENNEDY LG, SHATFORD J, AMOS CI, SIMINOVITCH K, RUBIN L, CALIN A, WORDSWORTH BP: The role of germline polymorphisms in the T-cell receptor in susceptibility to ankylosing spondylitis. British Journal of Rheumatology 1998, 37:454-458. Organism:WELLCOME TRUST CTR HUMAN GENET,WINDMILL RD/OXFORD OX3 7BN//ENGLAND/ (REPRINT); UNIV HOSP BENJAMIN FRANKLIN,DEPT ENDOCRINOL & NEPHROL, RHEUMATOL SECT/BERLIN//GERMANY/; QUEEN ELIZABETH HOSP,/ADELAIDE/SA/AUSTRALIA/; ROYAL NATL HOSP RHEUMAT DIS,/BATH BA1 1RL/ Abstract: The role of germline polymorphisms of the T-cell receptor A/D and B loci in susceptibility to ankylosing spondylitis was investigated by linkage studies using microsatellite markers in 215 affected sibling pairs. The presence of a significant susceptibility gene (lambda greater than or equal to 1.6) at the TCRA/D locus was excluded (LOD score < -2.0). At the TCRB locus, there was weak evidence of the presence of a susceptibility gene (P = 0.01, LOD score 1.1). Further family studies will be required to determine whether this is a true or false-positive finding. It is unlikely hat either the TCRA/D or TCRB loci contain genes responsible for more than a moderate proportion of the non-MHC genetic susceptibility to ankylosing spondylitis
BYRNE PAC, RAJAN KT: Spondylo-epiphyseal dysplasia tarda with progressive arthropathy mimicking juvenile chronic arthritis [2]. British Journal of Rheumatology 1998, 37:233-234. Organism:P.A.C. Byrne, Department of Rheumatology, East Glamorgan Hospital NHS Trust, Church Village, Nr Pontypridd, Mid Glamorgan CF38 1AD
DEAN JCS, DE S, REARDON W, DI ROCCO M, BUOCOMPAGNI A, PICCO P, VIGNOLA S, BORRONE C, GIMELLI G, HUNTER A, RYAN A, GOODSHIP JA, WILSON DI, SARAIVA JM, MATOSO E, MARQUES I: Craniosynostosis and chromosome 22q11 deletion (multiple letters) [1]. J.Med.Genet. 1998, 35:346-348. Organism:J.C.S. Dean, Department of Medical Genetics, Medical School, Aberdeen AB25 2ZD
FISHMAN D, FAULDS G, JEFFERY R, MOHAMED-ALI V, YUDKIN JS, HUMPHRIES S, WOO P: The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 1998, 102:1369-1376. Organism:Paediatric Rheumatology Unit, Windeyer Institute of Medical Sciences, University College London Medical School, London W1P 6DB. Abstract: During active disease, patients with systemic-onset juvenile chronic arthritis (S-JCA) demonstrate a rise and fall in serum interleukin-6 (IL-6) that parallels the classic quotidian fever. To investigate the possibility that this cytokine profile results from a difference in the control of IL-6 expression, we examined the 5' flanking region of the IL-6 gene for polymorphisms. A G/C polymorphism was detected at position -174. In a group of 383 healthy men and women from a general practice in North London, the frequency of the C allele was 0.403 (95% confidence interval 0.37-0.44). In comparison, 92 patients with S-JCA had a different overall genotype frequency, especially those with onset of disease at < 5 yr of age. This was mainly due to the statistically significant lower frequency of the CC genotype in this subgroup. When comparing constructs of the 5' flanking region (-550-+61 bp) in a luciferase reporter vector transiently transfected into HeLa cells, the -174C construct showed 0.624+/- 0.15-fold lower expression than the -174G construct. After stimulation with LPS or IL-1, expression from the -174C construct did not significantly change after 24 h, whereas expression from the -174G construct increased by 2.35+/-0.10- and 3.60+/-0.26-fold, respectively, compared with the unstimulated level. Plasma levels of IL-6 were also measured in 102 of the healthy subjects, and the C allele was found to be associated with significantly lower levels of plasma IL- 6. These results suggest that there is a genetically determined difference in the degree of the IL-6 response to stressful stimuli between individuals. The reduced frequency of the potentially protective CC genotype in young S-JCA patients may contribute to its pathogenesis. Similarly the individual's IL-6 genotype may be highly relevant in other conditions where IL-6 has been implicated, such as atherosclerosis Type: JOURNAL ARTICLE Internet :
GILCHRIST FC, BUNCE M, LYMPANY PA, WELSH KI, DU B: Comprehensive HLA-DP typing using polymerase chain reaction with sequence-specific primers and 95 sequence-specific primer mixes. Tissue Antigens 1998, 51:51-61. Organism:GILCHRIST FC,UNIV LONDON IMPERIAL COLL SCI TECHNOL & MED,NATL HEART & LUNG INST DEPT ENVIRONM & OCCUPAT MED;EMMANUEL KAYE BLDG MANRESA RD;LONDON SW3 6LR, ENGLAND. Abstract: HLA-DP is the third of the class II molecules. Its role is antigen presentation, and it has been suggested to play a part in the susceptibility to certain diseases such as berylliosis, sarcoidosis and juvenile chronic arthritis. The standard typing method is SSO typing, although other methods have been used. Probably the best is sequence-based typing, but this is time-consuming and requires expensive equipment. We describe a method for comprehensive HLA-DPB1 and HLA-DPA1 typing using sequence-specific primers. This method has the advantages that it is rapid - typing a single DNA sample takes under 3 hours - and does not require any special equipment or reagents. The method has been shown to be highly accurate by typing 60 cell line DNA samples in which there was 100% agreement between the types obtained and the published information Similarly typing of 20 DNA samples previously typed by sequence-based typing gave 100% concordance. We used the method to type DNA samples from 102 UK Caucasoid kidney donors. The allele frequencies agree with previously published data. Linkage disequilibria between HLA-DPB1, HLA-DPA1 and the other class II antigens have been investigated. Strong linkage disequilibria exist between certain HLA-DPB1 and HLA-DPA1 alleles. This is unsurprising in view of their proximity on the chromosome. More unexpectedly, the data also suggest that genes further away along the chromosome are in linkage disequilibrium with HLA-DP, forming extended haplotypes 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK
KIEM OEN, SCHROEDER M, JACOBSON K, ANDERSON S, WOOD S, CHEANG M, DOOLEY J: Juvenile rheumatoid arthritis in a canadian First Nations (aboriginal) population : Onset subtypes and HLA associations. Rinsho Ganka 1998, 25:783-790. Organism:Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada; HLA Laboratory, Children's Hospital, Health Sciences Centre, Winnipeg, Manitoba, Canada; Department of Community Health Sciences, University of Manitoba, Winnip Abstract: Objective. To determine onset subtypes and HLA associations of juvenile rheumatoid arthritis (JRA) in a First Nations (aboriginal) population; to determine whether population frequencies of HLA antigens may explain the distribution of subtypes of JRA in this population. Methods. All patients were children from Manitoba and Northwestem Ontario seen in a single pediatric rheumatology clinic between 1975 and 1996. Patients were identified from a clinic registry. Controls were adults of Algonkian Cree and Ojibway heritage. Class I and II major histocompatibility (HLA) typing was performed for First Nations patients and controls. Results. There were a total of 74 First Nations patients with JRA. The relative frequency of rheumatoid factor (RF) positive polyarticular JRA was higher and that of pauciarticular JRA was lower in First Nations compared with Caucasian patients (42 versus 3% and 22 versus 58%, respectively; p = 0.00000). HLA-DRB1*04 (63%), 08 (43%), and 1402 (25%) were the most common DRB I antigens among controls. The main subtypes of DRB1*04 were 0404 (33% of controls) and 0407 (23%). HLA typing was performed for 39 First Nations patients; 27 were Cree or Ojibway, 4 were from other tribes, and 8 were part First Nations. Among Cree and Ojibway, 59% of controls and 63% of patients with RF positive polyarticular JRA (n = 16) had HLA-DRB1 antigens bearing the rheumatoid arthritis (RA) shared epitope (OR 1.16, 95% CI: 0.38, 3.48). The OR for polyarticular RF positive JRA in those with DRB1*0802 and 0901 were 0.15, 95% CI: 0.02; and 1.24 and 5.83, 95% CI: 1.58, 28.38, respectively. Conclusion. There was a high frequency of the RA shared epitope represented by both HLA-DRB 1*0404 and 1402 in this Algonkian population. This high frequency may explain the high frequency of RF positive polyarticular JRA. DRB1*0802 may be protective, whereas DRB1*0901 may increase the risk for this subtype of JRA
MERCURIALI F, FANTINI F: Correlation between juvenile chronic arthritis (JCA) and DPB1*02012: A family study. Eur.J.Immunogen. 1998, 25:61 Organism:_Ist. Ortopedico Gaetano Pini, Centro Transfusionale, Milano Italy
MITCHELL LA, TINGLE AJ, MACWILLIAM L, HORNE C, KEOWN P, GAUR LK, NEPOM GT: HLA-DR class II associations with rubella vaccine-induced joint manifestations. J.Infect.Dis. 1998, 177:5-12. Organism:MITCHELL LA,UNIV BRITISH COLUMBIA,DEPT PATHOL BC RES INST CHILD & FAMILY HLTH;950 W 28TH AVE;VANCOUVER,BC V5Z 4H4 CANADA. Abstract: HLA class Ii (HLA-DR) frequencies were examined in relation to incidence of acute arthralgia or arthritis in 283 white women who had received RA27/3 rubella vaccine (n = 146) or placebo (n = 137) postpartum. Leukocyte DNA was molecularly typed for HLA-DRB1 gene expression. Univariate analysis revealed higher frequencies of DR2 (odds ratio [OR], 4.8; 95% confidence interval [CI], 1.2-18.8) and DR5 (OR, 7.5; 95% CI, 1.5-37.5) but lower frequencies of DR4 (OR, 2.3; 95% CI, 1.1-4.9) and DR6 (OR, 2.8; 95% CI, 1.4-5.8), in rubella vaccinees compared with placebo recipients with arthropathy. Logistic regression modelling of DR, treatment, age, time postpartum, and arthropathy revealed that the odds of developing arthropathy was 1.9 times greater (95% CI, 1.07-3.44) after rubella vaccine than placebo. Risk for arthropathy (regardless of rubella vaccination) was also influenced by DR interactions: odds were 8 times greater in individuals with both DR1 and DR4 (95% CI, 1.45-44.02) and 7.1 times greater with both DR4 and DR6 present (95% CI, 1.85-27.52]), suggesting that coexpression of these specificities may predispose to postpartum arthropathy 5720 S WOODLAWN AVE, CHICAGO, IL 60637 USA
NANDI D, MARUSINA K, MONACO JJ: How do endogenous proteins become peptides and reach the endoplasmic reticulum. 1998, Organism:INDIAN INST SCI,DEPT BIOCHEM/BANGALORE 560012/KARNATAKA/INDIA/ (REPRINT); UNIV CINCINNATI,HOWARD HUGHES MED INST/CINCINNATI//OH/45267; UNIV CINCINNATI,DEPT MOL GENET/CINCINNATI//OH/45267
OU DW, MITCHELL LA, TINGLE AJ: A new categorization of HLA DR alleles on a functional basis. Human Immunology 1998, 59:665-676. Organism:UNIV BRITISH COLUMBIA,DEPT PAEDIAT, BC RES INST CHILD & FAMILY HLTH, FAC MED, 950 W 28TH AVE/VANCOUVER/BC V5Z 4H4/CANADA/ (REPRINT); UNIV BRITISH COLUMBIA,FAC MED, DEPT PATHOL/VANCOUVER/BC V5Z 4H4/CANADA/ Abstract: In this analysis, we introduce a new categorization of HLA DR alleles which are important members of HLA class II genes encoding cell surface glycoproteins that function to present antigenic peptides to T cells. We have grouped all HLA DR molecules into seven different functional categories on the basis of their ability to bind and present antigenic peptides to T cells and their association with susceptibility or resistance to disease. This novel categorization of DR alleles on the basis of function allows for the prediction of seven similar subregion structures (supertypes or supermotifs) within pocket 4 of HLA DR peptide binding groove as the molecular basis for grouping these alleles. The physicochemical characteristics of HLA DR supertype residues, charge in particular, may influence the selectivity for binding peptide, dominate promiscuous T-cell recognition of antigenic peptides, and affect HLA DR disease associations. To rationalize the functional categories of DR alleles, we have further combined the seven DR supertype patterns into three groups based on the charges of residues within the supertypes. Grouping HLA DR alleles into functional categories may assist in understanding the mechanistic basis of autoimmunity, resolving current paradoxes in HLA disease associations, and developing new immunotherapy strategies
PINA-NETO JMD, VELLUDO MA: Retinal changes and tumorigenesis in Ramon syndrome: Follow-up of a Brazilian family. Am.J.Med.Genet. 1998, 77:43-46. Organism:Dep. Genet., Fac. Med. Ribeirao Preto-USP, Avenida Bandeirantes 3900, Ribeirao Preto, Sao Paulo Brazil Abstract: We report on the clinical evolution of the Brazilian family with Ramon syndrome described by de Pina-Neto et al. (1986, Am J Med Genet 25:441-443). Three members (patients IV-2, IV-18, and IV-19) have developed pigmentary changes in the retina and paleness of the optic disk. Patient IV-18 also has developed giant hypertrophy of the labia minora that, when examined histopathologically, was found to be due to neoplastic fibroblast and epithelial proliferation caused by a fibromatous process similar to that reported in the gingivae of the patients with this syndrome. Audiologic function of patient IV-2 was normal, and no skin lesions were detected. The articular signs and symptoms show that the affected relatives developed rheumatoid arthritis, which is currently inactive in patient IV-18, whereas patient IV-2 did not develop these alterations
RIDER LG, GURLEY RC, PANDEY JP, GARCIADELATORRE I, KALOVIDOURIS AE, OHANLON TP, LOVE LA, HENNEKAM RCM, BAUMBACH LL, NEVILLE HE, GARCIA CA, KLINGMAN J, GIBBS M, WEISMAN MH, TARGOFF IN, MILLER FW: Clinical, serologic, and immunogenetic features of familial idiopathic inflammatory myopathy. Arthritis And Rheumatism 1998, 41:710-719. Organism:US FDA,CTR BIOL EVALUAT & RES, DIV MONOCLONAL ANTIBODIES, NIH, BLDG 29B, ROOM 2G11/BETHESDA//MD/20892 (REPRINT); NIAMSD,NIH/BETHESDA//MD/20892; MED UNIV S CAROLINA,/CHARLESTON//SC/29425; UNIV GUADALAJARA,/GUADALAJARA 44430/JALISCO/MEXICO/; HOSP GEN OCCIDE Abstract: Objective. To describe the clinical, serologic, and immunogenetic features of familial idiopathic inflammatory myopathy (IIM) and to compare these with the features of sporadic IIM. Methods. Clinical signs and symptoms, autoantibodies, HLA-DRB1 and DQA1 alleles, and GM/KM phenotypes were compared among 36 affected and 28 unaffected members of 16 unrelated families in which 2 or more blood relatives developed an IIM. In addition, findings in patients with familiar IIM were compared with those in 181 patients with sporadic IIM, The families included 3 pairs of monozygotic twins with juvenile dermatomyositis, 11 families with other siblings or relatives with polymyositis or dermatomyositis, and 3 families with inclusion body myositis. Results, The clinical features of familial IIM were similar to those of sporadic IIM, although the frequency of myositis-specific autoantibodies tvas lon cr in familial than in sporadic IIM. DRB1*0301 mas a common genetic risk factor for familial and sporadic IIM, but contributed less to the genetic risk of familial IIM (etiologic fraction 0.35 versus 0.51 in sporadic IIM), Homozygosity at the HLA-DQA1 locus was found to be a genetic risk factor unique to familial IIM (57% versus 24% of controls; odds ratio 4.2, corrected P = 0.002), Conclusion. These findings emphasize that 1) familial muscle weakness is not always due to inherited metabolic defects or dystrophies, but may be the result of the development of IIM in several members of the same family, and 2) multiple genetic factors are likely important in the etiology and disease expression of familial IIM, as is also the case for sporadic myositis, but DQA1 homozygosity is a distinct risk factor for familial IIM
SCHETT G, REDLICH K, XU QB, BIZAN P, GROGER M, TOHIDASTAKRAD M, KIENER H, SMOLEN J, STEINER G: Enhanced expression of heat shock protein 70 (hsp70) and heat shock factor 1 (HSF1) activation in rheumatoid arthritis synovial tissue - Differential regulation of hsp70 expression and HSF1 activation in synovial fibroblasts by proinflammatory cytokines, shear stress, and antiinflammatory drugs. Journal Of Clinical Investigation 1998, 102:302-311. Organism:UNIV VIENNA,DEPT INTERNAL MED 3, DIV RHEUMATOL, WAHRINGER GURTEL 18 Abstract: shock proteins (hsp) have been repeatedly implicated to participate in the pathogenesis of rheumatoid arthritis (RA), Herein, we investigated the regulation of synovial hsp70 expression by analyzing the DNA-binding activity of heat shock transcription factor 1 (HSF1) as well as inducible hsp70 expression, Experiments were performed both on synovial tissue and on synovial fibroblast-like cells (SFC). Gel mobility shift analysis revealed increased HSF1 activation, and Western blotting and immunohistochemistry revealed increased hsp70 expression in RA synovial tissue, but not in synovial tissue derived from patients with osteoarthritis, Proinflammatory cytokines (TNF-alpha, IL-1 alpha, IL-6), but not IFN-gamma or TGF-beta, induced activation of HSF1-DNA binding and hsp70 expression in cultivated SFC, Activation of HSF1 in SFC was accompanied by hyperphosphorylation and nuclear translocation of HSF1, Furthermore, shear stress also induced a complete heat shock response in cultivated synovial cells, In contrast, nonsteroidal antiinflammatory drugs triggered only an incomplete heat shock response, with HSF1 activation but not hsp70 induction, whereas steroids and immunosuppressive drugs did not affect the heat shock response at all, In summary, these data suggest that induction of hsp70 expression in rheumatoid synovial tissue is based on transcriptional activation of HSF1 due to the presence of proinflammatory cytokines (and possibly also shear stress)
SCOLARI F, GHIGGERI GM, CASARI G, AMOROSO A, PUZZER D, CARIDI GL, VALZORIO B, TARDANICO R, VIZZARDI V, SAVOLDI S, VIOLA BF, BOSSINI N, PRATI E, GUSMANO R, MAIORCA R: Autosomal dominant medullary cystic disease: A disorder with variable clinical pictures and exclusion of linkage with the NPH1 locus. Nephrology Dialysis Transplantation 1998, 13:2536-2546. Organism:F. Scolari, Division of Nephrology, Spedali Civili, Piazza Spedali Civili 1, I-25125 Brescia Abstract: Background. The nephronophthisis-medullary cystic disease (NPH/MCD) complex represents a heterogeneous group of hereditary tubulointerstitial nephritis. The most common variant is juvenile recessive NPH, for which a gene locus (NPH1) has been mapped on chromosome 2q13. MCD is a less common dominant condition usually recognized later in life, which resembles NPH in many aspects, still presenting remarkable clinical differences. Nothing is known about the chromosome locus of MCD. Methods. Five MCD families were studied. Diagnosis was made by inference from family history, type of inheritance, clinical signs and histology. Multipoint linkage analysis was performed by markers D2S293, D2S340 and D2S160 spanning the entire NPH1 locus. Results. Diagnosis of MCD was made in 28 affected members (16 males; 12 females), belonging to five families. Histological diagnosis was available in 10 patients; clinical diagnosis in 11; seven deceased relatives had diagnosis of chronic nephritis. The age at diagnosis ranged from 8 to 65 years. Renal medullary cysts were found in a minority of patients. In family 1, the disease was associated with hyperuricaemia and gouty arthritis. Progression of renal disease presented intra- and extra-family variability with members of the same family showing mild elevation of creatinine or terminal renal failure. The NPH1 locus associated to recessive NPH was excluded from linkage to the dominant MCD. Conclusions. MCD might be more common than previously assumed. Variability in clinical presentation and absence of histopathological hallmarks contribute to make the diagnosis uncommon. The most remarkable clinical difference with NPH is the age of onset in some kindreds and a delayed progression towards renal failure. The exclusion of linkage to the NPH1 locus suggests the existence of an MCD responsible locus, still to be mapped
ZULIAN F, SCHUMACHER HR, CALORE A, GOLDSMITH DP, ATHREYA BH: Juvenile arthritis in Turner's syndrome: A multicenter study. Clinical And Experimental Rheumatology 1998, 16:489-494. Organism:UNIV PADUA,DIPARTIMENTO PEDIAT, VIA GIUSTINIANI 3/I Abstract: Objective Turner's syndrome (TS) is a disorder associated with characteristic defects in the X chromosome. Autoimmune conditions such as thyroiditis, inflammatory bowel diseases and diabetes have been described in association with TS. Methods We have studied the association between TS and juvenile arthritis (JA) by using a survey in which 28 pediatric rheumatology centers (15 in the USA, 10 in Europe, and 3 in Canada) participated. Results Eighteen cases of TS in a population of approximately 15,000 JRA patients have been found. Two different patterns of arthritis were present: polyarticular (7) and oligoarticular (11). Children with polyarticular disease had early onset, seronegative, progressively deforming arthritis and growth retardation. Those with oligoarticular arthritis had a benign course and were ANA+ (8/11). The oligoarticular children had varying karyotypes whereas almost all of the polyarthritic patients shared the same 45X0 karyotype (6/7). The light and electron microscopic studies of synovium performed in two patients showed chronic inflammation and hyperplasia of the synovial lining cells, vascular proliferation and infiltration with lymphocytes, plasma cells and mononuclear phagocytes. Conclusion Juvenile arthritis is a new autoimmune condition associated with Turner's syndrome. The prevalence seems to be at least six times greater than would be expected if the two conditions were only randomly associated. This is the first description of the synovium in Turner's syndrome; no differences from other forms of juvenile rheumatoid arthritis were found
BALLOW MK, NELSON RT: Immunopharmacology Immunomodulation and Immunotherapy Article. JAMA, The Journal of the American Medical Association 1997, 22 Abstract: Immunopharmacology has changed dramatically over the past 25 years. Although a variety of traditional nonspecific immunosuppressive drug therapies are available for the treatment of autoimmune disease and organ transplantation rejection, with advances in cell biology and monoclonal antibody technology, a highly specific antibody can be engineered to cell surface determinants on immune cells or tumors or to neutralize inflammatory and immune mediators from an immune response. Many of these modalities are still in early phases of study for the treatment of autoimmune disease. In addition to therapies that suppress immune responses, advances in molecular biology have led to new agents and methods to enhance immune responses and correct immune deficits, such as growth factor replacement and cytokine therapies. Finally, gene therapy is a method for the long-term treatment of disorders in which a defective gene leads to disease.JAMA. 1997;278:2008-2017
DE BENEDETTI F, ALONZI T, MORETTA A, LAZZARO D, COSTA P, POLI V, MARTINI A, CILIBERTO G, FATTORI E: Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-I. A model for stunted growth in children with chronic inflammation. J.Clin.Invest. 1997, 99:643-650. Organism:Clinica Pediatrica, Universita degli Studi di Pavia, IRCCS Policlinico San Matteo, ItalyPMID- 9045866 Abstract: Stunted growth is a major complication of chronic inflammation and recurrent infections in children. Systemic juvenile rheumatoid arthritis is a chronic inflammatory disorder characterized by markedly elevated circulating levels of IL-6 and stunted growth. In this study we found that NSE/hIL-6 transgenic mouse lines expressing high levels of circulating IL-6 since early after birth presented a reduced growth rate that led to mice 50-70% the size of nontransgenic littermates. Administration of a monoclonal antibody to the murine IL-6 receptor partially reverted the growth defect. In NSE/hIL-6 transgenic mice, circulating IGF-I levels were significantly lower than those of nontransgenic littermates; on the contrary, the distribution of growth hormone pituitary cells, as well as circulating growth hormone levels, were normal. Treatment of nontransgenic mice of the same strain with IL- 6 resulted in a significant decrease in IGF-I levels. Moreover, in patients with systemic juvenile rheumatoid arthritis, circulating IL-6 levels were negatively correlated with IGF-I levels. Our findings suggest that IL-6- mediated decrease in IGF-I production represents a major mechanism by which chronic inflammation affects growth
EL-SHANTI HE, OMARI HZ, QUBAIN HI: Progressive pseudorheumatoid dysplasia: report of a family and review. J Med Genet 1997, 34:559-563. Abstract: 97366153 Address: Department of Paediatrics, School of Medicine, Jordan University of Science and Technology, Irbid, Jordan Progressive pseudorheumatoid dysplasia is an inherited skeletal dysplasia with radiographic changes notably in the spine, similar to spondyloepiphyseal dysplasia tarda. There is also articular cartilage involvement which gives it some clinical resemblance to rheumatoid arthritis. We report here on six subjects from one inbred family from Jordan. Based on previously published reports and this one, we review the clinical and radiological features and discuss the genetics and differential diagnosis of the disorder. We suggest the addition of the word "spondyloepiphyseal" to the name adopted by the International Working Group on Constitutional Diseases of Bone, to become "progressive pseudorheumatoid spondyloepiphyseal dysplasia". We also speculate on candidate genes for this disorder Type: JOURNAL ARTICLE Type: REVIEW Type: REVIEW OF REPORTED CASES ISSN: 0022-2593 Language: Eng
GATTORNO M, FACCHETTI P, GHIOTTO F, VIGNOLA S, BUONCOMPAGNI A, PRIGIONE I, PICCO P, PISTOIA V: Synovial fluid T cell clones from oligoarticular juvenile arthritis patients display a prevalent Th1/Th0-type pattern of cytokine secretion irrespective of immunophenotype. Clin.Exp.Immunol. 1997, 109:4-11. Organism:II Division of Pediatrics, G. Gaslini Institute for Children, Genova, Italy. Abstract: The aim of the present study was to investigate the patterns of cytokine production by T cell clones raised from in vivo activated synovial fluid (SF) mononuclear cells (MNC) of five patients with oligoarticular juvenile arthritis (JA). Freshly isolated SF T cells were cultured in vitro with low dose recombinant IL-2 and subsequently cloned by limiting dilution. Sixty-four clones were obtained from the five patients studied. Fifty-nine clones were TCR alpha/beta+, either CD4+ (n = 43) or CD8+ (n = 15). The remaining five clones were TCR gamma/delta+, CD4-, CD8-. Clone immunophenotypes differed in the individual patients. Forty-four T cell clones were stimulated with phytohaemagglutinin (PHA) and phorbol myristate acetate (PMA) and supernatants tested for the presence of IL-2, IL-4, IL-5 and interferon-gamma (IFN-gamma) by ELISA or bioassays. Cytokine mRNA accumulation was tested by reverse transcriptase-polymerase chain reaction (RT-PCR). Most of 44 clones tested released large amounts of IFN-gamma irrespective of the immunophenotype. Of these, 27 were classified as Th1-type and 17 as Th0-type based upon the IFN-gamma/IL-4 ratio in culture supernatants. Finally, when 10 representative T cell clones were tested for pro- and anti-inflammatory cytokines, gene expression by RT-PCR, all of them were found to express the granulocyte-macrophage colony- stimulating factor (GM-CSF), tumour necrosis factor-alpha (TNF- alpha), IL-10 and transforming growth factor-beta 1 (TGF-beta1) genes, and half of them IL-6 and IL-8 mRNA. In conclusion, T cell clones, that represent the progeny of in vivo activated SF T cells from oligoarticular JA patients, display heterogeneous immunophenotypes, but all share the ability to produce large amounts of IFN-gamma, with a predominant Th1/Th0 pattern. The expression of pro- and anti-inflammatory cytokine genes in these clones suggests that in vivo activated SF T cells modulate joint inflammation in a complex fashion
HASELTINE W: Du géne au traitement. Pour la Science 1997, 235:25
HEWARD J, GOUGH SCL: Genetic susceptibility to the development of autoimmune disease. Clin.Sci. 1997, 93:479-491. Organism:GOUGH SCL,BIRMINGHAM HEARTLANDS HOSP,;BORDESLEY GREEN E;BIRMINGHAM B9 5SS,W MIDLANDS ENGLAND. Abstract: 1. Autoimmune diseases are common conditions which appear to develop in genetically susceptible individuals, with expression of disease being modified by permissive and protective environments, Familial clustering and data from twin studies provided the impetus for the search for putative loci, Both the candidate gene approach in population-based case-control studies and entire genome screening in families have helped identify susceptibility genes in a number of autoimmune diseases, 2, After the first genome screen in type 1 (insulin-dependent) diabetes mellitus it seems likely that most autoimmune diseases are polygenic with no single gene being either necessary or sufficient for disease development, Of the organ-specific autoimmune diseases, genome screens have now been completed in insulin-dependent diabetes mellitus and multiple sclerosis, Furthermore, the clustering of autoimmune diseases within the same individuals suggests that the same genes may be involved in the different diseases, This is supported by data showing that both HLA (human leucocyte antigen:, and CTLA-4 (cytotoxic T-lymphocyte-associated-4) appear to be involved in the development of insulin-dependent diabetes mellitus and Graves' disease, 3, Genome screens have also been completed in some of the non-organ-specific autoimmune diseases including rheumatoid arthritis, inflammatory bowel disease and psoriasis, Many candidate genes have also been investigated although these are predominantly in population-based case-control studies, 4, Substantial progress has been made in recent years towards the identification of susceptibility loci in autoimmune diseases, The inconsistencies seen between case-control studies may largely he due to genetic mismatching between cases and controls in small datasets, Family-based association studies are being increasingly used to confirm genetic linkages and help with fine mapping strategies, It will, however, require a combination of biology and genetics, as has been necessary with the major histocompatibility complex in insulin-dependent diabetes mellitus, to identify primary aetiological mutations 59 PORTLAND PLACE, LONDON, ENGLAND W1N 3AJ
LEACH M: Juvenile chronic arthritis: epidemiology and genetics. Nurs.Times. 1997, 93:46-48. Organism:Institute for Bone and Joint Medicine, Medical School, University of Sheffield Abstract: This article looks at the classification, epidemiology and possible causes of juvenile chronic arthritis. The clinical manifestations of the different types of this disease are discussed. Finally the course and prognosis of this disease are described. A second article on juvenile chronic arthritis will appear on May 28 1997 Type: JOURNAL ARTICLE Type: REVIEW Type: REVIEW, TUTORIAL ISSN: 0954-7762 Language: Eng
MURRAY K, THOMPSON SD, GLASS DN: Pathogenesis of juvenile chronic arthritis: genetic and environmental factors. Arch Dis Child 1997, 77:530-534. Organism:Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA. Abstract: Type: JOURNAL ARTICLE Type: REVIEW Type: REVIEW, TUTORIAL
MURRAY KJ, SZER W, GROM AA, DONNELLY P, LEVINSON JE, GIANNINI EH, GLASS DN, SZER IS: Antibodies to the 45 kDa DEK nuclear antigen in pauciarticular onset juvenile rheumatoid arthritis and iridocyclitis: selective association with MHC gene. J.Rheumatol. 1997, 24:560-567. Organism:Department of Pediatrics, Children's Hospital Medical Center, University of Cincinnati College of Medicine, OH 45229, USAPMID- 9058666 Abstract: OBJECTIVE: To study the frequency of autoantibodies to the 45 kDa DEK nuclear antigen, a putative oncoprotein, in a sample of patients with juvenile rheumatoid arthritis (JRA), and to make correlations with disease subtype and complications such as iridocyclitis. Class I and Class II HLA associations with reactivity to the antigen were also sought. METHODS: Sera from 146 HLA typed patients with JRA representing all subtypes were analyzed for reactivity with the 45 kDa DEK protein by immunoblotting. The antigen was purified to near homogeneity from nuclei of HeLa cells. RESULTS: Antibodies to DEK were found in 57% of all patients with JRA compared to 3% of controls (p < 0.0001). Antibodies were detected more frequently in pauciarticular onset (78%) than in polyarticular onset patients (29%; p < 0.01) and controls (3%; p < 0.0001). 97% of patients with JRA (regardless of onset subtype) and iridocyclitis had anti- DEK antibodies compared to 47% of patients without eye disease (p < 0.0001). Anti-DEK antibodies were found more frequently in females compared to males in the pauciarticular onset disease group (84 vs 42%; p < 0.01). The occurrence of anti-DEK antibodies was closely associated with positive antinuclear antibody serology, and a strong association with the Class I gene HLA-A2 was also observed. CONCLUSION: Antibodies to the 45 kDa DEK protein are characteristic of the pauciarticular onset subtype of JRA, particularly in patients with a history of iridocyclitis. The occurrence of anti-DEK antibodies is significantly but paradoxically associated with the presence of the HLA-A2 allele in such patients
PRIEUR AM, STAVROPOULOS-GIOKAS C, GERMENIS A, SPYROPOULOU M, PRATSIDOU P, KANAKOUDI F: Juvenile chronic arthritis (JCA) joint report. Inconnu 1997, Organism:Hôpital Necker, PARIS; Dept of immunology and national tissue typing Lab, General Hospital of AThens Abstract: Results of the international study on HLA in JCA
RUMBA I, DENISOVA A, SOCHNEV A, NILSSON B, SANJEEVI CB: Hla class II genes in latvian patients with juvenile rheumatoid arthritis. Tissue Antigens. 1997, 49:56-60. Organism:Clinic of Pediatrics, Medical Academy of Latvia, Riga, Latvia Abstract: PCR-based HLA genotyping was used to analyze the association of HLA-DR and -DQ genes in 127 juvenile rheumatoid arthritis patients and 111 population-based controls froth Latvia. The results show DQA1*03 to be positively associated in overall patients and DRB 1*01-DQA1*0101-DQB1*0501 to be negatively associated with JRA in overall patients and in polyarthritis patients compared to controls. These data indicate the immunogenetic heterogeneity in the JRA patients, in the disease subgroups and in different ethnic groups. Rheumatoid factor (RF) was assayed in patients (n = 119) and controls (n = 98). RF was present in patients (7/119, 6%) compared to controls (5/98, 5%). None of the DQA1, DQB1 alleles, DQ and DR-DQ haplotypes was associated in seropositive patients compared to seropositive controls. DR1-DQ5 (DQA1*0101-B*0501) was decreased in seronegative patients (11/111, 10%) compared to seronegative controls (24/105, 23%), but the difference was not significant after correction of the p value
RUPERTO N, RAVELLI A, LEVINSON JE, SHEAR ES, MURRAY K, LINK TAGUE B, MARTINI A, GLASS DN, GIANNINI EH: Long-term health outcomes and quality of life in American and Italian inception cohorts of patients with juvenile rheumatoid arthritis. II. Early predictors of outcome. J.Rheumatol. 1997, 24:952-958. Organism:William S. Rowe Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Abstract: OBJECTIVE: To determine whether demographic, clinical, and immunogenetic variables measurable during the first 6 months of illness long-term health outcomes and quality of life in patients with juvenile rheumatoid arthritis (JRA). METHODS: Patient eligibility criteria: (1) first examined in our units between 1958 and 1990 within 6 months of onset of symptoms; (2) diagnosis of JRA by American College of Rheumatology criteria; (3) disease duration of at least 5 years at the time of assessment of outcome. Instruments used: (1) the Health Assessment Questionnaire (HAQ, short form), or Childhood HAQ (CHAQ) to measure disability (0-3 scale), (2) pain, and (3) parental assessment of overall well being, each scored on a 15 cm visual analog scale; (4) the Quality of Life Scales (QOLS) (adults only). Independent variables that showed significant results using univariate tests underwent multiple logistic regression analysis. RESULTS: 227 patients were available for analysis. Mean duration of disease at time of assessment of outcome was 15 years (range 5.3-36.1). Univariate tests allowed 11 variables for disability, 9 for pain, 7 for overall well being, and 4 for QOL into the multivariate analysis. The best predictor of higher disability was the articular severity score (odds ratio, OR, 5.69) while antinuclear antibody positivity foretold less disability (OR 0.29). HLA-DR5 positivity conferred the greatest risk for pain (OR 3.34), while HLA-B5, DR3, and C3 were protective (OR 0.25, 0.28, 0.33, respectively). Early hand involvement was the strongest predictor of poorer overall well being (OR 8.75). Only the erythrocyte sedimentation rate was predictive of future QOL, but the model yielded a low C statistic (< 70%) and the OR 95% confidence limits were extreme (OR 9.77; 95% confidence interval, 1.22-77.8). CONCLUSION: Clinical and immunogenetic variables measurable within 6 months of onset of JRA can be used to predict future disability, pain, and well being. QOL appears more difficult to forecast, perhaps due to the multiple domains that make up this outcome. Further study is needed to identify other genetic and laboratory factors that predict outcome in JRA with greater precision
STEINER LL, MCCURDY DK, CAVALLI A, MOONSAMY PV, BEGOVICH AB: Two new DPB1 alleles identified in a study of the genetics of susceptibility to pauciarticular juvenile rheumatoid arthritis. Tissue Antigens. 1997, 49:262-266. Organism:Department of Human Genetics, Roche Molecular Systems, Alameda, California, USAPMID- 9098934
SULLIVAN KE, MCDONALD-MCGINN DM, DRISCOLL DA, ZMIJEWSKI CM, ELLABBAN AS, REED L, EMANUEL BS, ZACKAI EH, ATHREYA BH, KEENAN G: Juvenile rheumatoid arthritis-like polyarthritis in chromosome 22q11.2 deletion syndrome (DiGeorge anomalad/velocardiofacial syndrome/conotruncal anomaly face syndrome). Arthritis Rheum. 1997, 40:430-436. Organism:Division of Allergy, Immunology, and Infectious Diseases, Children's Hospital of Philadelphia, PA 19104, USAPMID- 9082929 Abstract: OBJECTIVE: To investigate the association of polyarthritis and chromosome 22q11.2 deletions. METHODS: Eighty patients with chromosome 22q11.2 deletion syndrome followed up at The Children's Hospital of Philadelphia were examined for evidence of arthropathy or arthritis. Patients with chromosome 22q11.2 deletion syndrome and polyarthritis underwent laboratory evaluations of immunologic function to determine the relationship of their immunodeficiency to the polyarthritis. RESULTS: The prevalence of polyarthritis in patients with chromosome 22q11.2 deletion syndrome was markedly increased over the prevalence of polyarticular juvenile rheumatoid arthritis (JRA) in the general population. All 3 patients with polyarthritis had evidence of impaired T cell function. Two of the patients with polyarthritis also had IgA deficiency. CONCLUSION: The chromosome 22q11.2 deletion syndrome represents a primary T cell disorder which can be associated with a JRA- like polyarthritis. All 3 patients with polyarthritis had evidence of more extensive immunoregulatory derangements than those typically seen in patients with chromosome 22q11.2 deletion, and these derangements may have predisposed to the development of polyarthritis
WHITCUP SM, NUSSENBLATT RB: Immunologic Mechanisms of Uveitis New Targets for Immunomodulation Article : Mechanisms of Ophthalmic Disease. Arch.Ophthalmol. 1997, Abstract: The uvea consists of the choroid, ciliary body, and iris, and inflammation of the uveal tract is termed uveitis. Nevertheless, uveitis is commonly used to more generally describe intraocular inflammation involving not only the uvea, but also the retina, vitreous, and sclera. Fifty years ago, infectious organisms such as syphilis and tuberculosis were thought to be the cause of most forms of uveitis./1/ Since that time, many causes of uveitis have been described as infectious and noninfectious. Scientists have shown thatthe immune response plays a critical role in the development of infectious and noninfectious forms of the disease. With a more detailed understanding of the immune mechanisms leading to the development of uveitis, we are now able to develop new therapeutic approaches based on targeting various components of the immune response.^ Arch Ophthalmol. 1997;115:520-525
WOO P: The cytokine network in juvenile chronic arthritis. Ann.Med. 1997, 29:145-147. Organism:Department of Molecular Pathology, University College London Medical School, UK. patricia.woo@ucl.ac.uk Abstract: This is a brief overview of the cytokine network within juvenile chronic arthritis, introducing the concept of the production of T- helper 1 (TH-1) or TH2-cell differentiation as a result of cytokine production, as well as the concept of the balance between pro- and anti-inflammatory cytokines. The balance of TH1 and TH2 cells of pro- and anti-inflammatory cytokines could be altered as a result of genetic differences in the expression levels of a number of key cytokines and may be the critical events leading to chronic inflammation. Finally, the importance of identifying molecular targets for intervention therapy to change the balance of the cytokine network is proposed
ZHANG H, PHANG D, LAXER RM, SILVERMAN ED, PAN S, DOHERTY PJ: Evolution of the T cell receptor beta repertoire from synovial fluid T cells of patients with juvenile onset rheumatoid arthritis. J.Rheumatol. 1997, 24:1396-1402. Abstract: OBJECTIVE: To determine the level of T cell clonal expansion and the proportion of T cells that persist over time in the synovial fluid (SF) of patients with juvenile onset rheumatoid arthritis (JRA). METHODS: We collected SF samples from each of 3 patients with JRA at 2 to 3 year intervals. To measure expression across the entire spectrum of Vbeta families in each of 7 fluids examined, we synthesized and amplified dscDNA from all 24 Vbeta families with a single reverse transcriptase- polymerase chain reaction (RT-PCR). RESULTS: The proportion of clonally expanded T cells and persistent T cells is low and variable among patients. CONCLUSION: The data are supportive of disease models not centered on T cells but centered on the changing nature of the disease over time Department of Medicine, Toronto Hospital (Western Division), CanadaPMID- 9228144
ALMOND L: Link between selective IgA deficiency and RA or other autoimmune diseases . Liste Internet : misc.health.arhtritis 1996, Abstract: ach1@bga.com (A. C. Hamilton) wrote ..My doctor says he believes that the IgA/JRA connection explains many of the very un-arthritis-like symptoms I've suffered in between. >I have been able to dig up very little on this subject. ---------------------------------19380254102705 Content-Transfer-Encoding 7bit Content-Type text/plain A.C., You wrote Does anyone have any information on the link between selective IgA deficiency and RA or other autoimmune diseases. Interesting question.
As Don Wiss pointed out The Jeffrey Modell Foundation has created a web site to deal with the issues of immunodeficiency The Jeffrey Modell Foundation - Selective IgA Deficiency http//www.mssm.edu/peds/modell/iga-defi.html Don't forget its partner in crime The Jeffey Modell Foundation - IgG Subclass Deficiency http//www.mssm.edu/peds/modell/igg-sub.html For additional information concerning IgG molecules and rheumatoid arthritis see Medline Abstract 89156449 "Origin of autoreactive anti-type II response. II Specificities, antibody isotypes and usage of V gene families of anti-type II collagen B cells." J Immunol 142 1881-6 (1981)
"Autoantibodies play an important role in the pathogenesis of type II collagen-induced arthritis in mice. ... It is shown here that anti-CII antibodies produced during primary immune responses are IgG-antibodies mainly of IgG2a, IgG1 and IgG2b subclasses. ... Anti-CII antibodies generated during the primary immune response recognize at least five different epitopes on the CII molecule."
Returning to the question about selective IgA deficiency.
OMIM Entry #137100 Selective Deficiency of IgA http//www3.ncbi.nlm.nih.gov80/htbin-post/Omim/dispmim?137100
"Oxelius et al. (1981) pointed out that deficiency of IgG2 in combination with IgA deficiency is a critical factor in whether or not IgA-deficient persons have illness (frequent infections, autoimmune disorders, atopy, malabsoption). ...HLA-A1,B8,DR3, a haplotype associated with selective IgA deficiency."
The Medline abstracts implicate parts and/or all of the preceeding haplotype and its associated class II heterodimer (DQ2) with numerous autoimmune illnesses (IDDM [Medline 92392539], Celiac Disease [93121631], Sjogren's Syndrome [93224768], Lupus, Thyroiditis, Scleroderma and Autoimmune Hepatitis [94063766]) including AIDs , cancer melanoma and lymphoma and drug reactions gold, aspirin and d-penicillamine.
The research focus for autoimmune diseases has shifted
Medline abstract 95378670 "HLA-DQ polymorphisms are highly selective for peptide binding interactions" W.W. Kwok et al, J Immunol 155 2468-2476 (1995)
"The impact of HLA-DQ allelic polymophism on peptide interactions was investigated. ... Class II heterodimers of different combinations of DQ alpha-chain and DQ beta chain independently influence specific peptide interactions. Each of the peptides tested bound differentially to DQ alleles."
The abstract concludes
"These studies demonstrate the critical role of specific DQ polymorphisms in establishing the nature of bound Ag {antigen}and thereby influencing the potential immune repertoire. Analysis of the ability of DQ molecules to bind and present antigenic peptides should aid in understanding their role in immunity and in development of HLA-DQ associated autoimmune disease."
Medline abstract 93066302 "Shared HLA class II-associated genetic susceptiblity and resistance, related to the HLA-DQB1 gene, in IgA deficiency and common variable immunodeficiency" O. Olerup et al, Proc Natl Acad Sci U S A 89 10653-7 (1992)
"Disease susceptibiity and resistance are most closely associated with a gene(s) within the DR-DQ region, alleles of the DQB1 locus being candidate genes".
Note Observe the non-Asp amino acid at position 57 of the HLA DQ beta chain, in IgA selective deficiency, Celiac Disease and Insulin Dependent Diabetes Mellitus [IDDM] as described in the related preceeding documents.
In the Medline abstract 95391061 "Could HLA-DRB1 be the protective locus in rheumatoid arthritis?" C.S. David et al, Immunology Today 16 p. 274-278 (1995)
The authors acknowledge the long held association between susceptibility to the development of arthritis (RA) with the third hypervariable region of the major histocompatibility complex (MHC) HLA-DR beta 1 molecule. However, the authors "propose that the HLA-DRB1 locus is associated with protection to RA and that the actual arthritogenic peptide-presenting molecule is HLA-DQ. Thus the development of RA would depend upon the expression of the susceptible DQ allele and the nonprotective DRB1 alleles, along with environmental factors that trigger the autoimmune process."
If you decide to sift through Medline articles looking for the connection between RA and HLA-DQ start with
Medline abstract 86115169 "Autoimmunity to native type II collagen a distinct genetic subset of rheumatoid arthritis" P.S. Klimiuk et al, J Rheumatol 12 865-70 (1985)
A link between DQ2 [IE HLA-DQA1*0501 and DQB1*0201] and autoimmunity to native II collagen is suggested.
An additional link to the DQ molecules was made more recently to the DQ8 heterodimer [IE DQA1*0301 and DQB1*0302]
Medline 96136745 "HLA-DQ8 transgenic mice are highly susceptible to collagen-induced arthritis a novel model for human polyarthritis." C.S. David et al, J Exp Med 183 27-37 (1996)
A strong antibody response to type II collagen is elicited in mice selected to express the DQ8 heterodimer.
If you surf the Medline, you will observe an increased frequency of the DQ2 and/or DQ8 heterodimers and other autoimmune diseases Celiac Sprue and Insulin Dependent Diabetes Mellitus [IDDM], etc.
A relationship between the HLA-B8,DR3 markers and a decrease in complement levels has also been established.
The Primer on Rheumatic Diseases - (1993) explains that a deficiency of complement protein is the result of inheriting a null allele. p51 They observe, "C4a null alleles are part of an extended haplotype with the markers HLA-B8 and DR3, the influence of these class I and class II alleles on disease susceptibility may reflect linkage disequilibrium with complement deficiency." p103
Keep in mind that rheumatoid arthritis is a polygenic disease. A potential connection to the extended HLA-A1,B8,DR3 haplotype has been made linking it to the HLA class II marker DPB1*0301
Medline abstract 92029105 "HLA-DPB1*0301 is a major risk factor for rheumatoid factor-negative adult rheumatoid arthritis." X. Gao et al, Arthritis Rheum 34 1310-2 (1991)
The authors highlight the genetic link between seronegative RA and seronegative polyarticular JRA.
The following abstracts provide some insight into the role of IgA and its effects on the autoimmune system
Medline Abstract 94162626 - "Human serum IgA downregulates the release of inflammatory cytokines (tumor necrosis factor- alpha, interleukin-6) in human monocytes." H.M. Wolf et al. Blood 83 1278-88 (1994)
"Our results show that IgA downregulates TNF-alpha and IL-6 production... Regulation of TNF-alpha and IL-6 release by IgA may be among the antiinflammatory mechanisms preventing an uncontrolled release of potentially noxious levels of inflammatory cytokines during acute and/or chronic inflammation."
Medline Abstract 94141802 - "Interleukin 6 and autoantibodies in juvenile rheumatoid arthritis." K. Oen et al. J Rheumatol 20 1949-56 (1993)
"suggest that IL-6 may promote the production of IgG and IgA RF and IgG antinative type II collagen."
Saw an enticing Medline abstract 96167028 "Cytokine mediated effects in mucosal immunity." D.R.Kramer Immunol Cell Biol 73 389-396 (1995) The article might help answer some of your questions regarding IgA deficiency and RA.
There appears to be an interest in the effects of retinoic acid (vitamin A) on Rheumatoid Arthritis. The most promising results were published recently
Medline abstract 96140729 "Novel synthetic retinoic acid inhibits rat collagen arthritis and differentially affects serum immunoglobulin subclass levels." K. Kuwabara et al, FEBS Lett 378 153-156 (1996)
The authors suggest that Am-80 but not 13-cis-RA strongly reduced the serum level of anti-collagen II antibody and differentially affected the levels of immunoglobulin (Ig) subclasses in vivo IgG1 and IgG2a levels were decreased, while IgA level was increased without any change in the IgM level. These findings indicate that Am-80 may be one of the lead retinoic acids of a new class of anti- inflammatory agents."
All the Medline abstracts cited above can be viewed at the Entrez Query URL http//www3.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=0 Set search field to Medline ID & Type the Medline ID # listed above next to Enter Term.
Note The Entrez Query is a bit particular about how some things are entered.
Out of curiousity, what kind of JRA do you have? I have seronegative polyarticular JRA. Prior test results for anti-cardiolipin Ab (IgA, IgG, IgM) indicated that I have some kind of IgA deficiency.
Hope this helps you. If any http links fail or Medline numbers connect incorrectly - Let me know - my typing isn't very good.
Hope this gets you started,
Lisa Almond
---------------------------------19380254102705--
-- "Live as one already dead." --Japanese saying
BRENNAN P, OLLIER B, WORTHINGTON J, HAJEER A, SILMAN A: Are both genetic and reproductive associations with rheumatoid arthritis linked to prolactin?(Hypothesis). The Lancet 1996, 348:106-109. Organism:Arthritis and Rheumatism Council Epidemiological Research Unit, University of Manchester Medical School, UK. Abstract: Rheumatoid arthritis (RA) may be associated with high blood levels of the hormone prolactin and a specific HLA gene. RA is more common in women and the risk of RA is higher in women who are infertile and those who breastfeed. Both of these conditions are characterized by high prolactin levels. In addition, many women with RA have the HLA DRB1*0401 and DRB1*0404 genes. These genes produce molecules that activate CD4 T cells, which also have a receptor for prolactin. The prolactin gene is also located close to the HLA genes on chromosome 6 The risk of rheumatoid arthritis (RA) seems to be associated with reduced fecundity and with breastfeeding; these apparently contradictory risk factors can be explained by their association with high prolactin concentrations. The only consistent genetic association with RA is for genes encoded in the HLA complex, particularly HLA DR4. We have identified some data indicating that the effects of breastfeeding and nulliparity are modified by HLA DR4 status, suggesting an interaction between genetic and reproductive risk factors in the aetiology of RA. The prolactin gene is in close proximity to the HLA region on the short arm of chromosome six. We therefore propose the hypothesis that the associations between DR4 and reproductive risk factors in RA are due to linkage disequilibrium between DR4 and an abnormally regulated prolactin gene polymorphism
CALDWELL JR: Intra-articular corticosteroids. guide to selection and indications for use. Drugs 1996, 52:507-514. Organism:USA Abstract: Physicians have used intra- and periarticular corticosteroids for treating a variety of rheumatic diseases for nearly 50 years. Yet publications that have carefully examined the mechanisms of action, the pharmacokinetics and the comparative safety and efficacy of the available agents are sparse. This limits our ability to choose a drug scientifically, Similarly, we know little about the long term outcomes of joints injected with corticosteroids versus those nor injected, Highly branched esters of methylprednisolone or triamcinolone are the preferred agents used by American rheumatologists. Pharmacokinetic studies reveal that triamcinolone hexacetonide, the least soluble of all the corticosteroid esters, is retained in the joint for 2 to 3 weeks. Intra-articular corticosteroids may implement their anti- inflammatory effect by down-regulating genetic expression of several pro-inflammatory proteins. A literature review suggests that judicious use of intra- and periarticular corticosteroids is very helpful in temporarily reducing pain and inflammation in musculoskeletal structures and may facilitate increased motion and function in selected cases. Their use in juvenile arthritis also appears to be safe and beneficial. Infection in or about the joint is the chief contraindication to use. Adverse effects are very few but the number of injections per joint should probably be limited to 4 or less per year
CORNELIS F: Recherche et Génétique. Réadaptation 1996, Organism:Centre Vigo Petersen, Hôpital Lariboisiére, PARIS, France Abstract: La polyarthrite rhumatoide est de diagnostic difficile au début, son pronostic ne peut être déterminé avec fiabilité, et sa physiopathogénie reste mal comprise et son facteur déclenchant inconnu. Le but de la recherche génétique est de contribuer à l'amélioration de cette situation.
EVANS HE, ROBBINS PD: Pathways to gene therapy in rheumatoid arthritis. Curr.Opin.Rheumatol. 1996, 8:230-234. Abstract: Gene therapy offers novel possibilities for the treatment of rheumatoid arthritis. Present research is directed toward harnessing gene transfer technology to deliver genes whose products possess antiarthritic properties; the current emphasis is on transferring genes encoding secreted proteins. Genes may be delivered locally to individual diseased joints or systemically to extra-articular sites where the secreted gene products may enter the circulation. Local delivery is more laborious and unlikely to address systemic components of rheumatoid arthritis but should avoid side effects. Either ex vivo or in vivo strategies may be used to deliver the genes to the target tissues. Ex vivo techniques are more cumbersome but safer, because all genetic manipulations occur outside the body and cells may be extensively screened prior to implantation. A variety of vectors, including retrovirus, adenovirus, herpes simplex virus, and liposomes, as well as naked DNA, have been tested for their ability to deliver genes to joints. At the present stage of vector development, adenovirus seems best suited for in vivo gene delivery to synovium, but several authors have noted an inflammatory response, resulting in loss of gene expression. Ex vivo gene transfer using a retrovirus encoding human interleukin-1 receptor antagonist has succeeded in obtaining high intra-articular transgene expression with promising antiarthritic effects in animal models. Based on these data, the first human gene therapy trial for arthritis has been approved by the US Food and Drug Administration and will begin shortly.
GARE BA: Epidemiology of rheumatic disease in children. Curr.Opin.Rheumatol. 1996, 8:449-454. Abstract: Major problems associated with interpreting and comparing epidemiologic studies on chronic arthropathies in children include the diversity of classification criteria and selection bias. A new set of classification criteria for peripheral arthritis in children, aiming toward defining biologically homogeneous subgroups, was recently proposed and should be further tested. Descriptive studies from all over the world are now emerging on childhood rheumatic diseases, increasing the potential for comparing the impact of genetic and environmental factors on disease frequency and manifestations. Awareness about pain syndromes in children, such as juvenile primary fibromyalgia and reflex sympathetic dystrophy, has increased, and this population now forms a substantial portion of clinic visits in pediatric rheumatology. The impact of the rheumatic diseases in children on disability and quality of life during childhood and in adult life is still to a large extent unknown and must be further studied in an epidemiologic context Type: JOURNAL ARTICLE Type: REVIEW Type: REVIEW, TUTORIAL ISSN: 1040-8711 Language: Eng
GROM AA, VON KNORRE C, MURRAY KJ, DONNELLY PA, GLASS DN, CHOI E: T-cell receptor bv6s1 null alleles and hla-dr1 haplotypes in polyarticular outcome juvenile rheumatoid arthritis. Human Immunology 1996, 45:152-156. Organism:USA Abstract: JRA is a complex of disease subtypes which are normally identified by clinical features such as age of onset and extent of joint involvement both at onset and during the course of the disease. We previously identified an association between TCR BV6S1, null allele and one subgroup of early-onset pauciarticular patients positive for HLA-DQA1*0101, an HLA haplotype predisposing to a polyarticular course of the disease. In this report we extend this observation by identifying an increased prevalence of this nonfunctional or null allele in the patients with a polyarticular disease course regardless of the mode of onset. This increase was most prominent in clinical subsets that have early onset of the disease and a polyarticular outcome. In one clinical group, stratification of patients by the HLA allele DQA1*0101 strengthened the association considerably. This implies that there is an increased genetic load defined by specific alleles of both MHC and TCR genes
GROM AA, MURRAY KJ, LUYRINK L, EMERY H, PASSO MH, GLASS DN, BOWLIN T, EDWARDS C: Patterns of expression of tumor necrosis factor alpha, tumor necrosis factor beta, and their receptors in synovia of patients with juvenile rheumatoid arthritis and juvenile spondylarthropathy. Arthritis Rheum. 1996, 39:1703-1710. Organism:Children's Hospital Medical Center, Cincinnati, OH 45229-2899, USA. Abstract: OBJECTIVE: To assess the expression of tumor necrosis factor alpha (TNF alpha), TNF beta, and their receptors in synovia of patients with juvenile rheumatoid arthritis (JRA) and juvenile spondylarthropathy (JSpA), and to determine similarities with and differences from adult RA. METHODS: Twenty-eight synovial tissue samples from patients with JRA, 6 from patients with JSpA, and 6 from patients with RA, selected for the presence of inflammatory infiltrates, were analyzed for the expression of TNF alpha, TNF beta, and their receptors (p55 and p75 TNFR), utilizing the dual approach of reverse transcriptase-polymerase chain reaction and immunohistochemistry analysis. RESULTS: The presence of both TNF alpha and TNF beta expression was demonstrated in most JRA and JSpA tissues, although samples from patients with pauciarticular JRA had somewhat lesser amounts of these cytokines. TNF beta expression correlated significantly with the occurrence of lymphocytic aggregates in tissues. Staining with monoclonal antibodies specific for the p55 and p75 receptors revealed that a diverse range of cell types expressed the receptors, with the most intense p55 staining on vascular endothelial cells. In the vast majority of synovial tissues, far greater numbers of cells expressed the p55 form of the receptor than the p75 form. CONCLUSION: JRA and JSpA synovia are characterized by the presence of TNF alpha, TNF beta, and cells expressing TNFR. These findings provide further evidence that TNF, through autocrine/paracrine mechanisms, may amplify local inflammation, leading to joint destruction. The prominence of TNF beta in the synovium in particular subgroups of JRA patients and in JSpA patients may be a distinguishing feature of these diseases
HEDLUND TE, MOFFATT KA, MILLER GJ: Vitamin D receptor expression is required for growth modulation by 1 alpha,25-dihydroxyvitamin D3 in the human prostatic carcinoma cell line ALVA-31. J.Steroid Biochem.Mol.Biol. 1996, 58:277-288. Organism:Department of Pathology, University of Colorado Health Sciences Center, Denver 80262, USA. Abstract: Epidemiological data suggest that vitamin D3, obtained from dietary sources and sunlight exposure, protects against mortality from prostate cancer (PC). In agreement with this, the most active vitamin D metabolite 1 alpha,25-dihydroxyvitamin D3 [1, 25(OH)2 D3] regulates the growth and differentiation of several human PC cell lines. Both genomic and non-genomic signalling pathways for 1,25(OH)2 D3 have been reported, although the mechanism of action in PC cells has not been defined. We now provide data supporting an active role for the nuclear vitamin D receptor (VDR) in mediating the growth-inhibitory effects of 1, 25(OH)2 D3 on these cells. In the VDR-rich cell line ALVA-31, the observed changes in growth by 1,25(OH)2 D3 are preceded by significant changes in VDR mRNA expression. In contrast, the cell line JCA-1, containing few VDRs, fails to show both early changes in VDR gene expression and later changes in growth with 1,25(OH)2 D3. To assess the role of the VDR more directly, transfection studies were pursued. ALVA-31 cells were stably transfected with an antisense VDR cDNA construct in an attempt to reduce VDR expression. Antisense mRNA expression among clones was associated with: (a) reduced or abolished sensitivity to the effects of 1, 25(OH)2 D3 on growth; (b) decreased numbers of VDRs per cell, as measured by radiolabelled-ligand binding; and (c) a lack of induction of the VDR-regulated enzyme 24-hydroxylase in response to 1,25(OH)2 D3. From these studies we conclude that the antiproliferative effects of 1,25(OH)2 D3 require expression of the nuclear VDR in this system
MIELANTS H, VEYS EM, CUVELIER C, DE VOS M: Course of gut inflammation in spondylarthropathies and therapeutic consequences. Bailliere's Clinical Rheumatology 1996, 10:147-164. Organism:Belgium Abstract: Gut inflammation plays a crucial role in the pathogenesis of spondylarthropathies (SpA) since ileocolonoscopic studies have demonstrated the presence of gut inflammation in different forms of this concept: in ankylosing spondylitis (AS) (60%), in enterogenic (90%) and urogenital reactive arthritis (20%), in undifferentiated SpA (65%), in the pauci-articular and axial forms of psoriatic arthritis (16%), in late onset pauci-articular juvenile chronic arthritis (80%) and in acute anterior uveitis (66%). The strong relationship between gut and joint inflammation was demonstrated by performing a second ileocolonoscopy: remission of the joint inflammation was always connected with a disappearance of gut inflammation, whereas persistence of locomotor inflammation was mostly associated with the persistence of gut inflammation. During further evolution 20% of the non- ankylosing spondylitis SpA patients can develop AS. About 6% of the total group SpA patients, in whom inflammatory bowel disease (IBD) was excluded, developed Crohn's disease 5 to 9 years later. All these patients initially presented with gut inflammation, which indicates that this finding has prognostic value. The high prevalence of evolution to IBD in SpA patients confirms the thesis that both disease entities bear common pathogenic mechanisms, and confirms the place of IBD in the concept of SPA. Sulphasalazine (SASP), a successful drug in the treatment of IBD, has demonstrated its effectiveness in the treatment of SpA. The beneficial effect of the drug in this disease entity could be due to its anti-inflammatory effect on the gut wall, by normalizing its permeability and by preventing the entrance of antigens through the defective gut wall. However, SASP could not prevent the evolution to IBD
MILLER IJJ, BIEBER MM, LEVINSON JE, ZHU S, TSOU E, TENG NNH: V(h)4-34 (v(h)4.21) gene expression in the chronic arthritides of childhood: studies of associations with anti-lipid a antibodies, hla antigens, and clinical features. J.Rheumatol. 1996, 23:2132-2139. Organism:USA Abstract: Objective. To determine if the germ line gene V(H)4-34 (V(H)4.21) encodes the antimonophosphoryl lipid A (MPL) polyspecific antibodies found in oligoarticular arthritis of childhood. Methods. Sera from a range of rheumatic diseases of childhood were assayed for V(H)4-34 derived antibodies by ELISA using the antiidiotype monoclonal antibody 9G4. Results were compared to assays for anti-MPL antibodies, C4d, and Bb, and for HLA type, joint count, and sedimentation rate. Results. V(H)4-34 derived antibodies were elevated in all diseases studied except rheumatoid factor positive polyarticular disease. In oligoarticular arthritis, V(H)4-34 gene expression correlated with C4d concentration, and V(H)4-34 encoded globulins were more concentrated in synovial fluid than in blood. No association was found with HLA type. An association between V(H)4-34 expression and IgG anti-MPL was found in sera from patients from Cincinnati but not from Stanford. No other evidence supported a direct association between V(H)4-34 derived and anti-MPL antibodies in these children. Conclusion. The expression of V(H)4-34 is increased in several rheumatic diseases of childhood, but, as in adults, not in rheumatoid arthritis. V(H)4-34 expression is not associated with HLA type. The polyspecific autoantibody nature of some V(H)4-34 derived antibodies may explain the wide range of the unusual antibodies found in oligoarticular arthritis
PRYHUBER KG, MURRAY KJ, DONNELLY P, PASSO MH, MAKSYMOWYCH WP, GLASS DN, GIANNINI EH, COLBERT RA: Polymorphism in the LMP2 gene influences disease susceptibility and severity in HLA-B27 associated juvenile rheumatoid arthritis. J.Rheumatol. 1996, 23:747-752. Organism:William S. Rowe Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA. Abstract: OBJECTIVE. To determine the potential contribution of the MHC class II region proteasome subunit gene, LMP2, to disease susceptibility, severity, and phenotype in patients with juvenile rheumatoid arthritis (JRA). METHODS. A CfoI restriction site polymorphism in the coding region of the LMP2 gene was evaluated in 279 patients with JRA and 107 healthy controls of similar ethnicity. Patients were divided into 5 groups on the basis of clinical presentation; 46% had early onset pauciarticular disease, 10% early onset polyarticular, 10% late onset pauciarticular, 20% late onset polyarticular, and 11% systemic onset arthritis. The influence of this LMP2 polymorphism on susceptibility to disease, clinical subtype of disease at onset (age and number of joints involved), progression and severity of joint disease (pauci to polyarticular course and radiographic changes), and occurrence of inflammatory eye disease was evaluated. RESULTS. Comparison of genotypes revealed a significantly increased prevalence of homozygosity for the LMP2 B allele (LMP2 BB genotype) in patients who were older (> or = 6 years) at onset of disease (65%, p < 0.05), particularly in those with pauciarticular (71%) involvement at presentation (p < 0.05), compared to controls (51%). The BB genotype was also more prevalent in patients with a polyarticular course, either from onset (63%) or those who progressed from pauciarticular disease (69%), compared with controls, (p = 0.05 and < 0.05, respectively). Stratification for HLA-B27 and DR4, the HLA alleles most frequently associated with late onset pauciarticular and late onset polyarticular JRA, respectively, revealed a persistent effect of LMP2 BB homozygosity on disease susceptibility and phenotype that remained statistically significant in HLA-B27 positive children, and was not due to linkage disequilibrium. CONCLUSION. We show that homozygosity of the B allele of the proteasome subunit LMP2 increases susceptibility to certain subgroups of JRA, and influences the phenotype of disease, predisposing to more progressive and severe articular disease
TIPOLD A, SOMBERG R, HENTHORN P, RADUCHA M, FEESBURG P: Restriction fragment length polymorphism of the t-cell receptor beta- chain gene in dogs. Vet.Immunol.Immunopathol. 1996, 51:225-233. Organism:Switzerland Abstract: Since T cells and the T-cell receptor (TCR) play a pivotal role in the response of the immune system, they are a target for pathogenesis studies in immune mediated diseases and have been used to generate markers for T-cell dependent diseases in humans and dogs. TCR rearrangement is generated at the genomic DNA level and can be analyzed by Southern blotting techniques. In the present study this method to detect rearrangement of the TCR beta chain in the dog was critically examined. To search for restriction fragment length differences clue to either inherited polymorphism or in diseases with suspected superantigen influence (X-linked severe combined immune deficiency and canine juvenile polyarteritis syndrome) 13 dog families of three different breeds were examined. In addition primary spleen cell cultures, stimulated with either phytohemagglutinin A (PHA) or staphylococcus enterotoxin A (SEA) and B (SEB) were studied. The germline digest pattern of the enzymes Pst I, Sst I, Bgl II, Eco RI and Eco RV were identical in all dogs examined with the exception of one dog with canine juvenile polyarteritis syndrome. In this dog an additional band was found in the Bgl II and Eco RV digestion suggestive of specific TCR rearrangement. Bam HI digestion revealed restriction fragment length polymorphisms (RFLPs) showing Mendelian inheritance. After digestion of the genomic DNA extracted from PHA, SEA or SEB stimulated spleen cells and Southern blot analysis, no differences in fragment patterns between the unstimulated cells and the stimulated cells could be detected. An important point to consider before a specific pattern variation between dogs is classified to be a marker for a specific disease or is used in pathogenesis studies, is the possibility of an inherited RFLP, especially after Bam HI digestion. In such studies the combined examination of the parents and the offspring must be recommended
CHARMLEY P, NEPOM BS, CONCANNON P: Use of a polymorphic dinucleotide repeat DNA marker in a T-cell receptor V beta gene to identify a distinct subset of pauciarticular-onset juvenile rheumatoid arthritis patients. Ann.N.Y.Acad.Sci. 1995, 756:444-446. Organism:Virginia Mason Research Center, Seattle, Washington 98101, USA.
EPPLEN C, RUMPF H, ALBERT E, HAAS P, TRUCKENBRODT H, EPPLEN JT: Immunoprinting excludes many potential susceptibility genes as predisposing to early onset pauciarticular juvenile chronic arthritis except HLA class II and TNF. Eur.J.Immunogen. 1995, 22:311-322. Organism:Department of Molecular Human Genetics, Ruhr University at Bochum, Germany. Abstract: DNA profiles (immunoprints) were generated for 120 patients suffering from early onset pauciarticular chronic arthritis (EOPA- JCA) and > 500 healthy controls utilizing highly polymorphic microsatellites in the vicinity of immunorelevant genes. Six T cell receptor (TCR) markers for the CD3D, TCRDVAJ, TEA, TCRBV6S1, BV6S3, BV6S7 and BV13S2 genes were analysed. Furthermore markers for the cell surface molecule CD40L, for cytokine genes (IL-1A, IL-2, IFN-alpha, FGF-alpha, TNF-alpha), the chromosomal region of the IRF2 and the cytokine receptor gene IL5RA were studied as well as two polymorphisms within the promotor region of the TNF- alpha gene. Coding region polymorphisms were evidenced indirectly by repeat length variation or they were predicted from the microsatellite distribution profiles and then confirmed by direct sequence analysis. Statistical evaluations were performed with respect to known predispositions, predominance of females (> 80%) and HLA-DR and -DQ haplotypes. Cell surface molecules (TCR, CD40L, IL5RA) as well as almost all cytokines (IL-1A, IFN alpha, FGFA, IRF2 region) were excluded as predisposing in our JCA panel. The TNF-alpha microsatellite alleles (GT)10-12 contribute considerably to manifestation of the disease, in HLA-DRB1*11(12) individuals (RR = 12.8). The TNF-alpha allele is not found in linkage disequilibrium with HLA-DRB1*11(12) and may be present on either chromosome 6. Thus, a novel susceptibility factor probably within the TNFA/TNFB gene region has been identified via linkage with the TNF-alpha microsatellite allele. Apparently complex compositions of the genetic background rather than single genes provide the precondition for manifestation of the autoimmune disease EOPA-JCA. Immunoprinting unravels the variability of the immunological genome via the semi-directed microsatellite approach efficiently
EPPLEN C, BUITKAMP J, RUMPF H, D'SOUZA M, EPPLEN JT: Immunoprinting reveals different genetic bases for (auto)immuno diseases. Electrophoresis 1995, 16:1693-1697. Organism:Ruhr-Universitat, Bochum, Germany. Abstract: The genetic basis of complex (auto)immune diseases has been studied for an ovine nematode infection, human rheumatoid arthritis (RA), early onset pauciarticular arthritis (EOPA) and multiple sclerosis (MS). Immunoprinting combines the powerful simplicity of polymerase chain reaction (PCR)-based amplification of discrete, highly informative microsatellite loci with the principle of genetic associations. This approach has allowed us to define novel genetic risk factors in adult RA patient categories whereas EOPA forms in juveniles display other prominent genetic contributions. Differentially regulated tumor necrosis factor (TNF) expression may lead to a better understanding of the causal pathogenesis of EOPA while T cell receptor (TCR) gene polymorphisms appear crucial for RA manifestations in certain patient groups. Statistically significant marker associations have still to be defined for MS in larger panels of patient and control cohorts. The clinical course of the disease will probably have to be taken into account when associations with lymphokine levels are evaluated. In essence a convoluted myriad of negative and a few positive disease association data have been generated efficiently by immunoprinting. As expected, the interrelationships are truly complicated between the polymorphic genetic instances predisposing to autoimmune disease. Nevertheless, risk factors may be defined on an individualized basis by indirect gene diagnosis revealing predispositions and providing a more solid basis for differential diagnosis and treatment
FINK CW, FERNANDEZ-VINA M: The genetics of juvenile rheumatoid arthritis. Bull.Rheum.Dis. 1995, 44:5-8. Organism:University of Texas Southwestern Medical Center, Dallas, USA
GIANNINI EH, CAWKWELL GD: Drug treatment in children with juvenile rheumatoid arthritis. Past, present, and future. Pediatr.Clin.North Am. 1995, 42:1099-1125. Organism:Department of Pediatrics, University of Cincinnati, College of Medicine, Ohio, USA. Abstract: Rheumatology made its debut as a legitimate subspecialty of pediatrics sometime in the 1940s in Europe, and in the 1970s in North America. Therapy of juvenile rheumatoid arthritis has evolved from salicylates and gold injections to newer, less toxic nonsteroidal anti-inflammatory drugs and methotrexate. Corticosteroids remain as important drugs when life-threatening complications or blinding iridocyclitis develop. Immune response modifiers and gene therapies offer considerable potential for eventually halting or curing the disease but have yet to make a substantial impact on therapy. Methods for the correct conduct and interpretation of data from clinical trials are discussed
HAAS JP, KIMURA A, TRUCKENBRODT H, SUSCHKE J, SASAZUKI T, VOLGGER A, ALBERT ED: Early-onset pauciarticular juvenile chronic arthritis is associated with a mutation in the Y-box of the HLA-DQA1 promoter. Tissue Antigens. 1995, 45:317-321. Abstract: 95381232 Immunogenetics Laboratory, LMU Munich, Germany (DENMARK) 0001-2815 ENGLISH 9512 INDEX MEDICUS Early-onset pauciarticular juvenile chronic arthritis (EOPA-JCA) has associations with different alleles of the MHC region (HLA-A2, DR5, 6, 8, DQA1*0401, *0501, *0601 and DPB1*0201). All susceptible DQA1 alleles carry an exclusive sequence motif. MHC- class II gene expression is controlled by 5' flanking upstream regulatory regions (URR). A hypervariable region in the promoter region of the HLA-DQA1 gene (-240 and -200 base pairs upstream) defines ten different QAP (DQA1-Promoter) alleles, which are associated with certain DQA1-alleles. The Y-Box in the DQA1 promoter (YC- Box -125 to -115 upstream from the ATG) differs from the consensus sequence (-123 A for G) of all other MHC class II Y-Boxes, resulting in a lower affinity to the NF-Y transcription factor and in a reduced expression of DQA1. A second substitution in the Y-Box of QAP 4.1 and 4.2 (-119 A for G) is found in the promoter alleles of the DQA1-alleles (DQA1*0401, *0501, *0601) and is strongly associated with susceptibility to EOPA-JCA 0 (HLA-DQ Antigens);0 (HLA-DQA1)
MCDOWELL TL, SYMONS JA, PLOSKI R, FORRE O, DUFF GW: A genetic association between juvenile rheumatoid arthritis and a novel interleukin-1 alpha polymorphism. Arthritis Rheum. 1995, 38:221-228. Abstract: 95151050 University of Sheffield, Royal Hallamshire Hospital, UK (UNITED STATES) 0004-3591 ENGLISH 9505 AIM^INDEX MEDICUS OBJECTIVE. The genetic factors that predispose to the development of juvenile rheumatoid arthritis (JRA) and its complications are not completely understood. The cytokine interleukin-1 (IL-1) has been implicated in the pathogenesis of JRA and other inflammatory diseases. This study was performed to test whether polymorphisms of the IL-1 alpha gene might be associated with JRA. METHODS. We sequenced the 5' regulatory region (containing the promoter) of the human IL-1 alpha gene in 18 normal subjects. This revealed a C (IL-1A1) to T (IL-1A2) transition polymorphism at position -889. We studied the frequencies of both alleles in patients with JRA (n = 269) and controls (n = 99). RESULTS. An increased gene JRA (EOPA-JRA; n = 103) compared with controls (0.66 versus 0.49; P = 0.01, odds ratio [OR] = 2.1). Within this subset of JRA, the association with IL- 1A2 was particularly strong in the patients in whom chronic iridocyclitis developed (n = 28) compared with those without chronic iridocyclitis (0.89 versus 0.57; P = 0.002, OR = 6.2). Within the group of EOPA-JRA patients, IL-1A2 was also associated with elevation of the erythrocyte sedimentation rate (P < 0.0025). CONCLUSION. This is the first report of a cytokine gene association with JRA, and we conclude that IL-1 alpha itself, or a gene for which the IL-1 alpha polymorphism is a marker, may contribute to the pathogenesis of EOPA-JRA and the ocular complications found in this group 0 (Interleukin-1)
PLOSKI R, FLATO B, VINJE O, MAKSYMOWYCH W, FORRE O, THORSBY E: Association to HLA-DRB1*08, HLA-DPB1*0301 and homozygosity for an HLA-linked proteasome gene in juvenile ankylosing spondylitis. Hum.Immunol. 1995, 44:88-96. Organism:Institute of Transplantation Immunology, National Hospital, Oslo, Norway. Abstract: To assess the role of HLA genes other than those encoding B27 in predisposing to JAS and AAS, we analyzed the distribution of B*4001, as well as the DRB1, DPB1, and LMP2 alleles, using PCR- based techniques in 63 JAS and 44 AAS patients (all B27 positive). The NBMDR (N = 4724) provided a source of controls matched with the patients for B27 (or other markers when necessary). We found an increase of the B*4001, DRB1*08, and DPB1*0301 alleles, as well as the LMP2 b/b genotype (the latter was most pronounced among patients with acute iridocyclitis), in JAS compared to B27-positive controls. The increase of DRB1*08 and DPB1*0301 was due to an increase of DRB1*08 and DPB1*0301 in combination, whereas the association with B*4001 could be due to linkage disequilibrium with LMP2b. None of these associations were detected in AAS. We conclude that in JAS, in addition to the association to B27, there are also weaker but distinct associations to the DRB1*08, DPB1*0301 alleles and homozygosity for LMP2b
PLOSKI R, MCDOWELL TL, SYMONS JA, FLATO B, DUFF GW, THORSBY E, FORRE O: Interaction between HLA-DR and HLA-DP, and between HLA and interleukin 1 alpha in juvenile rheumatoid arthritis indicates heterogeneity of pathogenic mechanisms of the disease. Hum.Immunol. 1995, 42:343-347. Organism:Institute of Transplantation Immunology, National Hospital, Oslo, Norway. Abstract: EOP-JRA is an autoimmune disease that displays associations with DPB1*0201, DR8, DR5, and DR6, as well as an association with IL1A2 (a variant of IL1 alpha gene, not HLA linked). The purpose of this study was to analyze interactions between these genetic factors. We studied 103 EOP-JRA patients, 181 random controls, and 69 DR8-positive controls. We found a positive interaction between DPB1*0201 and the DRB1 alleles encoding DR3, DR5, or DR6, but not DR8. In addition, we found evidence for an interaction between IL1A2 and DR(3, 5, or 6) and DP2, but not DR8. We interpret the data to suggest heterogeneity in the HLA-associated pathogenic mechanisms of EOP-JRA
THOMPSON KM, BORRETZEN M, RANDEN I, FORRE O, NATVIG JB: V-gene repertoire and hypermutation of rheumatoid factors produced in rheumatoid synovial inflammation and immunized healthy donors. Ann.N.Y.Acad.Sci. 1995, 764:440-449. Organism:Institute of Immunology and Rheumatology, National Hospital, University of Oslo, Norway. Abstract: We have compared RF from normal, immunized donors and RF derived from the synovial tissues of RA patients. We have found a difference in the preferential use of VL and VH gene families. In both conditions, RFs were found to have accumulated somatic mutations. However, there was a striking difference in the patterns of mutation. RFs from normals were characterized by a very low R:S ratio in the CDR1+2, considerably lower than seen among the RARFs. In addition, there was little increase in affinity with increasing numbers of mutations in a group of clonally related RFs from an immunized normal. This contrasts with RF from RA, where there is evidence of both affinity maturation and class switching. Together these data suggest that in healthy persons there is a controlling mechanism to limit the affinity of RF autoantibodies, and that this is lost in RA. The higher affinity of the RA-derived RF may be of significance in the pathology of the disease
YOSHIMURA I, WU JM, CHEN Y, NG C, MALLOUH C, BACKER JM, MENDOLA CE, TAZAKI H: Effects of 5 alpha-dihydrotestosterone (DHT) on the transcription of nm23 and c-myc genes in human prostatic LNCaP cells. Biochem.Biophys.Res.Commun. 1995, 208:603-609. Organism:Department of Biochemistry & Molecular Biology, New York Medical College, Valhalla 10595. Abstract: Proliferation of the androgen-dependent human prostate LNCaP cells was increased by the androgen DHT. Changes in the steady state level of the nm23 and c-myc mRNA in LNCaP cells, with or without 10 nM DHT, showed the nm23 mRNA to change rapidly, beginning to rise after 2 h and reaching its peak by 4 h of DHT treatment. In contrast, increases in the c-myc gene only became apparent after 4 h of treatment. Maximal increase of nm23 mRNA was observed at 10(-9) M DHT. The basal expression of c-myc and nm23 mRNAs was between 30-70% lower in the LNCaP cells, as compared with the androgen-independent PC-3 and JCA-1 human prostatic human carcinoma cells. Thus nm23 may be classified as a member of the early androgen-responsive genes
ALBANI S, RAVELLI A, MASSA M, DE BENEDETTI F, ANDREE G, ROUDIER J, MARTINI A, CARSON DA: Immune responses to the Escherichia coli dnaJ heat shock protein in juvenile rheumatoid arthritis and their correlation with disease activity. J.Pediatr. 1994, 124:561-565. Organism:Department of Medicine, University of California, San Diego 92093-0663. Abstract: Patients with juvenile rheumatoid arthritis frequently have abnormal immune responses to the hsp65 class of bacterial heat shock proteins. However, lymphocytes from children with other inflammatory diseases may also recognize hsp65, and the role of these antigens in juvenile rheumatoid arthritis remains controversial. We have studied humoral and cellular immune responses to a distinct, recently described bacterial heat shock protein, designated dnaJ. The Escherichia coli dnaJ gene was cloned and expressed, and the purified recombinant protein was used as an antigen. Neither normal children nor children with various chronic inflammatory diseases had lymphocyte proliferative responses to recombinant dnaJ. However, lymphocytes from patients with polyarticular, pauciarticular, and systemic manifestations of juvenile rheumatoid arthritis responded strongly to the antigen. Cellular immune responses to dnaJ were higher in synovial fluid than in blood and higher in children with active disease than in children in remission. These data show that increased immune reactivity to dnaJ is characteristic of juvenile rheumatoid arthritis and that the magnitude of the immune response is linked to disease activity. The results suggest that an abnormal immune response to antigens on commensal gut bacteria may contribute to the generation of chronic inflammation in juvenile rheumatoid arthritis
BHETTAY E, MARTELL R, CREEMERS PC: Association of HLA-DR10 with juvenile chronic arthritis in South Africans of mixed ancestry. Tissue Antigens. 1994, 43:47-49. Organism:Department of Paediatrics and Child Health, Princess Alice Orthopaedic Hospital, Cape Town, South Africa.
CERNA M, VAVRINCOVA P, HAVELKA S: HLA and juvenile rheumatoid arthritis. Acta Univ Carol [Med] (Praha) 1994, 40:69-73. Organism:Institute for Clinical and Experimental Medicine, Prague, Czech Republic. Abstract: HLA class II analysis in a group of 153 Czech children with juvenile rheumatoid arthritis by PCR and oligonucleotide hybridization demonstrated associations with several alleles. DRB1*0801 (RR = 5.3, p < 0.005) and DRB1 * 11 (RR = 2.2, p < 0.01) including all subtypes were shown to be increased in the rheumatoid factor-negative group (N = 137). The same results were observed in Italy, England and Norway. In patients with the pauciarticular onset with conversion to polyarticular within 3 years, a statistically significant increase in DR2 (RR = 10.1, p < 0.00005), mostly due to DRB1*1501, was found. In the iridocyclitis and antinuclear factor groups, susceptibility to DRB1*1201 was observed. There was a striking decrease in DRB1*0701 (RR = 0.3, p < 0.00005) in all groups. There was neither an increase in DRB1*1301 or DPB1*0301 nor a decrease in DRB1*04, as reported from other studies in Texas and Norway. The rheumatoid factor-positive group with polyarticular onset (N = 13) was associated with DRB1*04 (RR = 7.1, p < 0.005), as observed in adults. DPB1*0201 was increased in the persistent pauciarticular group (RR = 3.7, p < 0.0005). DPB1*0402 was decreased in all pauciarticular groups with or without conversion (RR = 0.3, p < 0.005). Taken together, there are not only genetic differences and clinical heterogeneity in juvenile rheumatoid arthritis patients but, also, common predisposing factors Type: JOURNAL ARTICLE
CHARMLEY P, NEPOM BS, CONCANNON P: HLA and T cell receptor beta-chain DNA polymorphisms identify a distinct subset of patients with pauciarticular-onset juvenile rheumatoid arthritis. Arthritis Rheum. 1994, 37:695-701. Organism:Virginia Mason Research Center, Seattle, Washington 98101. Abstract: OBJECTIVE. To evaluate and extend upon a reported association of a T cell receptor (TCR) V beta coding region polymorphism with pauciarticular-onset juvenile rheumatoid arthritis (JRA). METHODS. TCR V beta 6.1 genotypes and haplotypes in JRA and control groups were determined by DNA amplification. RESULTS. Haplotypes of the V beta 6.1 gene which encode a nonfunctional form of V beta 6.1 were significantly associated with pauciarticular JRA in patients possessing the HLA-DQA1*0101 allele (P = 0.0073). CONCLUSION. A TCR V beta gene segment in the vicinity of V beta 6.1, possibly V beta 6.1, is apparently involved in the pathogenesis of pauciarticular-onset JRA in DQA1*0101-positive individuals
DONN RP, DAVIES EJ, HOLT PL, THOMSON W, OLLIER W: Increased frequency of TAP2B in early onset pauciarticular juvenile chronic arthritis. Ann.Rheum.Dis. 1994, 53:261-264. Abstract: 94263276 ARC/ERU, Manchester University, United Kingdom (ENGLAND) 0003-4967 ENGLISH 9409 INDEX MEDICUS OBJECTIVES--To determine whether polymorphisms of the TAP genes, which lie within the major histocompatibility complex (MHC), are associated with juvenile chronic arthritis (JCA). METHODS--Eighty five JCA patients and 166 white controls were typed for the TAP gene alleles using ARMS-PCR. The same populations were analysed for DRB1 and DPB1 alleles using PCR-SSO typing. RESULTS--TAP2B was increased in early onset pauciarticular JCA (EOPA-JCA) compared with controls (62% v 44% Odds ratio (OR) 2.1, 95% CI 0.9- 4.7). After allowing for the known linkage disequilibrium between TAP2B and DR1 the association of TAP2B and EOPA-JCA was maintained (OR 3.5, 95% CI 1.3- 9.7). HLA-DRB1*04 and TAP2D were found to be in linkage disequilibrium in both the control (delta 0.018 p < 0.05) and JCA patient groups (delta 0.021 p < 0.05). No linkage disequilibrium was found between the TAP and DPB1 alleles. CONCLUSIONS--The association between TAP2B and EOPA-JCA is a further indication of the heterogeneity which exists in this clinically defined subgroup of patients 0 (Carrier Proteins);0 (Histocompatibility Antigens Class II);0 (HLA- DP Antigens);0 (HLA-DPB1);0 (HLA-DR Antigens);128338-86-3 (HLA-DRB1); 145892-13-3 (Tap-2 protein)
FERNANDEZ-VINA M, FINK CW, STASTNY P: HLA associations in juvenile arthritis. Clin.Exp.Rheumatol. 1994, 12:205-214. Organism:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-8886. Abstract: This review of the current status of HLA associations in juvenile arthritis begins with a discussion of the terms used to identify these patients and an approach for their clinical classification. The authors suggest that seven different types should be identified on the basis of clinical features and associated immunogenetic factors and that each of them should be recognized and called by a separate name. Different combinations of patients have been included in the studies performed in different cities and this fact may explain some of the observed differences in HLA associations in various reports. Results from an on-going study in Dallas are compared with published reports from Prague, Cincinnati, and Houston. HLA alleles associated with susceptibility in pauciarticular patients include certain DR and DQ alleles, one DP allele (DPB1*0201) and one HLA class I allele (HLA-A*0201). Susceptibility for polyarticular onset disease was found by the authors to be uniquely associated with DPB1*0301. Important interactions were observed between alleles at the different loci, with markedly increased odds ratios when combinations of susceptibility alleles were analyzed. The possibility that interaction between class I and class II susceptibility factors might be due to the effect of an allele at one of the TAP loci was examined by probing for polymorphic variants of the TAP1 and TAP2 genes. In addition, class I alleles associated with resistance for the development of juvenile arthritis were discussed. The main allele associated with rheumatoid arthritis (DRB1*0401) appears to be protective for the development of several forms of arthritis prevalent in children
GROM AA, GIANNINI EH, GLASS DN: Juvenile rheumatoid arthritis and the trimolecular complex (HLA, T cell receptor, and antigen). Differences from rheumatoid arthritis. Arthritis Rheum. 1994, 37:601-607. Organism:University of Cincinnati School of Medicine, Children's Hospital Medical Center, Ohio 45229-2899.
MIYAZAKI T, KWON KW, YAMAMOTO K, TONE Y, IHARA H, KATO T, IKEDA H, SEKIGUCHI S: A human monoclonal antibody to high-frequency red cell antigen Jra. Vox Sang. 1994, 66:51-54. Organism:Hokkaido Red Cross Blood Center, Sapporo, Japan. Abstract: A human-mouse heterohybridoma (HMR0921) secreting human monoclonal IgG3, lambda antibody was produced from peripheral blood lymphocytes of a healthy blood donor with serum antibody to Jra, by EBV transformation and hybridization with mouse myeloma cell line P3X63Ag8.653. The reactivity of HMR0921 antibody was assessed by antiglobulin test with a panel of red cells including 14 different rare blood types. Only Jr(a-) red cells were negative. The strict specificity of this antibody to Jra antigen was further confirmed by absorption test with fluorescence flow cytometry. On screening of 28,744 blood donor samples by HMR0921 antibody, we detected 19 agglutination-negative samples, which were confirmed as Jr(a-) by conventional anti-Jra antisera. Therefore, our HMR0921 antibody is extremely useful for detecting rare Jr(a-) blood
PAUL C, HAAS JP, SCHOENWALD U, TRUCKENBRODT H, BETTINOTTI MP, BONISCH J, BRUNNLER G, KELLER E, NEVINNY STICKEL C, YAO Z, ET AL: HLA class I/class II interaction in early onset pauciarticular juvenile chronic arthritis. Immunogenetics 1994, 39:61-64. Organism:Immunogenetics Laboratory, University of Munich, Germany.
PLOSKI R, FORRE O: Non-HLA genes and susceptibility to juvenile chronic arthritis. Clin.Exp.Rheumatol. 1994, 12 Suppl 10:S15-7. Organism:Institute of Transplantation Immunology, National Hospital, Oslo, Norway. Abstract: Recent studies addressing the possible role of tap, lmp2, t-cell receptor and il1alpha genetic polymorphism in predisposing to juvenile chronic arthritis ar reviewed
PLOSKI R, UNDLIEN DE, VINJE O, FORRE O, THORSBY E, RONNINGEN KS: Polymorphism of human major histocompatibility complex-encoded transporter associated with antigen processing (TAP) genes and susceptibility to juvenile rheumatoid arthritis. Hum.Immunol. 1994, 39:54-60. Organism:Institute of Transplantation Immunology, National Hospital, Oslo, Norway. Abstract: The TAP1 and TAP2 genes encode a peptide transporter supplying peptides for binding to HLA class I molecules. Both genes are located in the class II region of the HLA complex and are polymorphic. Here we report the distribution of TAP alleles in a group of 285 JRA patients (including various subsets), 165 random controls, and 82 DR8-positive controls. We found a pronounced increase of TAP1B and TAP2C/D in patients, compared with controls. The difference was, however, mainly secondary to a strong linkage disequilibrium between these TAP alleles and DR8, which is significantly increased in JRA. When we compared patients and controls after stratification for DR8 the differences decreased, although an increase of TAP1B in DR8- negative patients remained significant. We conclude that a primary association of JRA with given TAP allels cannot explain the HLA class II associations in JRA. However, we cannot exclude the possibility that TAP1B acts as an additive susceptibility factor in JRA
REZAI-DELUI H, MAMOORI G, SADRI-MAHVELATI E, NOORI NM: Progressive pseudorheumatoid chondrodysplasia: a report of nine cases in three families. Skeletal.Radiol. 1994, 23:411-419. Organism: Department of Radiology, Mashad University, Ghaen Hospital, IranPMID- 7992106 Abstract: Nine cases of progressive pseudorheumatoid chondrodysplasia in subjects aged 7-60 years are reported. Six of them were members of one large family with several consanguineous marriages. Evaluation of six generations of this family suggested an autosomal recessive mode of inheritance. The presentation of the disease was between the ages of 3 and 8 years with waddling gait and fusiform swelling of the interphalangeal joints of the hands, clinically resembling juvenile rheumatoid arthritis. Most of the other joints become progressively involved, with crippling disability. One of the patients had typical features of Blount disease at presentation
WANG XH, WHYZMUZIS CA, AN S, CHEN Y, WU JM, SCHNEIDAU TA, MALLOUH C, TAZAKI H: Regulation of cell growth and the c-myc proto-oncogene expression by phorbol ester 12-0-tetradecanoyl phorbol-13-acetate (TPA) in the androgen-independent human prostatic JCA-1 cells. Biochem.Mol.Biol.Int. 1994, 34:47-53. Organism:Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla 10595. Abstract: The proliferation of the human prostatic cancer JCA-1 cells showed a complex response to different concentrations of TPA. Whereas cells exposed for 24 h had growth reduction which was proportional to the concentration of TPA added to the culture media, they showed resistance to low (0.016 and 0.16 nM) but not high (> or = 1.6 nM) doses of TPA after 72 h. Growth-inhibited, treated cells also displayed a distinct cell morphology compared with the controls. Since c-myc expression has previously been shown to be correlated with cellular proliferation, we determined changes in its steady-state level in control and treated cells by Northern analysis. Following a 24h, 48h, and 72h treatment, with 16 nM TPA, c-myc mRNA was suppressed by 91%, 83%, and 78%, respectively, in good agreement with the extent of growth reduction observed. At the low dose of TPA (0.16 nM), however, the c-myc mRNA expression remained inhibited by 85% even though cell growth was only reduced by 10-14%. No difference in the total amount of c-myc protein could be detected between control and treated cells by Western analysis
BERNSTEIN BH, MILTENBURG AM, VAN LAAR JM, HERTZBERGER R, BREEDVELD FC: T cell receptor rearrangements in juvenile rheumatoid arthritis: a search for oligoclonality. Clin.Exp.Rheumatol. 1993, 11:209-213. Organism:Division of Rheumatology, Childrens Hospital Los Angeles, CA 90027. Abstract: Southern blot analysis of DNA from paired samples of synovial compartment (membrane and/or fluid) and peripheral blood T cells from nine children with juvenile rheumatoid arthritis (JRA) was carried out. Using a T cell receptor C beta probe, dominant TCR rearrangements were discovered in specimens from three patients: synovial fluid T cells from one, synovial fluid and synovial membrane cells from a second, and synovial membrane and peripheral blood cells from a third. The patient showing dominant bands in peripheral blood as well as in synovium was the only child in the series with systemic disease. Since non-specific T cell recruitment is likely to dilute antigen specific clones to low levels, the finding of dominant rearrangements in three of nine patients may indicate that oligoclonality is indeed a feature of JRA
BRUNNER HI, IVASKOVA E, HAAS JP, ANDREAS A, KELLER E, HOZA J, HAVELKA S, SCHOLZ S, SIERP G, ALBERT ED: Class I associations and frequencies of class II HLA-DRB alleles by RFLP analysis in children with rheumatoid-factor-negative juvenile chronic arthritis. Rheumatol.Int. 1993, 13:83-88. Abstract: 93361906 Labor fur Immungenetik, Kinderpoliklinik der LMU Munchen, Germany (GERMANY) 0172-8172 ENGLISH 9311 INDEX MEDICUS A total of 94 patients with juvenile chronic arthritis (JCA) was tested for HLA class I by serology and for class II by RFLP typing. Early onset JCA (EOPA) is associated with HLA-A2, DR5 and DR8 in both males and females. The combination (joint occurrence) of these JCA associated alleles (A2, DR5, DR8) is frequently seen in patients with chronic iridocyclitis. Late onset pauciarticular disease has an increased frequency of HLA-B27, especially in males. Our data confirm that polyarticular JCA with early childhood onset (< or = 4 years) is associated with DR5 and DR8 and has a different immunogenetic background from polyarticular JCA with later childhood (> 4 years) onset (associated with DR4) 0 (Histocompatibility Antigens Class I);0 (HLA-A Antigens);0 (HLA-B Antigens);0 (HLA-B27 Antigen);0 (HLA-DR Antigens);9007-49- 2 (DNA); 9009-79-4 (Rheumatoid Factor)
DE INOCENCIO J, GIANNINI EH, GLASS DN: Can genetic markers contribute to the classification of juvenile rheumatoid arthritis?J.Rheumatol.Suppl. 1993, 40:12-18. Organism:Children's Hospital Medical Center, Division of Rheumatology, Cincinnati, OH 45229.
FORRE O, SIOUD M: T cell receptor variable region gene usage in juvenile chronic arthritis. Clin.Exp.Rheumatol. 1993, 11 Suppl 9:S43-6. Organism:Oslo Sanitetsforenings Rheumatism Hospital, Norway. Abstract: Up to now the data regarding T cell receptor V-gene usage by juvenile chronic arthritis synovial T lymphocytes has been conflicting. Thus, some studies claim that locally in the diseased joint there is an oligoclonal expansion of T cells with restricted T cell receptor variable region gene usage while others have found V-gene usage in the joint compatible with a polyclonal expansion of the T cells
GROM AA, THOMPSON SD, LUYRINK L, PASSO M, CHOI E, GLASS DN: Dominant T-cell-receptor beta chain variable region V beta 14+ clones in juvenile rheumatoid arthritis. Proc.Natl.Acad.Sci.U.S.A. 1993, 90:11104-11108. Organism:Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, OH 45229-3039. Abstract: The characteristic histopathology and major histocompatibility complex associations in juvenile rheumatoid arthritis suggest an oligoclonal antigen-specific T-cell population may be critical to pathogenesis. To test this, we analyzed the T-cell repertoire of a polyarticular HLA-DR4+ juvenile rheumatoid arthritis patient with an aggressive form of disease that required arthrocentesis of the knee joints and early replacement of both hip joints. A comparison of T-cell-receptor beta chain variable region (V beta) gene expression in peripheral blood and synovial fluid performed by semiquantitation of cDNA samples amplified by the PCR revealed overexpression of the T-cell-receptor V beta 14 gene family. To determine the nature of V beta 14 overexpression, we sequenced randomly cloned amplification products derived from two synovial fluid, two synovial tissue, and three peripheral blood samples by using a V beta 14/beta chain constant region primer pair. Sequence data showed that the T-cell response in the synovia was oligoclonal. Of four clones found, one was present in all joints examined and persisted over time. This clone accounted for 67% and 74% of all V beta 14+ clones sequenced in two synovial fluid samples and 75% and 40% in two synovial tissue samples. This clone was also found at a lesser frequency in peripheral blood samples. Further studies provided evidence for the presence of oligoclonally expanded populations of T cells utilizing the V beta 14 T-cell receptor in 6 of 27 patients examined. In contrast to the remaining patients studied, 3 with a late onset polyarticular course who exhibited especially marked clonality were characterized by features typical of adult rheumatoid arthritis (IgM rheumatoid factor-positive and HLA-DR4+). These data suggest a role for V beta 14+ T cells in a group of juvenile rheumatoid arthritis patients
HORNEFF G, HANSON M, WAHN V: T-cell receptor V beta chain expression in patients with juvenile rheumatoid arthritis. Rheumatol.Int. 1993, 12:221-226. Organism:Department of Pediatrics, University of Dusseldorf, Germany. Abstract: The V beta chain repertoire in peripheral blood T-cell was analyzed in 23 patients with juvenile rheumatoid arthritis (JRA). Of these, 15 patients had active disease as defined by tender and swollen joints. The ESR was elevated in all but three patients, C- reactive protein (CRP) was elevated in eight. Three patients were investigated during active and inactive phases of the disease. In the active phase of the disease T-cell composition was characterized by an increased number of CD4+ helper cells due to a marked increase in the CD4+CD45RA+ subgroup (34.0 +/- 10.9%, P < 0.001) and a decrease in CD8+CD29+ T-cells (10.3 +/- 5.6%, P < 0.05) compared to controls (15.4 +/- 10.0% and 17.8 +/- 12.3%, respectively). Using the monoclonal antibodies available to determine T-cell receptor (TCR) expression, patients with active disease demonstrated a significant predominance of T-cells bearing TCRs of the V beta 5 family as determined by flow cytometry (7.6 +/- 6.7 vs 3.4 +/- 1.3 in controls, P = 0.01). In active polyarthritis, up to 24% of peripheral blood T-cells expressed TCRs of the same family. In the majority of JRA patients and especially in non-active disease, no preferential TCRs were found compared to controls. However, even defining only a part of TCRs by immunofluorescence, in certain patients a preferential or dominant expression of a single V beta gene family in the T-cells was found, supporting the concept of an involvement of T-cells in the autoimmune pathogenesis of JRA
LUYRINK L, GABRIEL CA, THOMPSON SD, GROM AA, MAKSYMOWYCH WP, CHOI E, GLASS DN: Reduced expression of a human V beta 6.1 T-cell receptor allele. Proc.Natl.Acad.Sci.U.S.A. 1993, 90:4369-4373. Organism:Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, OH 45229-2899. Abstract: We have previously described an allelic polymorphism in the V beta 6.1 T-cell receptor gene. The V beta 6.1B allele is associated with disease in a subgroup of patients with juvenile rheumatoid arthritis. Limited sequence data demonstrated nucleotide differences that resulted in two amino acid changes between the two alleles in positions predicted to be important in major histocompatibility complex/antigen recognition. The present study demonstrates substantially reduced expression of mRNA from the disease-associated allele (V beta 6.1B) in peripheral blood and thymic tissue. The complete genomic sequence of both alleles revealed two additional amino acid changes in the V beta 6.1B gene as well as nucleotide differences in the promoter and intron. A cysteine-to-arginine substitution at position 92 in the disease-associated allele makes this a non-functional beta chain, since this conserved cysteine is involved with disulfide bonding to cysteine-23 to form an immunoglobulin-like domain structure, thus resulting in a potential hole in the T-cell receptor repertoire
OBATA F: Genetic polymorphism of HLA-DR in the Japanese population. Kitasato.Arch.Exp.Med. 1993, 65 Suppl:13-24. Organism:Department of Immunology, School of Medicine, Kitasato University, Kanagawa, Japan. Abstract: As a result of carrying out sequence analyses on the HLA-DR genes of several Japanese donors, we found three new DRB1 alleles, DRB1-12b, DRB1-14c, and DRB1-JX6, that had not been identified using immunological procedures. Sequence-specific oligonucleotide (SSO) probes directed against various DRB1 alleles, including the above three, enabled DNA typing of all the DRB types in the Japanese population and calculation of their gene frequencies based on this typing to be carried out for the first time. The SSO-DNA typing yielded higher DR13 and DR14 gene frequencies than those reported by serological workshops. Next, we applied this DR- DNA typing to the analysis of Japanese patients with juvenile rheumatoid arthritis (JRA) and found that DRB1*0405 was the allele susceptible to rheumatoid factor-positive polyarticular JRA, which is one of the four types of JRA that has been classified clinically. Analysis of the DR types of patients who suffered unexplained recurrent spontaneous abortion (URSA) using DNA typing demonstrated that 1) URSA is not correlated with any particular DR type and 2) no difference between the DR sharing rate of patients and normal couple was detected, which contradicts the results obtained in some serological studies
OKUBO H, ITOU K, TANAKA S, WATANABE N, KASHIWAGI N, OBATA F: Analysis of the HLA-DR gene frequencies in Japanese cases of juveniles rheumatoid arthritis and rheumatoid arthritis by oligonucleotide DNA typing. Rheumatol.Int. 1993, 13:65-69. Organism:Department of Pediatrics, Kyorin University School of Medicine, Tokyo, Japan. Abstract: HLA-DR gene frequencies in 59 Japanese children with juvenile rheumatoid arthritis (JRA) and 62 Japanese adults with rheumatoid arthritis (RA) were analyzed by oligonucleotide DNA typing. As in other studies, the frequency of DRB1*0405 in RA patients was significantly higher than in the Japanese controls. In a comparison of non-classified JRA patients with Japanese controls, no significant differences were observed in the frequency of DR types. However, when the JRA patients were classified into four clinical types, i.e., a rheumatoid factor-positive [RF(+)] polyarticular type, a rheumatoid factor-negative [RF(-)] polyarticular type, a pauciarticular type, and a systemic onset type, DRB1*0405 was found to be significantly higher in the RF(+) polyarticular JRA patients than in the controls (P < 0.05). Thus, the RF(+) polyarticular type of JRA had the same HLA association as RA. This result is consistent with the fact that both RF(+) polyarticular JRA and RA cases have a similar clinical course
OXELIUS VA, SVANTESSON H, CARLSSON AM: Gm phenotype linkage to subsets of juvenile chronic arthritis (JCA) with influence on IgG subclass response. Scand.J.Rheumatol. 1993, 22:284-288. Abstract: 94090262 Department of Pediatrics, University Hospital, University of Lund, Sweden (SWEDEN) 0300-9742 ENGLISH 9403 INDEX MEDICUS The serum hyper IgG of 76 JCA patients of different clinical subsets, 8 systemic, 37 polyarticular and 31 oligoarticular, were investigated by IgG subclass quantitation and Gm allotype determination. The well known increased serum IgG in JCA was confirmed as increased IgG1, IgG2 and IgG3 in the whole group. Investigating the clinical subsets IgG1 was significantly increased in all subsets while IgG2 and IgG3 increased only in the polyarticular form. In search of a genetic linkage for the clinical JCA subsets and the different IgG subclass patterns found, the alternative Gm allotypes G1m(a), G1m(f) for IgG1, G2m(n), G2m(") for IgG2 and G3m(g) , G3m(b) for IgG3 gene loci were investigated. The Gm (a,",g) haplotype was significantly increased in the whole JCA group and in the polyarticular subset. In the systemic subset the Gm (a,",g/a",g) phenotype was significantly increased, but the Gm (a,'h,g/f,n,b) phenotype was increased in the oligoarticular subset. The number of JCA patients with G1m(f,f)- ,G3m(b,b)-phenotypes were significantly decreased. In such phenotypes, remission was more common. The susceptibility of JCA, its different clinical subsets and outcome of the disease is determined by Gm allotypes, affecting characteristic IgG subclass patterns 0 (IgG);0 (Immunoglobulin Gm Allotypes)
PAUL C, SCHOENWALD U, TRUCKENBRODT H, BETTINOTTI MP, BRUNNLER G, KELLER E, NEVINNY-STICKEL C, YAO Z, ALBERT ED: HLA-DP/DR interaction in early onset pauciarticular juvenile chronic arthritis. Immunogenetics 1993, 37:442-448. Abstract: 93170891 Immunogenetics Laboratory, University of Munich, Germany (UNITED STATES) 0093-7711 ENGLISH 9305 INDEX MEDICUS We investigated the polymorphic second exon of the HLA-DPB1 and HLA-DRB1 genes, using in vitro DNA amplification by polymerase chain reaction (PCR) and oligonucleotide hybridization in 136 patients with early onset pauciarticular juvenile chronic arthritis (EOPA-JCA) and 199 healthy controls. The analysis of the HLA-DRB1 system revealed that most of the DRB1 alleles are not indifferent with respect to susceptibility to EOPA-JCA. There is a hierarchy of susceptible (DRB1*08, DR5), "permissive" (DRB1*01), moderately "protective" (DR2, DRB1*04), and "protective" (DRB1*07) alleles. In contrast, no hierarchy could be shown for the HLA-DPB1 system. DPB1*0201 was found to be susceptible. The relatively frequent alleles DPB1*0402 and DPB1*0401 seem to be indifferent. The associations with DPB1*0201, DR5, and DRB1*08 are independent of each other: that is to say they, are not brought about by linkage disequilibrium. The susceptible alleles DPB1*0201 and DR5 show evidence for interaction in the pathogenesis of EOPA-JCA. Interaction seems likely between DPB1*0201 and DRB1*08, DR5 and DRB1*08, or between DR6 and DRB1*08. The strongest interaction exists between DPB1*0201 and a common DQ factor associated with both DR5 and DRB1*08. Finally, we observed a hierarchy among the various marker combinations, where the risk of developing EOPA-JCA increases with the number of associated markers present in an individual 0 (HLA-DP Antigens);0 (HLA-DR Antigens);0 (Oligodeoxyribonucleotides)
PLOSKI R, HANSEN T, FORRE O: Lack of association with T-cell receptor TCRBV6S1*2 allele in HLA-DQA1*0101-positive Norwegian juvenile chronic arthritis patients. Immunogenetics 1993, 38:444-445. Organism:Institute of Transplantation Immunology, University of Oslo, Norway.
REGUEIRO JR, ARNAIZ VILLENA A, VICARIO JL, MARTINEZ LASO J, PACHECO A, RIVERA GUZMAN JM: A decrease in the estimated frequency of the extended HLA haplotype B18 CF130 DR3 DQw2 is common to non-insulin-dependent diabetes, juvenile rheumatoid arthritis, and Berger's disease. Experientia 1993, 49:553-556. Organism:Hospital 12 de Octubre, Facultad de Medicina, Universidad Complutense, Madrid, Spain. Abstract: Extended HLA haplotypes frequencies were estimated from the HLA, C2, Bf and C4 phenotypes of 74 patients with non-insulin- dependent diabetes (NIDD), 92 with juvenile rheumatoid arthritis (JRA), 44 with Berger's disease (BD), 83 with insulin-dependent diabetes (IDD), and 140 healthy controls. The extended HLA haplotype B18 CF130 DR3 DQw2, which is common (around 10% phenotype frequency) in healthy Spaniards and in other populations of paleo-North African origin, was found to be significantly less frequent in NIDD, JRA and BD, whereas its frequency was normal in IDD (although DR3 DQw2 haplotypes were increased in the latter disease). These data support the existence of a common HLA-linked pathogeneic mechanism in NIDD, JRA and BD, and point to a genetic difference between IDD and NIDD at the HLA level. This effect is readily detectable in our population because the uncommon BfF1 allele marks that haplotype instead of the more common BfS, which marks B8 CS01 DR3 DQw2 in other Caucasians. Our results support the hypothesis of strong selective pressures operating at the HLA level to preserve extended HLA haplotypes with advantageous gene sets from dilution by crossing-over. Imbalanced incomplete haplotypes may give rise to inappropriate T-cell repertoire selection in the thymus and/or antigen handling in the periphery, and be partly responsible for the pathogenesis of certain HLA-linked diseases (i.e. NIDD, JRA, and BD)
SCHOLZ S, ALBERT ED: Immunogenetic aspects of juvenile chronic arthritis. Clin.Exp.Rheumatol. 1993, 11 Suppl 9:S37-41. Abstract: 93358554 Labor fur Immungenetik, Kinderpoliklinik der LMU Munchen, FRG (ITALY) 0392-856X ENGLISH 9311 INDEX MEDICUS The HLA associations of Juvenile Chronic Arthritis are reviewed in the light of the newest results. The most convincing data are available about the early onset pauciarticular Juvenile Chronic Arthritis (EOPA-JCA), where there are highly significant associations with 3 different regions of the HLA system: the HLA- A locus (HLA-A2), the HLA-DR/DQ region (HLA-DR5 and DR8 haplotypes) and the DP region (DPB1*0201). All these associations are independent of each other and not brought about by linkage disequilibrium. There are significant interactions between the associated alleles DPB1*0201 and DR5 haplotypes, DPB1*0201 and DR8 haplotypes as well as between A2 and DR5 and DR8 haplotypes, and between A2 and DPB1*0201. The association with the DR/DQ haplotypes reveal that most likely the DQA1 gene locus is primarily associated with JCA. There is a common motif which is present on all susceptible DQA1 alleles (0401, 0501, 0601) and not present on all the others (12). Taking all these information together, the following hypothesis is proposed: the observed HLA associations are a reflection of the direct involvement of the HLA genes in pathogenesis. The normal function of HLA molecules, namely the presentation of peptides of the T- cell receptor, is assumed to be a key mechanism in pathogenesis where an arthritogenic peptide is specifically bound by the DQ molecules, with binding specificity determined by the common motive on the DQA chain. It is possible that some of the arthritogenic peptides may be derived from self- histocompatibility antigens such as HLA- A2 and/or DPB1*0201 0 (HLA-DP Antigens);0 (HLA-DQ Antigens);0 (HLA-DR Antigens)
TANG AT, LAU YL, JONES B, HALPERN GM, YEUNG CY: Cefadroxil reduces the production of IgE in a 3 year old asthmatic with juvenile rheumatoid arthritis. Allergol.Immunopathol.Madr. 1993, 21:131-135. Organism:Department of Pediatrics, University of Hong Hong. Abstract: Cefadroxil, a cephalosporin, had been prescribed to children with superinfected atopic dermatitis, and was shown to improve both the infection, the clinical status and induced a dramatic lowering of the serum total IgE levels. Further studies have confirmed the IgE immunomodulating properties of cefadroxil. We report the case of a 3 year old asthmatic child who was hospitalized for superimposed pneumonia and was included in a study evaluating cefadroxil. The child was also suffering of juvenile rheumatoid arthritis. After treatment with cefadroxil and oral salbutamol, the child fully recovered. The initially elevated serum IgE (day 1:556 IU/ml) dropped to normal values (day 21: 52 IU/ml), while the production of IgE in vitro by peripheral blood B cells was normalized. We suggest that one mechanism of action of cefadroxil is the stimulation of production of gamma interferon in patients with atopic disorders; this mechanism interferes with the IL-4 primary signal, as well as with other second signals recognized for the synthesis of IgE. Gamma interferon may also prove beneficial for the control of juvenile rheumatoid arthritis
WALLACE CA, SHERRY DD, MELLINS ED, AIKEN RP: Predicting remission in juvenile rheumatoid arthritis with methotrexate treatment. J.Rheumatol. 1993, 20:118-122. Organism:Department of Pediatrics, University of Washington, Seattle. Abstract: Forty-nine children with a polyarticular course of juvenile rheumatoid arthritis treated with methotrexate (MTX) for at least one year were analyzed to identify clinical characteristics that would predict remission of arthritis after MTX treatment. Twenty- two children (45%) had remission of arthritis after a mean of 13.6 months of treatment and did not differ from the 27 with persistently active arthritis regarding years of disease before starting MTX, age starting MTX, maximum MTX dose, disease onset type, presence of radiographic joint destruction, concomitant treatment with hydroxychloroquine, sulfasalazine or prednisone, or presence of rheumatoid factor or antinuclear antibodies. Higher dose MTX, earlier treatment, genetic markers, and a standardized route of therapy may yield important information in future studies
WOO P: Cytokines in childhood rheumatic diseases. Arch.Dis.Child 1993, 69:547-549. Organism:Section of Molecular Rheumatology, Clinical Research Centre, Harrow, Middlesex.
BIRO J, BALOGH Z, SZONGOTH M, MEGYERI A, BELY M, FALUS A: [Molecular genetic, laboratory and clinical study of serum amyloid P] Szerum amiloid P molekularis genetikai, laboratoriumi es klinikai vizsgalata. Orv.Hetil. 1992, 133:841-845. Organism:Orszagos Reumatologiai Intezet, Budapest. Abstract: Studying the gene polymorphism of serum amyloid P a common constituent of amyloid deposits two restriction fragment length polymorphism patterns were found among Hungarian rheumatoid arthritis (RA), juvenile rheumatoid arthritis (JRA), systemic lupus erythematosus (SLE) patients and healthy controls. Although no direct connection between DNA polymorphism and the frequency of amyloidosis in three patient groups was found, a marked predominance of the heterozygosity in all studied groups has been described. Authors found close correlation between the serum levels of SAP and CRP in juvenile rheumatoid arthritis, but failed to find the same correlation in SLE and healthy controls. Moreover, the serum level of CRP of heterozygous patients were significantly higher than that of homozygous patients within the juvenile rheumatoid arthritis patient groups
LANGEVITZ P, BANK I, ZEMER D, BOOK M, PRAS M: Treatment of resistant rheumatoid arthritis with minocycline: an open study [see comments]. J.Rheumatol. 1992, 19:1502-1504. Organism:Department of Medicine F, Chaim Sheba Medical Center, Tel-Hashomer, Israel. Abstract: In a 48-week open trial, 18 patients with active rheumatoid arthritis (RA), resistant to second line agents, received 200 mg minocycline daily. Twelve patients completed 48 weeks of therapy. Statistically significant improvement was noted in almost all variables of disease activity. Three patients discontinued therapy because of lack of improvement, 2 patients because of side effects and one patient was lost to followup. Cytofluorographic analysis revealed a significant decrease in expression of a T cell activation antigen (gp 26). Our data suggest that minocycline could be a useful therapeutic agent in RA
LEWKONIA RM, BECH HANSEN NT: Spondyloepiphyseal dysplasia tarda simulating juvenile arthritis: clinical and molecular genetic observations. Clin.Exp.Rheumatol. 1992, 10:411-414. Organism:Department of Pediatrics, University of Calgary, Canada. Abstract: A sibship is reported in which two of three children developed a symmetrical polyarthropathy associated with a mild spondyloepiphyseal dysplasia. Although the physical findings resembled juvenile arthritis, laboratory investigations for inflammatory disease were entirely negative. Molecular studies in members of this family showed that none of them had any structural rearrangements or other major abnormality of the type II procollagen gene (COL2A1). The laboratory findings in this family with "pseudo-rheumatoid arthritis" do not exclude the possibility of a minor mutation of the type II procollagen gene or a defect in the processing of articular cartilage collagens
MAKSYMOWYCH WP, GABRIEL CA, LUYRINK L, MELIN ALDANA H, ELMA M, GIANNINI EH, LOVELL DJ, VAN KERCKHOVE C, LEIDEN J, CHOI E, ET AL: Polymorphism in a T-cell receptor variable gene is associated with susceptibility to a juvenile rheumatoid arthritis subset. Immunogenetics 1992, 35:257-262. Organism:Department of Pediatrics, College of Medicine, University of Cincinnati, OH 45229. Abstract: This report demonstrates a T-cell receptor (Tcr) restriction fragment length polymorphism, defined by a Tcrb-V6.1 gene probe and Bgl II restriction enzyme, to be absolutely correlated with allelic variation in the coding sequence of a Tcrb-V6.1 gene. A pair of non-conservative amino acid substitutions distinguish the Tcrb-V6.1 allelic variants. An association of this Tcrb-V6.1 gene allelic variant with one form of juvenile rheumatoid arthritis (JRA) was established in a cohort of 126 patients. The association was observed in patients possessing the HLA-DQA1*0101 gene. Among HLA-DQA*0101 individuals, 19 of 26 patients (73.1%) carried one particular Tcrb-V6.1 gene allele as opposed to 11 of 33 controls (33%; p less than 0.005). Haplotypes carrying this HLA gene have previously been shown to confer increased risk for progression of arthritis in JRA. This demonstration of a disease- associated Tcrb-V gene allelic variant has not, to our knowledge, been previously reported and supports the contribution of polymorphism in the Tcr variable region genomic repertoire to human autoimmune disease
MALAGON C, VAN KERCKHOVE C, GIANNINI EH, TAYLOR J, LOVELL DJ, LEVINSON JE, PASSO MH, GINSBERG J, BURKE MJ, GLASS DN: The iridocyclitis of early onset pauciarticular juvenile rheumatoid arthritis: outcome in immunogenetically characterized patients. J.Rheumatol. 1992, 19:160-163. Organism:Children's Hospital Medical Center, Cincinnati, OH 45229-2899. Abstract: In a cohort of 72 patients with iridocyclitis (iritis) and early onset pauciarticular juvenile rheumatoid arthritis (EOPA-JRA) the course of the eye disease was matched with ocular outcome. Chronicity of inflammation (greater than 6 months/episode) was correlated with complications of eye disease that caused impairment of vision. HLA antigens in these patients were compared with the HLA antigens in a cohort of 77 patients with EOPA-JRA in whom iridocyclitis had failed to develop over a followup of 5 years or longer. HLA-DR5 (11) was correlated with the presence of eye disease, and HLA-DR1 with its absence; HLA- DRw8, which strongly predisposes to EOPA-JRA, was neutral with respect to eye disease
MELIN ALDANA H, GIANNINI EH, TAYLOR J, LOVELL DJ, LEVINSON JE, PASSO MH, GINSBERG J, BURKE MJ, GLASS DN: Human leukocyte antigen-DRB1*1104 in the chronic iridocyclitis of pauciarticular juvenile rheumatoid arthritis. J.Pediatr. 1992, 121:56-60. Organism:Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, Ohio 45229. Abstract: To determine whether genetic markers for chronic iridocyclitis could be identified, we used both serologic and oligonucleotide dot blot techniques to characterize immunogenetically 164 children with early-onset pauciarticular juvenile rheumatoid arthritis. Seventy-eight children (47.6%) had chronic iridocyclitis and 86 (52.4%) had not had evidence of eye disease during a mean follow-up period after the onset of arthritis of 15.8 years (minimum of 5.5 years). Control subjects were 218 healthy, unrelated individuals. The analysis was limited to alleles known to be associated with an increased or decreased risk of early-onset pauciarticular juvenile rheumatoid arthritis or of chronic iridocyclitis in this form of juvenile rheumatoid arthritis. Only one split of human leukocyte antigen (HLA)-DR5, HLA-DRB1* 1104, showed a statistically significant association with a risk of chronic iridocyclitis (chi-square value = 7.52; p = 0.036 adjusted; odds ratio 3.45); HLA-DQA1* 0501 and HLA-DQB1* 0301, both in linkage disequilibrium with HLA-DRB1* 1104, also were significantly associated with eye disease. Patients with both the DRB1* 1104 and DPB1* 0201 genes had a 7.7-fold increased risk for chronic iridocyclitis compared with that for other patients. The presence of HLA-DRB1* 1104 was about four times as specific, but only about one third as sensitive, as antinuclear antibodies in identifying patients at risk for eye disease. Although all children with early-onset pauciarticular juvenile rheumatoid arthritis should undergo periodic slit-lamp examinations, those with the HLA class II gene DRB1* 1104 are at particularly high risk for eye disease, and we recommend that they be monitored carefully for its evolution
NEPOM BS, GLASS DN: Juvenile rheumatoid arthritis and HLA: report of the Park City III workshop. J.Rheumatol.Suppl. 1992, 33:70-74. Organism:Virginia Mason Research Center, Department of Pediatrics, University of Washington School of Medicine, Seattle. Abstract: The workshop held during the Park City Meeting was directed toward developing a consensus about HLA associations in juvenile rheumatoid arthritis (JRA). Most agreement was achieved in pauciarticular JRA where the strongest associations were with the HLA-DRB1 alleles as is also the case in IgM rheumatoid factor positive polyarticular disease. In addition, HLA-DP associations are being identified although roles for linked genes are still possible. The critical nucleotides among HLA genes are not known; however, disease specific mutations have not been shown
SHCHERBAKOVA MI, KUZ'MINA NN, MALINOVSKAIA VV, GEVORKIAN MG: [The use of interferon in the combined therapy of juvenile rheumatoid arthritis] Ispol'zovanie interferona v kompleksnoi terapii iuvenil'nogo revmatoidnogo artrita. Ter.Arkh. 1992, 64:36-40. Abstract: The efficacy of recombinant gene engineering alpha 2-interferon (reaferon) was studied and compared in 60 patients suffering from verified juvenile rheumatoid arthritis (JRA). Reaferon was shown to possess good tolerance and to produce an adequate therapeutic effect. The combined use of reaferon and methotrexate permits potentiating the therapeutic effect of interferon and avoiding side effects seen with methotrexate used alone. Besides, it makes it possible to reduce the incidence of respiratory infections which are often associated with exacerbation of the underlying disease when treated by conventional methods
SIOUD M, KJELDSEN KRAGH J, SULEYMAN S, VINJE O, NATVIG JB, FORRE O: Limited heterogeneity of T cell receptor variable region gene usage in juvenile rheumatoid arthritis synovial T cells. Eur.J.Immunol. 1992, 22:2413-2418. Organism:Institute of Immunology and Rheumatology, National Hospital, Oslo, Norway. Abstract: The aim of this study was to determine whether synovial fluid (SF) T cells in patients with juvenile rheumatoid arthritis (JRA) are restricted in their T cell receptor (TcR) gene repertoire. The quantitative polymerase chain reaction (QPCR) was used to compare the transcription of V beta and V alpha gene families in freshly isolated SF T cells, in interleukin-2 receptor-positive (IL-2R+) T cells and in peripheral blood (PB) T cells from 18 patients. Significantly less V beta families are detected in SF when compared with PB (p greater than 0.0003). The TcR V beta gene usage by IL-2R+ T cells was even less heterogeneous when compared with freshly isolated SF T cells (p greater than 0.0002). Freshly isolated SF T cells from the left and the right knees of four patients transcribed the same V beta families. Furthermore, we demonstrate that in SF the distribution of certain TcR V beta gene segments in CD4+ and CD8+ T cells differed from that in PB of the same patient. The TcR V alpha usage was studied in IL-2R+ T cells from six patients who had shown restriction in their SF TcR V beta gene usage. Only two to five TcR alpha transcripts were detected in three of these patients while a broad TcR V alpha usage was seen in the other three patients. Sequence analysis of the SF V beta 20 cDNA clones generated from the IL-2R+ T cells of two patients demonstrated an oligoclonal expansion. Taken together, our data could indicate an antigen- and/or superantigen-driven expansion of selected T cells in the synovial compartment
TUCKER LB: Heritable disorders of connective tissue and disability and chronic disease in childhood. Curr.Opin.Rheumatol. 1992, 4:731-740. Organism:Floating Hospital for Infants and Children, Boston, Massachusetts. Abstract: The heritable disorders of connective tissue encompass a broad range of diseases, many of which occur in childhood and present to the pediatric rheumatologist's attention. The underlying theme of these disorders is fragility of connective tissue components such as bone, cartilage, and blood vessels. Over the past few years, investigations of patients with the major forms of heritable disorders of connective tissue, osteogenesis imperfecta, Marfan syndrome, and Ehlers-Danlos syndrome have revealed genetic mutations of collagen genes as the cause of the diseases. Review of the newest genetic information in these three disorders is presented. The rheumatic disorders of childhood present a paradigm for the effects of chronic disease on children and families. New work, discussed in this review, continues to suggest changes in psychosocial adaptation in children with chronic rheumatic diseases and their families, but these data are conflicting. The development of arthritis impact measures may help workers in pediatric rheumatology care to have a broader and more in-depth understanding of the effect of this chronic disease on functioning, psychosocial development, and family and peer interactions
ANSELL BM: Juvenile chronic arthritis and juvenile spondyloarthropathy. Curr.Opin.Rheumatol. 1991, 3:838-843. Organism:Dumgoyne, Stoke Poges, UK. Abstract: Clinically recognized subgroups of juvenile chronic arthritis and the juvenile spondyloarthropathies are gradually being shown to be immunogenetically distinct; greater subdivision may ultimately be required. Mechanisms by which the association of certain genes work await further elucidation. Meanwhile, therapy such as intravenous gamma globulin may be most effective in systemic disease. Sulfasalazine is recommended for patients with later-onset pauciarticular disease, particularly HLA-B27 patients. Methotrexate should probably be reserved for severe unresponsive disease, particularly polyarthritis, until side effect profiles are better evaluated
BARRON KS, JOSEPH AK, MACLEOD M, GONZALES JC, OWERBACH D, REVEILLE JD: DNA analysis of HLA-DR, DQ and DP genes in pauciarticular juvenile rheumatoid arthritis. J.Rheumatol. 1991, 18:1723-1729. Organism:Section of Pediatrics, Baylor College of Medicine, Houston, TX. Abstract: HLA-DR, DQ, and DP alleles were determined by restriction fragment length polymorphism (RFLP) and oligonucleotide hybridization analysis in 50 Caucasian children with pauciarticular juvenile rheumatoid arthritis (PaJRA) and 82 controls. There was an increased frequency of DR5, DRw8, and DQw4, as well as individual DQ alpha and beta chains, DQA*0401 and DQB1*0402, respectively, in this group of patients. There was an absolute association between DRw8, DQw4, DQA1*0401, and DQB1*0402 in the patient population. HLA-DPw2.1 was also increased in frequency. There was little evidence of linkage disequilibrium found between DPw2.1 and DR5, DRw8, or DQw4. These MHC Class II associations were more characteristic of those patients with young age of onset (less than 5 years), rather than those with onset greater than or equal to 5 years of age. Our data confirmed the previous associations of HLA-DR5, DRw8, and DPw2.1 with PaJRA and suggested a new association for DQ alpha and beta genes in the clinical expression of this disease
DE GRAEFF-MEEDER ER, VAN DER ZEE R, RIJKERS GT, SCHUURMAN HJ, KUIS W, BIJLSMA JW, ZEGERS BJ, VAN EDEN W: Recognition of human 60 kD heat shock protein by mononuclear cells from patients with juvenile chronic arthritis. Lancet 1991, 337:1368-1372. Abstract: 91245862 Department of Immunology, Het Wilhelmina Kinderziekenhuis, Utrecht, The Netherlands (ENGLAND) 0023-7507 ENGLISH 9109 AIM^INDEX MEDICUS A postulated mechanism for autoimmune disorders is that the immunoreactivity develops against bacterial antigens which show a high degree of sequence homology with mammalian proteins. The mycobacterial 65 kD heat shock protein (hsp) has been implicated in several forms of arthritis. Substantial amounts of the human 60 kD homologue (hsp60) were produced by insertion of the gene into Escherichia coli. To investigate the hypothesis that T-cell reactivity is directed against the endogenous hsp, T- cell proliferation of synovial-fluid and peripheral-blood mononuclear cells in response to hsp60 was studied in samples from six patients with juvenile chronic arthritis (JCA) and nine adult patients with rheumatoid arthritis (RA). There was no T- lymphocyte proliferative response to purified fractions of hsp60 in mononuclear cells from RA patients or healthy children and young adults. However, both synovial-fluid and peripheral- blood mononuclear cells from JCA patients showed substantial proliferative responses. There was a significant correlation between the stimulation indices for human hsp60 and for mycobacterial hsp65 (r = 0.948, p less than 0.02). A similar correlation for hsp60 and mycobacterial hsp70 did not achieve significance. Immunohistochemistry showed that hsp65 and hsp70 homologues were expressed in the synovial membrane in these patients but not in controls. These findings suggest a sequence of events in which hsps become expressed during synovial inflammation and function as autoantigens. In JCA this may be manifested by specific T-cell reactivity which apparently is lost in the more bone-eroding and non-remitting adult disease 0 (Antibodies, Monoclonal);0 (Autoantigens);0 (Heat-Shock Proteins);0 (Recombinant Proteins)
FUGGER L, MORLING N, RYDER LP, JAKOBSEN BK, ANDERSEN V, OXHOLM P, DALHOFF K, HEILMANN C, KARUP PEDERSEN F, FRIIS J, ET AL: Restriction fragment length polymorphism of two HLA-B-associated transcripts genes in five autoimmune diseases. Hum.Immunol. 1991, 30:27-31. Organism:Department of Clinical Immunology, State University Hospital, Copenhagen, Denmark. Abstract: The restriction fragment length polymorphism of the two human HLA-B-associated transcripts (BATs) genes, BAT1 and BAT2, identifying polymorphic bands of 12, 8, 2.5, and 1.1 kb, and at 3.3, 2.7, 2.3, and 0.9 kb, respectively, was investigated in patients with primary biliary cirrhosis (PBC), systemic lupus erythematosus (SLE), pauciarticular juvenile rheumatoid arthritis (P-JRA), rheumatoid arthritis (RA), and primary Sjogren's syndrome (pSS), and in healthy Danes. The BAT2/RsaI 2.7-kb band fragment was more frequent in PBC, pSS, and SLE than in controls, but the p values did not reach significance when corrected for multiple comparisons. For pSS and SLE, the associations may be secondary to primary associations with HLA-B8 because the BAT2/RsaI 2.3-kb band, which is allelic to the BAT2/RsaI 2.7-kb band, is strongly negatively associated with HLA-B8 and HLA-DR3. The only significance obtained shows that the HLA-B8 frequency is increased in BAT2/RsaI 2.7-kb positive pSS patients as compared to the corresponding controls indicating that the HLA-B8 association may be strongest. No missing or extra DNA fragments were observed in the disease groups when compared with controls indicating that gross deletions or duplications of the BAT1 and BAT2 genes in the patients are unlikely. In conclusions, it cannot be excluded that the BAT2/RsaI 2.7-kb band may contribute to the susceptibility to PBC, pSS, and SLE
GIANNINI EH, MALAGON CN, VAN KERCKHOVE C, TAYLOR J, LOVELL DJ, LEVINSON JE, PASSO MH, GINSBERG J, BURKE MJ, GLASS DN: Longitudinal analysis of HLA associated risks for iridocyclitis in juvenile rheumatoid arthritis. J.Rheumatol. 1991, 18:1394-1397. Organism:Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, OH 45229. Abstract: The risk of iridocyclitis in children with early onset pauciarticular juvenile rheumatoid arthritis (EOPA-JRA) has been shown to be associated with certain HLA haplotypes. Our report contains an actuarial analysis, using one-year intervals, of 161 subjects and estimates haplotype specific risks. Individuals who possess the major susceptibility haplotype HLA-DR5 (11) developed eye disease earlier and with a greater frequency than did those with the protective HLA-DR1 haplotype. Highly significant differences were found between the resulting life-table curves for HLA-DR5 and HLA-DR1 positive subjects (p = 0.00003). These time oriented risk estimates may aid clinicians in determining more precisely the probability of iridocyclitis throughout the course of the disease in children with EOPA-JRA
ILOWITE NT, WEDGWOOD JF, MOORE TL, RAMAKRISHNAN T, BONAGURA VR: Hidden rheumatoid factor and Wa idiotype expression in juvenile rheumatoid arthritis. Scand.J.Immunol. 1991, 34:453-460. Organism:Department of Pediatrics, Schneider Childrens Hospital, New Hyde Park, NY 11042. Abstract: The major rheumatoid factor cross-reactive idiotype, which was defined by prototypic monoclonal IgM rheumatoid factors from Waldenstrom's macroglobulinaemia patient Wa, is present on 60% of all monoclonal IgM RF paraproteins. One-third of patients with juvenile rheumatoid arthritis (JRA), who are seronegative for classic IgM rheumatoid factor (RF), express the Wa idiotype in high titre in their sera. To determine if the Wa idiotype is present on hidden rheumatoid factors in JRA patient sera, we studied hidden RF expression by both ELISA and haemolytic assay techniques. The majority of JRA sera with increased concentrations of the Wa idiotype did not have increased RF activity nor hidden RF activity. In some JRA patients, the Wa idiotype may be expressed on a parallel set of immunoglobulin molecules, related to RFs, but lacking the ability to bind to IgG
MORLING N, FRIIS J, FUGGER L, GEORGSEN J, HEILMANN C, PEDERSEN FK, ODUM N, SVEJGAARD A: DNA polymorphism of HLA class II genes in pauciarticular juvenile rheumatoid arthritis. Tissue Antigens. 1991, 38:16-23. Organism:Tissue Typing Laboratory, University of Copenhagen, Denmark. Abstract: We investigated the DNA restriction fragment length polymorphism (RFLP) of the major histocompatibility complex (MHC) class II genes: HLA-DRB, -DQA, -DQB, DPA, and -DPB in 54 patients with pauciarticular juvenile rheumatoid arthritis (PJRA) and in healthy Danes. The frequencies of DNA fragments associated with the following HLA class II genes were increased in PJRA when compared to normal controls: DRB1*08 (DRw8) (35.2% vs 10.3%, RR = 4.6, p less than 10(-3), DRB3*01/02/03 (DRw52) (76.3% vs 48.1%, RR 3.5, p less than 10(-3)), DQA1*0401 (41.0% vs 7.4%, RR = 7.9, p less than 10(-3)), DQA1*0501 (55.6% vs 29.7%, RR = 3.0, p less than 10(-2), DQB1*0301 (DQw7) (46.2% vs 17.5%, RR = 4.0; p less than 10(-2)), DPA1*0201 (44.2% vs 7.9%, RR = 8.7, p less than 10(- 5)), and DPB1*02 (DPw2) (40.7% vs 7.1%, RR = 8.5, p less than 10(- 6)). The frequency of DRB1*11 was not significantly increased. The frequencies of DNA fragments associated with the following HLA class II genes were decreased in PJRA although not statistically significantly so after 'correction' of p values: DRB1*04 (14.8% vs 40.2%, RR = 0.27; p less than 10(-3)), DRB1*07 (0% vs 25.9%, RR = 0.04, p less than 10(-3)), DRB4*0101 (DRw53) (25.9% vs 53.6%, RR = 0.31, p less than 10(-3)), DQA1*0102 (11.6% vs 36.0%, RR = 0.25, p less than 10(-4)), and DQA1*0201 (2.6% vs 34.2%, RR = 0.05, p less than 10(-2)).(ABSTRACT TRUNCATED AT 250 WORDS)
NEPOM B: The immunogenetics of juvenile rheumatoid arthritis. Rheum.Dis.Clin.North Am. 1991, 17:825-842. Organism:Immunology Program, Virginia Mason Research Center, Seattle, Washington. Abstract: Recent major advances in understanding the genetic structure of the human leukocyte antigen (HLA) region and how HLA molecules contribute to immune responses have been paralleled by more precise identification of specific HLA genes conferring susceptibility to the various forms of juvenile rheumatoid arthritis (JRA). This article presents current models for HLA- associated autoimmune disease susceptibility and summarizes the HLA Class II alleles currently known to be associated with JRA: primarily DR8, DR5, DR6, and DPw2.1 in pauciarticular onset JRA; and DR4 in rheumatoid factor-positive polyarticular onset JRA. Rheumatoid factor-negative polyarticular onset JRA and systemic onset JRA are variously associated with several of these same genes. Gene interactions and the clinical utility of HLA typing in this disease are also discussed
NEPOM BS, MALHOTRA U, SCHWARZ DA, NETTLES JW, SCHALLER JG, CONCANNON P: HLA and T cell receptor polymorphisms in pauciarticular-onset juvenile rheumatoid arthritis. Arthritis Rheum. 1991, 34:1260-1267. Organism:Immunology Program, Virginia Mason Research Center, Seattle, WA 98101. Abstract: The immunogenetic basis of pauciarticular-onset juvenile rheumatoid arthritis is unclear. We therefore analyzed the HLA and T cell receptor genes present in a clinically well-defined group of patients. We found that the DR8 haplotype contributes most of the HLA-associated risk, although alleles at other loci contribute independently. A candidate disease-associated T cell receptor polymorphism, in contrast, was not identified in this population. Mechanistic implications of these findings are discussed
SIOUD M, FORRE O, NATVIG JB: T cell receptor delta diversity of freshly isolated T lymphocytes in rheumatoid synovitis. Eur.J.Immunol. 1991, 21:239-241. Organism:Institute of Immunology and Rheumatology, University of Oslo, Norway. Abstract: In some patients with rheumatoid synovitis the distribution of V delta gene families used by freshly isolated T lymphocytes from the synovial fluid and peripheral blood is different: peripheral blood T lymphocytes preferentially use the V delta 2 gene segment, whereas the majority of synovial fluid T lymphocytes use the V delta 1. The antigenic diversity of T cell receptor gamma/delta is mainly dependent upon base sequences in the V-J junction. In the present study we investigated whether the synovial fluid T lymphocytes expressing the V delta 1 gene segment were derived from a polyclonal or monoclonal expansion. The sequences encoding the V-J junctions of 11 cDNA clones derived from the synovium of two patients with chronic arthritis were determined. Our data demonstrate that the V delta 1 cDNA clones have different V-J junction sequences. This indicates that the V delta 1-expressing T cells found in the synovial compartment are polyclonally expanded
SIOUD M, KJELDSEN KRAGH J, QUAYLE AJ, WIKER HG, SORSKAAR D, NATVIG JB, FORRE O: Immune responses to 18.6 and 30-kDa mycobacterial antigens in rheumatoid patients, and V beta usage by specific synovial T-cell lines and fresh T cells. Scand.J.Immunol. 1991, 34:803-812. Organism:Institute of Immunology and Rheumatology, University of Oslo, Norway. Abstract: We have investigated both the humoral and the cellular immune responses of patients with juvenile rheumatoid arthritis (JRA) and rheumatoid arthritis (RA) to mycobacterial antigens. The JRA group was not Bacillus Calmette Guerin (BCG) vaccinated whilst the majority of the RA group was. As determined by immunoblotting, 79% of sera from patients with JRA reacted mainly with a 18.6-kDa protein (P18.6), whilst 70% of sera from patients with RA reacted mainly with a 30-kDa protein (P30) of BCG, M. tuberculosis and M. kansasii. In contrast, only a moderate proportion of the control sera (25% of adult and 20% of children) showed reactivity to P30, and none of the samples had significant reactivity with the P18.6 antigen. Furthermore, T-cell proliferation to the P18.6 and P30 antigens was detected in the majority of JRA and RA patients, and was nearly always higher in synovial fluid (SF) than in the peripheral blood (PB). We also investigated the usage of V beta family genes in P18.6 and P30 antigen-specific T-cell lines established from the SF of one patient with active RA. We showed that V beta 2, -4, -5, -6, -7, -14, -17, -18 and V beta 19 were over-represented compared with other known V beta families. We also noted that the proportion of V beta 14 was higher in freshly isolated SF mononuclear cells compared with the blood in this patient and in 2 out of 4 other RA patients examined. Other V beta families such as V beta 6, V beta 8, V beta 16, V beta 18 and V beta 19 were also over-represented in the SF compared with the blood in some patients. Taken together our results provide more information concerning the role of mycobacterial antigens in RA and suggest that there may be an in vivo clonal expansion of T lymphocytes in the synovium
TIMON M, ARNAIZ VILLENA A, PEREZ ACIEGO P, MORALES P, BENMAMAR D, REGUEIRO JR: A diallelic RFLP of the CD3-epsilon chain of the clonotypic T- lymphocyte receptor is not associated with certain autoimmune diseases. Hum.Genet. 1991, 86:363-364. Organism:Hospital 12 De Octubre, Madrid, Spain. Abstract: A diallelic restriction fragment length polymorphism of the CD3- epsilon (epsilon) gene, which encodes for an invariant component of the human T-lymphocyte receptor, is observed when using genomic DNA TaqI digests probed with a CD3-epsilon chain cDNA probe. This combination shows two alleles of 9.1 kb and 8.4 kb with a frequency of 0.66 and 0.34, respectively, in the Spanish population. None of these alleles is associated with susceptibility to juvenile rheumatoid arthritis (JRA) or insulin- dependent diabetes mellitus (IDDM)
VAN KERCKHOVE C, LUYRINK L, TAYLOR J, MELIN ALDANA H, BALAKRISHNAN K, MAKSYMOWYCH W, ELMA M, LOVELL D, CHOI E, GLASS DN: HLA-DQA1*0101 haplotypes and disease outcome in early onset pauciarticular juvenile rheumatoid arthritis. J.Rheumatol. 1991, 18:874-879. Organism:Division of Pediatric Rheumatology, Children's Hospital Medical Center, Cincinnati, OH 45229-2899. Abstract: To further investigate a clinical impression that patients with early onset pauciarticular juvenile rheumatoid arthritis (EOPA- JRA) who carry HLA-DQw1 have more severe arthritis, we subtyped HLA-DQw1 in American midwestern patients with EOPA-JRA. The HLA- DQA1*0101 subtype was present in 10 of 19 patients who developed persistent polyarticular erosive disease compared with 18 of 92 healthy controls (chi 2 = 9.13, p = 0.003, RR = 4.6), and occurred more frequently in this polyarticular group than in patients without polyarticular erosive disease (chi 2 = 4.11, p = 0.040, RR = 3.0). The presence of HLA-DQA1*0101 was significantly lower in patients with chronic iridocyclitis than in patients without chronic iridocyclitis (chi 2 = 7.07, p = 0.008, RR = 0.21). In HLA-DQA1*0101 positive patients, DNA sequences of the beta-1 domain of the HLA-DQ alpha and HLA-DQ beta genes (HLA- DQA1*0101, HLA-DQB1*0501 and HLA-DQB1*0503) were identical to those in controls. In this midwestern EOPA-JRA population, HLA- DQA1*0101 or genes in linkage disequilibrium with it, are associated with a cohort of patients with EOPA-JRA with distinct clinical characteristics
EL DAHR SS, GOMEZ RA, KHARE G, PEACH MJ, CAREY RM, CHEVALIER RL: Expression of renin and its mRNA in the adult rat kidney with chronic ureteral obstruction. Am.J.Kidney Dis. 1990, 15:575-582. Organism:Department of Pediatrics, University of Virginia Health Sciences Center, Charlottesville 22908. Abstract: Angiotensin II has been implicated in mediating renal vasoconstriction resulting from chronic unilateral ureteral obstruction (UUO) in both mature and developing animals. We have previously shown that chronic neonatal UUO results in increased distribution of renin and its mRNA in the obstructed kidney, as well as of immunoreactive renin in the intact opposite kidney. The present study was designed to evaluate the effects of 24 hours versus 4 weeks of UUO on the distribution of renin mRNA and its protein in the adult rat kidney. Renin was detected by immunocytochemistry using a polyclonal anti-rat renin antibody. Renin mRNA was localized by in situ hybridization to an oligonucleotide complementary to renin mRNA. UUO of 24 hours' or 4 weeks' duration did not alter the distribution of renin and its mRNA in the obstructed kidneys as compared with sham-operated kidneys, although kidneys obstructed for 4 weeks had a significant increase in the percent of renin-containing juxtaglomerular apparatuses (JCA) when compared with the intact opposite kidneys (P less than 0.05). Compensatory hypertrophy was not present in the intact opposite kidneys after 24 hours of UUO and distribution of renin gene expression was not altered at that time. However, 4 weeks following contralateral UUO, the intact kidneys were hypertrophied and showed a decrease in renin gene expression relative to the obstructed and sham-operated kidneys. We conclude that unlike UUO during early development, chronic UUO in the mature animal does not activate renin gene expression nor alter renin distribution in the obstructed kidneys. Renin gene expression is suppressed in the hypertrophied kidney with prolonged contralateral UUO.(ABSTRACT TRUNCATED AT 250 WORDS)
FERNANDEZ-VINA M, FINK CW, STASTNY P: HLA antigens in juvenile arthritis. Pauciarticular and polyarticular juvenile arthritis are immunogenetically distinct. Arthritis Rheum. 1990, 33:1787-1794. Organism:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-8886. Abstract: Using DNA techniques, we investigated the role of HLA-DR, DQ, and DP alleles in susceptibility to juvenile arthritis (JA). We studied 2 groups of patients with JA having a different disease prognosis and course. The pauciarticular form is usually benign, while the polyarticular disease frequently leads to joint destruction and disability. Persistent pauciarticular disease developed preferentially in patients having HLA-DRw13-Dw18 and DQw6-Dw18, but these antigens did not confer susceptibility in patients whose disease converted to the polyarticular form. HLA- DPw2.1 was an additional susceptibility factor for patients with JA of pauciarticular onset. In the polyarticular form of JA, HLA- DPw3 was the major factor for susceptibility, giving a relative risk of 10.3 (P less than 0.0001). In addition, we found that DRw8.1 and DQw4 were increased, and HLA-DR4 was markedly decreased, in patients with pauciarticular and polyarticular disease. These results indicate that in addition to some shared factors, distinct HLA class II alleles are important in pauciarticular or polyarticular JA. We conclude that typing with oligonucleotide probes may be useful in predicting the outcome in some children with arthritis
FUGGER L, RYDER LP, MORLING N, ODUM N, FRIIS J, PEDERSEN FK, HEILMANN C, SANDBERG WOLLHEIM M, SVEJGAARD A: DNA typing for HLA-DPB1*02 and -DPB1*04 in multiple sclerosis and juvenile rheumatoid arthritis. Immunogenetics 1990, 32:150-156. Organism:Department of Clinical Immunology, State University Hospital, Copenhagen, Denmark. Abstract: DP gene typing using in vitro DNA amplification combined with sequence-specific oligonucleotide probes (SSOP) has recently been reported. The amplification step may be specific for the HLA-DPB locus, or it may be specific for one or a group of HLA-DPB alleles, thus increasing the discriminatory power of the system. We report the combined use of group-specific DNA in vitro amplification followed by SSOP in typing for DPB1*02 and DPB1*04 variants. The method was used to type for these variants in 96 randomly selected, healthy Danes, in 37 patients with pauciarticular juvenile rheumatoid arthritis (PJRA), and in 38 patients with multiple sclerosis (MS). Increased frequencies of the cellularly defined HLA-DPw2 in PJRA and of HLA-DPw4 in MS have previously been reported. In the patient groups, the frequencies of the DPB1*02 and DPB1*04 variants did not differ significantly from those expected based on the cellularly defined HLA-DP types of the patients and the frequencies of the DPB1*02 and DPB1*04 variants among healthy Danes
MELIN ALDANA H, GIANNINI EH, GLASS DN: Immunogenetics of early onset pauciarticular juvenile rheumatoid arthritis. J.Rheumatol.Suppl. 1990, 26:2-6. Organism:Division of Pediatric Rheumatology, Children's Hospital Medical Center, Cincinnati, Ohio 45229-2899. Abstract: Certain major histocompatibility complex (MHC) class I and class II genes are uniquely associated with early onset pauciarticular juvenile rheumatoid arthritis (JRA). As in other autoimmune diseases, these associations are likely to reflect contributions of the MHC to a trimolecular complex formed by HLA, lymphocyte T cell receptor and the putative antigen. The HLA genes associated with JRA are currently the best understood component of this complex. Recent findings demonstrated that combinations of genes, even within class II, play an important role. Data generated by DNA sequencing techniques have clarified the splits of given genes involved in disease, e.g., the HLA-DRw8 allele, HLA- DRB1*0801 rather than HLA-DRB1*0802, which does not carry an increased risk for disease. Recent findings suggest that aberrant sequences in particular genes are unimportant. Substantial challenges remain; including establishing the particular HLA DNA nucleotides critical to antigen presentation. It is probable that new and specific therapeutic approaches will be developed which will utilize the immunogenetic data now being accumulated
NATVIG JB, RANDEN I, THOMPSON K, FORRE O, MAGEED RA, JEFFERIS R, CARSON DA, TIGHE H, PASCUAL V, VICTOR KD, ET AL: Probing of the rheumatoid factor (RF) V gene repertoire in rheumatoid arthritis (RA) by hybridoma clones. Clin.Exp.Rheumatol. 1990, 8 Suppl 5:75-80. Organism:Institute of Immunology and Rheumatology, Oslo, Norway. Abstract: Twenty human monoclonal antibodies with rheumatoid factor (RF) specificity were produced from fusions using B lymphocytes derived from the synovial tissue of two patients with rheumatoid arthritis (RA) and one with the polyarticular form of juvenile rheumatoid arthritis (JRA) (1). All the 20 monoclonal antibodies were IgM. Fourteen of these were classical RFs with specificity restricted to IgG, and included 12 kappa and 2 lambda proteins. When the fine specificity for IgG Fc determinants were investigated most of them showed the Ga specificity. In addition, 5 lambda and 1 kappa monoclonal RF antibodies showed polyreactivity and also reacted with various other antigens than IgG (1). The 14 monoreactive RFs were further studied for the expression of RF-related cross-reactive idiotypes (CRI) and variable heavy (VH) and light chain (VL) subgroups. Only four of the twelve kappa RFs expressed the V kappa III subgroup. Three of them belong to the V kappa IIIb sub-subgroup and expressed the CRI 17.109. One of these 3 clones in addition expressed the VH I associated CRI G6. Five other monoreactive RFs expressed either or both of the VH III associated CRI B6 and D12 (2). Using staphylococcal protein A (SPA) binding as well as Northern blotting techniques (2), studies indicated that 10 out of the 12 RFs studied expressed the VH III regions and 2 expressed the VH I region. These data, both for the heavy and light chains, indicated a different V gene usage by the RF derived from RA patients than by the RF M-components derived from patients with mixed cryoglobulinemia and Waldenstrom's macroglobulinemia but without RA.(ABSTRACT TRUNCATED AT 250 WORDS)
RUMBA IV, SOCHNEV AM, KUKAINE EM, BURSHTEIN AM, BENEVOLENSKAIA LI: [HLA antigens in juvenile rheumatoid arthritis] Antigeny sistemy HLA pri iuvenil'nom revmatoidnom artrite. Revmatologiia.Mosk. 1990, 23-27. Abstract: Antigens of I class HLA system (locus A and B) were investigated in 67 patients of Latvian nationality suffering from juvenile rheumatoid arthritis (JRA). Associations of HLA antigens with juvenile rheumatoid arthritis partially coincided with the ones revealed earlier. Typing established an increased incidence of antigen B27 (p less than 0.01) and gaplotype A2, B40 (p less than 0.01). Antigen B15 possessed a protective action with respect to JRA. Interlocus combinations demonstrated a closer association with the disease than a single antigen. The authors also revealed markers of various clinico-anatomical variants of JRA
SIOUD M, KJELDSEN KRAGH J, QUAYLE A, KALVENES C, WAALEN K, FORRE O, NATVIG JB: The V delta gene usage by freshly isolated T lymphocytes from synovial fluids in rheumatoid synovitis: a preliminary report. Scand.J.Immunol. 1990, 31:415-421. Organism:Institute of Immunology and Rheumatology, University of Oslo, Norway. Abstract: Taking advantage of the polymerase chain reaction we have studied the usage of variable delta-(V delta) region genes in freshly isolated synovial fluid T cells from patients with rheumatoid synovitis. Amplified mRNA from one patient with rheumatoid arthritis (RA) was cloned into an SmaI-cleaved pUC19 vector and colonies were screened with probes for three of the known human variable delta-gene families (V delta 1, V delta 2, V delta 3). Of 10 clones, seven used V delta 1, two V delta 2 and one V delta 3. This pattern of distribution is different from that of normal peripheral blood, where approximately 60% of T gamma delta cells are reported to use the V delta 2 gene. Furthermore, Northern blot hybridization analyses of mononuclear cells from two additional synovial fluids derived from another patient with RA and one with juvenile rheumatoid arthritis (JRA) also showed significant hybridization only with V delta 1. In summary, these preliminary results suggest a usage of V delta gene families in T gamma delta lymphocytes in synovial fluid of rheumatoid patients different to that found in normal peripheral blood
VAN KERCKHOVE C, MELIN ALDANA H, ELMA MS, LUYRINK L, DONNELLY P, TAYLOR J, MAKSYMOWYCH WP, LOVELL DJ, CHOI E, GLASS DN: A distinct HLA-DRw8 haplotype characterizes patients with juvenile rheumatoid arthritis. Immunogenetics 1990, 32:304-308. Organism:Children's Hospital Medical Center, Cincinnati, OH. Abstract: We studied the first domain of the HLA-DRB1, HLA-DQA1, and HLA- DQB1 loci of 67 HLA-DRw8-positive Caucasians including 43 with early-onset pauciarticular juvenile rheumatoid arthritis (EOPA- JRA, alternatively known as early-onset pauciarticular juvenile chronic arthritis). Serology, restriction fragment length polymorphism (RFLP), and polymerase chain reaction (PCR) oligotyping revealed that 62, including all the EOPA-JRA patients, carried the HLA-DRB1*0801, DQA1*0401, DQB1*0402 genotype. Approximately one-fifth of the controls carried atypical HLA-DRB1, HLA-DQA1, and/or HLA-DQB1 loci on their HLA-DRw8 haplotype confirmed by family studies. DNA sequences of HLA-DRB1, DQA1, and DQB1 alleles in patients and controls were identical to those previously reported. Disease association studies in 113 EOPA-JRA patients and 207 controls unselected for HLA-DRw8 revealed that the HLA-DRB1*0801, DQA1*0401, DQB1*0402 genotype was associated with a higher relative risk (RR) for disease (RR = 12.8, chi 2 = 48.8, P less than 10(-4)) than was the serologically defined presence of HLA-DRw8 (RR = 8, chi 2 = 39, P less than 10(-4)). Further analysis suggested that the DQ genes on HLA-DRw8 haplotypes are as likely as the DR genes to contribute to the pathogenesis of EOPA-JRA. This study increases to five the number of HLA-DR/DQ haplotypes identified in HLA-DRw8 Caucasians
VEHE RK, BEGOVICH AB, NEPOM BS: HLA susceptibility genes in rheumatoid factor positive juvenile rheumatoid arthritis. J.Rheumatol.Suppl. 1990, 26:11-15. Organism:Virginia Mason Research Center, Seattle, WA 98101. Abstract: Rheumatoid factor positive (seropositive) juvenile rheumatoid arthritis (JRA) is a relatively uncommon but severe form of JRA which shares clinical features with classical adult onset rheumatoid arthritis. Immunogenetic analysis of these patients supports the concept that this likely represents childhood onset of the same disease process. In this report, we review the clinical features as well as previous HLA studies of this disease. We report complete DNA based HLA typing of a small group of these patients, and discuss mechanistic implications of the results
VICARIO JL, MARTINEZ LASO J, GOMEZ REINO JJ, GOMEZ REINO FJ, REGUEIRO JR, CORELL A, SEGURADO OG, ARNAIZ VILLENA A: Both HLA class II and class III DNA polymorphisms are linked to juvenile rheumatoid arthritis susceptibility. Clin.Immunol.Immunopathol. 1990, 56:22-28. Organism:Department of Immunology, Hospital 12 de Octubre, Universidad Alcala de Henares, Madrid, Spain. Abstract: HLA-DR5 and DRw8 are not significantly linked to juvenile rheumatoid arthritis (JRA) in the Spanish population. However, we have found restriction fragment length polymorphisms (RFLPs) beta DR-2.9-kb-EcoRI and C4-14.3-kb-EcoRI, that correlate significantly with JRA. Eighty-six percent of our patients present either HLA-DR5 or the beta DR-2.9-kb-EcoRI allogenotope or lack the C4-14.3-kb-EcoRI allogenotope compared to 48% in controls; however, these particular DR and C4 RFLPs may not represent the corresponding DRB1 or C4 genes but rather neighboring ones which may be relevant to confer JRA susceptibility. The C4-14.3-kb-EcoRI RFLP decrease in patients may reflect a decrease in C4 B "long" phenotypes. Also, both RFLPs are the only markers able to identify most of the JRA patients in our population. On the other hand, the findings of both class II and III genes associated to JRA may reflect the existence of epistatic interactions (cis or trans) within the HLA gene cluster which lead to a particular pathology in certain diseases
WOO P: Genetic aspects of juvenile chronic arthritis. Clin.Orthop. 1990, 11-17. Abstract: 91004985 Section of Molecular Rheumatology, Clinical Research Centre, Northwick Park Hospital, Harrow, United Kingdom (UNITED STATES) 0009-921X ENGLISH 9101 AIM^INDEX MEDICUS Immunogenetic studies in the past decade have confirmed the theory of an association between one's immunogenetic background and the manifestation of several forms of juvenile chronic arthritis (JCA), in particular pauciarticular-onset JCA. Considerable work has been done at the serologic level to demonstrate disease association with the major histocompatibility Class II antigens in pauciarticular-onset JCA. The polygenic nature of JCA is best illustrated by the findings in this particularly well-defined clinical subgroup. Evidence is now emerging that analysis of the DNA sequence, the derived protein sequence, and the structure of Class II molecules will yield significant insight into the genetic predisposition to JCA 0 (HLA Antigens)
ADAMS JC, WATT FM: Fibronectin inhibits the terminal differentiation of human keratinocytes. Nature 1989, 340:307-309. Organism:Keratinocyte Laboratory, Imperial Cancer Research Fund, London, UK. Abstract: In the epidermis proliferation of keratinocytes is restricted to the basal layer, which is in contact with the basement membrane, and cells undergo terminal differentiation as they move upwards through the suprabasal layers. In stratified cultures of human keratinocytes, upward migration is a consequence, not a cause, of terminal differentiation and occurs because keratinocytes become less adhesive to their substratum and to one another. Most keratinocytes can be induced to differentiate to completion by placing them in suspension in methylcellulose: within 12 h DNA synthesis is irreversibly inhibited and by 24 h most cells express involucrin (ref 4; P. A. Hall, J.C.A. and F.M.W., unpublished observations). Here we report that when fibronectin is added to the methylcellulose, keratinocytes still withdraw from the cell cycle, but induction of involucrin expression is largely inhibited. The effect of fibronectin is concentration- and time-dependent and is mediated by a receptor of the integrin family. These results provide an explanation for why overt terminal differentiation is normally restricted to suprabasal cells, whereas cell-cycle withdrawal occurs within the basal layer; they also have important implications for the mechanism of epidermal wound healing. Furthermore, our data show that the binding of an extracellular matrix protein to its receptor can regulate differentiated gene expression in the absence of changes in cell shape
ARNAIZ VILLENA A, VICARIO JL, MARTINEZ LASO J, CORELL A, REGUEIRO JR, GOMEZ REINO J: An Eco RI polymorphic site in the human complement C4 gene distinguishes juvenile rheumatoid arthritis (JRA) susceptibility- bearing haplotypes. Mol.Immunol. 1989, 26:427-430. Organism:Department of Immunology, Hospital 12 de Octubre, Madrid, Spain. Abstract: Susceptibility to acquire Juvenile Rheumatoid Arthritis (JRA) is linked to HLA-DR5 and DRw8 antigens in Caucasoid populations. However, the frequency of HLA-DR5 is too high in the normal Spanish population and JRA cannot thus be found to be associated with this antigen. It has been found a 14.3 kb-C4-Eco RI restriction fragment length polymorphism which correlates significantly with JRA and may be used as a marker for this disorder in Spaniards
BEGOVICH AB, BUGAWAN TL, NEPOM BS, KLITZ W, NEPOM GT, ERLICH HA: A specific HLA-DP beta allele is associated with pauciarticular juvenile rheumatoid arthritis but not adult rheumatoid arthritis. Proc.Natl.Acad.Sci.U.S.A. 1989, 86:9489-9493. Organism:Department of Human Genetics, Cetus Corporation, Emeryville, CA 94608. Abstract: Nonradioactive sequence-specific oligonucleotide probes specific for the HLA-DP beta locus have been used in a simple dot-blot format to type samples amplified by the polymerase chain reaction from 44 patients with pauciarticular juvenile rheumatoid arthritis, 32 patients with adult rheumatoid arthritis, and 50 random controls. The sequences of four new DP beta alleles derived from these patients and controls are reported, bringing the total number of alleles identified thus far to 19. The DPB2.1 allele is significantly increased in juvenile rheumatoid arthritis patients over controls; this allele is not increased in patients with adult rheumatoid arthritis. The association of juvenile rheumatoid arthritis with the DPB2.1 allele is independent of linkage with previously defined HLA-D region markers of disease. Analysis of the DPB2.1 sequence shows that it differs from the nonsusceptible DPB4.2 allele by only 1 amino acid at position 69 in the beta 1 domain
FUGGER L, MORLING N, BENDTZEN K, RYDER L, ANDERSEN V, HEILMAN C, KARUP PEDERSEN F, FRIIS J, HALBERT P, SVEJGAARD A: IL-6 gene polymorphism in rheumatoid arthritis, pauciarticular juvenile rheumatoid arthritis, systemic lupus erythematosus, and in healthy Danes. J.Immunogenet. 1989, 16:461-465. Organism:Tissue Typing Laboratory, State University Hospital, Copenhagen, Denmark. Abstract: The restriction enzymes MspI and BglII identify two different two-allele restriction fragment length polymorphisms (RFLP) in the human IL-6 genes of healthy Danes. Co-dominant segregation was demonstrated for both marker-systems and the test for Hardy- Weinberg equilibrium showed no significant deviation from expectations. There is a strong correlation between the two marker systems. The two IL-6 RFLP's were studied in Danish patients with rheumatoid arthritis, pauciarticular juvenile rheumatoid arthritis, and systemic lupus erythematosus. The frequencies of the MspI and BglII marker phenotypes did not differ between healthy controls and the three disease groups. No extra or missing DNA fragments were observed in the disease groups when compared with controls
HALL PJ, BURMAN SJ, BARASH J, BRIGGS DC, ANSELL BM: HLA and complement C4 antigens in polyarticular onset seronegative juvenile chronic arthritis: association of early onset with HLA-DRw8. J.Rheumatol. 1989, 16:55-59. Organism:Division of Rheumatology, Clinical Research Centre, Harrow, London, England Abstract: HLA-A,B,C,DR and DQ antigens were tested in 53 British Caucasian patients with polyarticular onset seronegative juvenile chronic arthritis (JCA); C4 allotypes were also tested in 46. A strong association with HLA-DRw8 was found (RR = 6.1, Fp = 7.6 x 10(-5)), with increased -B5(51) and C4A QO, and decreased -DR7 frequencies. DRw8 incidence correlated with an onset under 5 years, 9 of 12 DRw8+ cases being in this subgroup (Fp = less than 0.06), whereas B5 and C4A QO were prevalent in late onset (greater than or equal to 5 years). Erosions after 5 years associated with HLA-DRw6, and their absence with -Cw1 and -DR5. Genetic susceptibility factors and a further subdivision by onset age are thus demonstrated in this disease. Comparative data suggest that the genetic basis of susceptibility to early onset disease is similar to that of pauciarticular JCA 0 (Complement 4);0 (HLA Antigens);0 (HLA-DR Antigens);0 (HLA- DR8); 80295-49-4 (Complement 4a);80295-50-7 (Complement 4b);9009- 79-4 (Rheumatoid Factor)
PRIEUR AM: D-penicillamine in juvenile chronic arthritis. Z.Rheumatol. 1988, 47 Suppl 1:34-37. Organism:Groupe de Recherche d'Immunologie et de Rhumatologie Pediatriques, Hopital des Enfants-Malades, Paris, France Abstract: 89102095Juvenile chronic arthritis (JCA) is a heterogeneous disease, differing in most instances from adult rheumatoid arthritis. The diagnostic criteria generally used in Europe are those proposed in Oslo in 1977. There are three main types of onset: systemic, polyarticular and pauciartricular. However, when we observe patients during the course of the disease, this proposed classification seems too simple and does not reflect the reality of outcome. To be more efficient for therapeutic studies, we think that it should be more accurate to consider the type of course, rather than the type of onset. Thus, we will discuss in a first part of this paper subdivisions of the disease according to course, biology and genetics, and indicate in which circumstances a slow acting drug such as pencillamine should be a realistic therapeutic indication. In the second part of this paper, we will give the results of already published observations and of personal data on the effect and tolerance of D-penicillamine, and discuss a way of improving drug evaluation in JCA 52-67-5 (Penicillamine)
GOLDSTEIN R, ARNETT FC: The genetics of rheumatic disease in man. Rheum.Dis.Clin.North Am. 1987, 13:487-510. Abstract: 88126177 Department of Internal Medicine, University of Texas Health Science Center, Houston (UNITED STATES) 0889-857X ENGLISH 8805 INDEX MEDICUS This article reviews the current knowledge of genetic factors conferring susceptibility to several major rheumatic disorders, in particular, rheumatoid arthritis (RA), juvenile chronic arthritis (JCA), systemic lupus erythematosus (SLE), and Sjogren's syndrome. Emphasis is given to major histocompatibility complex associations with these diseases, particularly rapidly evolving knowledge of class II HLA genes and disease-conferring "epitopes." Non-MHC-linked genes, such as T cell receptor and immunoglobulin genes, also may be involved 0 (HLA-DR Antigens)
BRAUTBAR C, MUKAMEL M, YARON M, NAPARSTEK Y, KORMAN SH, AMAR A, COHEN I, LUDOMIRSKY A, LOTAN C, SCHARF J, ET AL: Immunogenetics of juvenile chronic arthritis in Israel. J.Rheumatol. 1986, 13:1072-1075. Abstract: 87169499 (CANADA) 0315-162X ENGLISH 8707 INDEX MEDICUS Typing for HLA-A,B,C and DR antigens was performed in 61 Israeli patients with juvenile chronic arthritis (JCA) and in 120 unrelated controls. No significant associations were apparent in the overall patient group. DR5 was significantly increased in the non-Ashkenazi patients with pauciarticular onset of disease. The only three DRw8 positive patients in the study had pauciarticular onset. DR5 and DRw8 were found in 9 of 10 patients with age of onset less than 3 years. Increased frequencies of Bw50 and Cw6 were observed in patients with systemic onset. Typing for properdin factor (Bf) and glyoxylase (GLO) was carried out in 45 and 50 of the patients, respectively. No associations with alleles of the complement Bf system or the HLA linked GLO system were evident. The confirmation in the ethnically distinct Israeli population of the previously described association of DR5 with pauciarticular JCA suggests that this gene may be closely related to the disease susceptibility gene 0 (HLA Antigens);0 (HLA-DR Antigens)
BURMAN SJ, HALL PJ, BEDFORD PA, HOWARD A, ANSELL BM: HLA antigen frequencies among patients with juvenile chronic arthritis and amyloidosis: a brief report. Clin.Exp.Rheumatol. 1986, 4:261-263. Abstract: 87028857 (ITALY) 0392-856X ENGLISH 8702 INDEX MEDICUS Amyloidosis is seen in a small number of patients with juvenile chronic arthritis (JCA). In order to determine whether particular HLA markers might predispose to the development of amyloid in JCA a group of 45 patients with amyloidosis confirmed by biopsy was typed for the HLA-A, B, C and DR loci. The results confirmed previous smaller studies that no HLA antigen detected by standard serological techniques was associated specifically with the development of amyloidosis. Those antigens which showed an altered frequency (ie. DR4 and DRw8) were known to be associated with the different types of JCA onset represented in this group 0 (HLA Antigens)
HALL PJ, BURMAN SJ, LAURENT MR, BRIGGS DC, VENNING HE, LEAK AM, BEDFORD PA, ANSELL BM: Genetic susceptibility to early onset pauciarticular juvenile chronic arthritis: a study of HLA and complement markers in 158 British patients. Ann.Rheum.Dis. 1986, 45:464-474. Abstract: 86268051 (ENGLAND) 0003-4967 ENGLISH 8610 INDEX MEDICUS To investigate the genetics of susceptibility to early onset pauciarticular juvenile chronic arthritis (JCA), 158 unrelated ethnic British patients with a mean disease onset of 3.2 years, together with controls, were tested for HLA-A, B, C, and DR antigens. Additionally, 117 patients were also investigated for complement Bf and C4 markers. New observations included an increased frequency of the C4B 2 allotype (p corrected (pc) less than 0.02) and C4A 4,B 2 phenotype (p less than 0.0005). Findings suggested a unique increase of the haplotype HLA-DRw8, Bf*S, C4A*4, C4B*2, HLA-B39, possibly predisposing to more severe disease. Strong positive associations were confirmed with HLA antigens A2 (pc = 2.5 X 10(-8)), DRw8 (pc = 3.5 X 10(- 14)), DR5 (pc less than 0.02), DRw52 (pc = 2.8 X 10(-6)) and DR5, w8 phenotype (pc = 3.9 X 10(-6)), and negative associations with DR7 (pc = 5.8 X 10(-7)), DR4 (pc less than 0.002), and DRw53 (pc = 0.004). Antinuclear antibody (ANA) seropositivity correlated with DR5 (p less than 0.02), and in children with chronic iridocyclitis (CIR) Bw62 incidence was raised (p less than 0.03) and B44 reduced (p less than 0.03). HLA-A2 was found in 88% of ANA+, CIR+ patients (p less than 0.01). A significant excess of DR5, w8 heterozygotes was present (relative risk = 41.1) and a lack of corresponding homozygotes. Results are inconsistent with a recessive, dominant, or intermediate mode of inheritance of susceptibility, and favour the existence of at least two DR linked 'disease' genes. Moreover, there may be an interaction in heterozygotes with DR5 and DRw8 in enhancing susceptibility. Possible immunogenetic mechanisms underlying the observed associations with three antigen classes are discussed. Evidence here suggests a role for the HLA-DQ locus in determining susceptibility to this disease 0 (Antibodies, Antinuclear);0 (Complement 4);0 (Enzyme Precursors);0 (HLA Antigens)
TOWNER SR, MICHET CJ, Jr., O'FALLON WM, NELSON AM: The epidemiology of juvenile arthritis in Rochester, Minnesota 1960- 1979. Arthritis Rheum. 1983, 26:1208-1213. Abstract: A 20-year community-based study of the epidemiology of juvenile arthritis in Rochester, Minnesota from January 1, 1960 to January 1, 1980 is described. Cases were identified using the 1977 revised American Rheumatism Association criteria for juvenile arthritis. Higher incidence and prevalence rates and a greater predominance of pauciarticular disease were observed than previously reported. Lower rates were observed when a minimum of 3 months' disease duration was used to identify incidence