Neuromyelitis Optica (NMO IgG+) and Genetic Susceptibility, Potential Ethnic Influences.

INTRODUCTION: Neuromyelitis optica (NMO) and Multiple Sclerosis (MS) have been reported in different populations. NMO is more frequent in non-Caucasians, and clinical phenotype differences between populations are likely influenced by genetic susceptibility. In Brazil, it has been reported that NMO patients have a mainly European ancestry background. Like other autoimmune diseases, NMO has a multifactorial origin (i.e., genetics, environmental and infectious factors). Regarding the genetics of NMO, epidemiological findings suggest that a polygenic background has an important role in the development of this type of disease. In this context, various genes have been studied, such as those involved in the synthesis of the T cell beta chain receptor, the VH2-5 gene, myelin basic protein, the CTLA-4 gene, and the interleukin-1 gene. MATERIALS AND METHODS: We performed a study with the main objective of identifying candidate genes involved in the susceptibility to develop NMO in a Mexican population. RESULT: We included 35 patients with an NMO diagnosis according to the Wingerchuk 2006 criteria. The mean age of the patients was 43.3 years old (20-67), and 80 percent of the patients were women. The presence of HLA-DRB1*03 and HLA-DRB1*10 alleles were more frequent in NMO patients than in controls (n=198; p=0.03 and 0.005, respectively). CONCLUSION: There were no differences in the other alleles that have been described in MS subjects, such as HLA-DRB1*04, HLA-DRB1*08 and HLA-DRB1*13. These findings may support the hypothesis that implicated immune-genetics as a key factor in development of this type of disease.

Autoimmune hepatitis in the Alaska Native population: autoantibody profile and HLA associations.

BACKGROUND & AIMS: The Alaska Native population is one of few populations in the world with a high prevalence of autoimmune hepatitis. The objective of this study was to determine the frequency and HLA and clinical associations of autoantibodies in Alaska Native people with autoimmune hepatitis. METHODS: Alaska Native individuals with autoimmune hepatitis were recruited in clinics conducted statewide. Sera were tested for the presence of autoantibodies described in either autoimmune hepatitis or rheumatic disease. Associations between autoantibodies and HLA alleles and clinical features were assessed. RESULTS: Seventy-one patients were included. At the study visit, 34 patients (47.9%) had antibodies to double-stranded DNA by immunofluorescence; 27 (38.0%) had anti-neutrophil cytoplasmic antibodies; and 11 (15.5%) had anti-Ro antibodies. Only one person had antibodies against soluble liver antigen, and in that person, anti-Ro was absent. Associations were found between autoantibodies and HLA alleles, including positive associations between HLA DR3 and anti-double-stranded DNA antibodies and between HLA DR14 and antineutrophil cytoplasmic antibodies. There was no association between autoantibodies and clinical outcomes. CONCLUSIONS: As in other populations, the prevalence of anti-double-stranded DNA antibodies and antineutrophil cytoplasmic antibodies is high in Alaska Native people with autoimmune hepatitis. In contrast to data from other populations, there is a lower prevalence of anti-soluble liver antigen and a lack of association between anti-Ro and anti-soluble liver antigen. In addition, the HLA profile and associations with autoantibodies are unique. No clear prognostic implications of autoantibodies have emerged in this population.

Autoantibody and human leukocyte antigen profiles in children with autoimmune liver disease and their first-degree relatives.

OBJECTIVE: Familial clustering of juvenile autoimmune liver disease (AILD), including autoimmune hepatitis and autoimmune sclerosing cholangitis (ASC), is rare, despite a high prevalence of autoimmune disorders in AILD families. METHODS: To investigate this discrepancy, we measured autoantibodies diagnostic for AILD, anti-nuclear, anti-smooth muscle, anti-liver kidney microsomal type 1, anti-liver cytosol type 1, and anti-soluble liver antigen antibodies, and human leukocyte antigen profiles in 31 patients and 65 of their first-degree relatives (FDR). The autoantibody profile was compared with that of 42 healthy subjects (HS). RESULTS: Autoantibodies were detected in 71% (22/31) patients. Anti-nuclear antibody or anti-smooth muscle antibody were present in 4/65 FDR (6.2%). HS were negative for all autoantibodies. The frequencies of homozygous HLA DRB1*0301 (DR3) genes and haplotype A1-B8-DR3 were higher in the patients (25% and 43%) than in FDR (9% and 27%) and HS (0% and 16%). The frequencies of disease-protective genes DR4 and/or DR15 were lower in the patients (25%) than in FDR (42%) and HS (42%). Only 1 family contained 2 patients with AILD, 1 with ASC and 1 with primary sclerosing cholangitis. Both patients possessed A1-B8-DR3 genes, the ASC being homozygous and the primary sclerosing cholangitis heterozygous. Six FDR had nonhepatic autoimmune disorders, none being autoantibody positive. CONCLUSIONS: Homozygosity for DR3 plays a major role in the predisposition to juvenile AILD. Diagnostic autoantibodies for AILD are rare among patients' FDR and not linked to clinical manifestation of AILD.

Clinical features of elderly Chinese patients with autoimmune hepatitis.

BACKGROUND/AIMS: To study the clinical features of elderly Chinese patients with autoimmune hepatitis. MATERIALS AND METHODS: The clinical features of 36 patients diagnosed at age >60 years were compared with those of 39 patients aged <50 years. RESULTS: The M:F ratio was 1:35 (>60 years) vs. 3:36 (<50 years). The patients >60 years had a higher frequency of cirrhosis at presentation than the patients <50 years (52.8% vs. 15.4%, p=0.001). The patients >60 years also had a significantly increased incidence of ascites at presentation (41.7% vs. 10.3%, p=0.001) and lower serum albumin levels (p=0.037). There were significant differences between older and younger patients with respect to the frequencies or titers of anti-nuclear antibody (46.2% vs. 83.3%, p=0.011). HLA DR3 positivity occurred more frequently in the patients <50 years than in those >60 years (59.0% vs. 19.4%, p<0.001), whereas HLA DR4 occurred more often in the patients >60 years (63.9% vs. 25.6%, p=0.001). Treatment failure occurred more frequently in the patients <50 years (28.2% vs. 9.1%, p=0.041). However, there were no significant differences between the groups with respect tomode of onset, other clinical signs at presentation biochemical parameters, and smooth muscle antibody positivity. CONCLUSION: Elderly patients have a greater frequency of cirrhosis at presentation, anti-nuclear antibody, HLA DR4 positivity than patients <50 years, and they have a lower occurrence of treatment failure. Conventional corticosteroid regimens may be an effective management for older patients with autoimmune hepatitis.

Autism spectrum disorders are associated with an elevated autoantibody response to tissue transglutaminase-2.

We report that a significant number of autistic children have serum levels of IgA antibodies above normal to the enzyme tissue transglutaminase II (TG2), and that expression of these antibodies to TG2 is linked to the (HLA)-DR3, DQ2 and DR7, DQ2 haplotypes. TG2 is expressed in the brain, where it has been shown to be important in cell adhesion and synaptic stabilization. Thus, these children appear to constitute a subpopulation of autistic children who fall within the autism disease spectrum, and for whom autoimmunity may represent a significant etiological component of their autism.

Interferon-gamma is increased in patients with primary Sjogren's syndrome and Raynaud's phenomenon.

OBJECTIVES: To determine the prevalence of Raynaud's phenomenon (RP) in patients with primary Sjogren's syndrome (pSS) and to identify clinical and immunological characteristics associated with this manifestation. Since increased interferon-gamma (INF-gamma) has been associated with RP, we also compared the INF-gamma production in pSS patients with or without RP. METHODS: RP was diagnosed if pSS patients presented with characteristic sequence of skin color changes of the digits. In uncertain cases noninvasive vascular tests were performed by ultrasound examination. The secretion of INF-gamma by peripheral blood mononuclear cells was assessed by enzyme-linked immunospot analysis. Further, we examined the expression of different lymphocyte activation markers (CD25, CD45RO, CD69) on CD4+ T-cells by flow cytometric analysis. RESULTS: Thirty-six of 108 patients with pSS had RP. In these patients we found a significantly increased number of INF-gamma-secreting peripheral blood mononuclear cells compared with patients without RP or to healthy controls. Further, in patients with RP a significantly increased percentage of CD25-positive T-helper cells was detectable. In addition we found an association of leukopenia, thyroiditis, and lower C3 levels with RP in pSS patients. CONCLUSIONS: These results suggest a pathogenic role of INF-gamma in pSS patients with RP. Whether the RP is immune-mediated or whether INF-gamma directly causes vasospasm still remains to be elucidated.

Clinical features of Japanese elderly patients with type 1 autoimmune hepatitis.

OBJECTIVE: In Caucasian type 1 autoimmune hepatitis patients with a main susceptibility of human leukocyte antigen DR3 and DR4, elderly patients have a higher frequency of concurrent autoimmune disease and cirrhosis at presentation. However, in Japanese patients, the disease is dominantly associated with DR4, and their clinical features may be different from those of previous reports. In this study, we assessed the clinical features of Japanese elderly patients with type 1 autoimmune hepatitis. METHODS: We investigated 160 consecutive patients with type 1 autoimmune hepatitis, consisting of 34 elderly patients (> or = 65 years) and 126 younger patients (< 65 years). RESULTS: There were no differences in form of clinical onset, frequencies of concurrent autoimmune disease, positive proportions of anti-nuclear antibody and/or anti-smooth muscle antibody, and human leukocyte antigen DR status between the two groups. However, the elderly patients had lower serum levels of albumin (p=0.0049), and higher frequencies of cirrhosis (F4) and pre-cirrhosis (F3) (p=0.014) compared with the younger patients. In contrast, in elderly patients, the cumulative incidental rate of the normalization of serum alanine aminotransferase levels within 6 months after the introduction of initial treatment was higher in those treated with prednisolone > or = 20 mg/day than those treated only with ursodeoxycholic acid (p=0.001). CONCLUSION: We speculate that more years may pass between the occurrence of the disease and the presentation in Japanese elderly patients than in younger patients, and we considered that, even in elderly patients, those with advanced fibrosis should be treated with prednisolone in order to prevent progress of the disease into liver failure.

Genetic control of immune response in carriers of the 8.1 ancestral haplotype: correlation with levels of IgG subclasses: its relevance in the pathogenesis of autoimmune diseases.

Ancestral haplotype (AH) 8.1(HLA-A1, Cw7, B8, TNFAB*a2b3, TNFN*S, C2*C, Bf*s, C4A*Q0, C4B*1, DRB1*0301, DRB3*0101, DQA1*0501, DQB1*0201) seems to be associated with susceptibility to autoimmune diseases. Different mechanisms are probably involved in increasing autoimmunity, such as unbalanced cytokine production and the lack of C4A protein. So AH 8.1 modifies immune response in many ways. In this study we demonstrate that IgG2 serum levels were significantly lower in 8.1 AH carriers than in 8.1 AH non-carriers. On the contrary, as regards IgG1, IgG3, IgG4 serum levels, no significant differences were observed between the two groups. In AH 8.1 carriers low IgG2 levels might take to slower clearance of the infectious agent and hence to a lasting presence of it. The persistence of infectious antigens could determine an increased production of autoantibodies with a higher risk of cross-reactions.

Predictors of graft and patient survival in hepatitis C virus (HCV) recipients: model to predict HCV cirrhosis after liver transplantation.

BACKGROUND: Hepatitis C virus (HCV) recurrence after liver transplantation (LT) is almost universal, but the natural history of recurrent HCV in the allograft is highly variable. Our study had two aims: 1) to assess the impact of different pre- and postLT factors on graft and patient survival in HCV transplant recipients and 2) to create a model which may predict the patients at risk for HCV-related graft cirrhosis at 5 years postLT. METHODS: A total of 168 LTs were considered for this study. Univariate and multivariate Cox proportional hazards regression model was used, as well as logistic regression analysis to create a model of prediction of HCV cirrhosis within 5 years after LT. RESULTS: Predictive factors for both decreased graft and patient survival included patients recently transplanted (2000-2004), induction without azathioprine, short-term therapy with mycophenolate mofetil and prednisone (< or =6 months), presence of early cholestasis, histologically proven early recurrence of hepatitis C. Recipient human leukocyte antigen DR3 positivity, presence of early cholestasis, and donor age >50 years were identified as independent predictors of graft cirrhosis within 5 years. A predictive model was established in order to calculate at 6 months a risk score for graft HCV cirrhosis within 5 years postLT using a formula that included the identified independent predictors. The area under receiver operating characteristic curve was 0.83, indicating a good ability to predict medium-term HCV allograft cirrhosis. CONCLUSION: This model may be a useful tool for better identifying high-risk HCV patients who should be selected for early initiation of antiviral therapy.

Don't do anything rash!

BACKGROUND: Peripartum and postpartum dermatologic lesions may or may not be an indicator of morbidity or mortality for either the fetus or mother. CASE: Postpartum dermatologic lesions occurred in a 41-year-old multipara, 1 week after a repeat cesarean delivery for severe intrauterine growth restriction and nonreassuring fetal testing. The diagnosis, using histopathologic techniques, and the pharmacologic management are discussed. CONCLUSION: This case raises intriguing questions regarding prompt diagnosis, treatment, and the counseling of patients with dermatologic lesions with respect to current and future pregnancy outcomes.

Genetic association of autoimmune hepatitis and human leucocyte antigen in German patients.

AIM: To report on our large German collective and updated data of 142 patients with autoimmune hepatitis (AIH) type 1. METHODS: Key investigations performed were liver biopsy, serum autoantibodies as well as serum markers such as IgG and elevated transaminases. Antinuclear antigen (ANA) and smooth muscle antigen (SMA) autoantibodies characterized type 1 AIH. Type 3 (AIH) was solely characterized by the occurrence of soluble liver antigen/liver-pancreas antigen (SLA/LP) autoantibodies either with or without ANA or SMA autoantibodies. RESULTS: Most prevalent HLAs were A2 (68 patients, 48%), B8 (63 patients, 44%), C7 (90 patients, 63%), DR3 (49 patients, 38%), DR4 (49 patients, 38%) and DQ2 (42 patients, 30%). Compared to the Italian and North American patients, we found fewer patients with a DQ2 subtype. Furthermore, the B8-DR3-DQ2 human leucocyte antigen (HLA) was also less prominent compared to the North American patients. However, prevalences of B8, DR3, DR4, DR7, DR11 and DR13 were comparable to the Italian and North American patients. Furthermore, we report on an additional subgroup of patients with SLA/LP positive AIH. Generally, in this subgroup of patients the same HLA subtypes were favoured as the AIH type 1. CONCLUSION: Although HLA subtypes were comparable between these three collectives, the German patients were distinct from the Italian and North American patients with respect to DQ2 and from the North American patients with respect to B8-DR3-DQ2 HLA. A clinical correlation, e.g. difference in severity or treatability of AIH type 1, has yet to be determined.

Frequency and significance of antibodies to cyclic citrullinated peptide in type 1 autoimmune hepatitis.

OBJECTIVES: Determine the frequency, clinical phenotype, and prognostic implications of antibodies against cyclic citrullinated peptides in patients with type 1 autoimmune hepatitis. METHODS: Three hundred and ninety-five serum samples from 179 patients were tested by enzyme-linked immunosorbent assay, and findings correlated with clinical and histological features, frequency of HLA DR3 and DR4, and treatment outcome. RESULTS: Twenty patients (11%) had antibodies against cyclic citrullinated peptides. Seropositivity was associated with a higher frequency of rheumatoid arthritis (RA) (25 vs. 0%, P < 0.001). Patients with antibodies against cyclic citrullinated peptides also had a significantly greater occurrence of histological cirrhosis at presentation (47 vs. 20%, P = 0.01) and death from hepatic failure than seronegative patients (25 vs. 9%, P = 0.04). Cirrhosis at presentation occurred more commonly in the patients with antibodies against cyclic citrullinated peptides and RA than in the other patients (100 vs. 21%, P = 0.005). CONCLUSIONS: Antibodies against cyclic citrullinated peptides occur in a subgroup of patients with type 1 autoimmune hepatitis who have a greater occurrence of cirrhosis at presentation and death from hepatic failure. Their presence with RA at accession characterizes a subgroup with cirrhosis.

Individual susceptibility to hexavalent chromium of workers of shoe, hide, and leather industries. Immunological pattern of HLA-B8, DR3-positive subjects.

BACKGROUND: This study was designed to examine the effects of hexavalent chromium [Cr(VI)] on the immunological pattern of shoe, hide, and leather industry workers, moving from the hypothesis that some haplotypes (HLA-B8,DR3) can be important hidden risk cofactors. METHODS: Workplaces of 20 firms were monitored for total and respirable dusts and for total and hexavalent chromium. Cr(VI) on materials was also measured. Assay of chromium levels in blood and urine of 44 serological human leukocytes antigen (HLA)-typed workers (20 exposed, 15 HLA-B8,DR3-negative/5-positive and 24 non-exposed, 18 HLA-B8,DR3-negative/6-positive subjects) was performed by atomic absorption, and lymphocyte subsets (FACS-analysis), mitogen-mediate lympho-proliferation ([3H]thymidine incorporation), cytokine levels (ELISA), natural killer (NK) cytotoxic activity (51Cr-release assay) were determined. RESULTS: The environmental parameter levels are lower than threshold limit value-time-weighted average (TLV-TWA); in the materials, the Cr(VI) values exceeded the levels allowed. The peripheral blood mononuclear cells (PBMC) proliferation and the T-helper1 (TH1) cytokine pattern of subjects chronically exposed were significantly raised; addition in vitro of Cr(VI) further stimulated these parameters and in general the entire TH1 system and NK activity. The TH2 system was unaltered. In the HLA-B8,DR3-positive workers, immunologically "low responders", the addition of Cr(VI) in vitro caused a further reduction of the considered parameters in the exposed subjects with a dramatic deficit of the TH1 system. CONCLUSIONS: Results indicate the unsuitability of TLV-TWA as a line of demarcation between safe and dangerous Cr(VI) concentrations and the importance of individual genetic susceptibility for occupational and preventative medicine. In particular, the presence of the HLA-B8,DR3 alleles can represent an important cofactor of immunotoxic susceptibility consequent to chronic low-dose Cr(VI) exposure.

Preproinsulin-specific CD8+ T cells secrete IFNgamma in human type 1 diabetes.

In animal models autoreactive CD8(+) T cells are crucial in the development of type 1 diabetes (T1D); however, their role in human T1D is still not known. To address the role of CD81 T cells we performed a pilot study by investigating CD8(+) T cell-mediated cytokine secretion after in vitro stimulation with 94 preproinsulin (PPI) peptides. We were able to show that CD8(+) T cells contribute to a strong IFNgamma reactivity against PPI in human T1D. Further investigations defining epitope specificity, cytokine secretion, and cytotoxic capacity are important to clarify their role in T1D development.

[Multiorgan autoimmune syndrome: case report]. / Osservazioni su un caso di sindrome autoimmune multipla.

The present case report refers to a multiorgan autoimmune disease manifesting following thymectomy performed for a benign thymoma. This disease is characterized by hypothyroidism, severe myasthenia, polymyositis and alopecia which are organ-specific diseases probably with a different time of onset but which are all an expression of the same immunopathologic process occurring in individuals who have a genetic predisposition. Characteristic of the present case is not only the association of the different immunopathologic clinical pictures but also the rather difficult differential diagnosis between a hypothyroidism-related myopathy and polymyositis. It was possible to formulate the diagnosis by integrating the results of clinical and laboratory evaluation with the therapeutic outcome. The onset of the syndrome was attributed to the withdrawal, following surgery, of the inhibitory effects of the thymoma on some clones of autoreactive lymphocytes.

HLA in Egyptian children with biliary atresia.

We studied the human leukocytes antigens in 18 Egyptian children with biliary atresia (BA) without extrahepatic congenital malformations. There was a significant increased frequency of both B8 and DR3 (83.3% and 94.4% in patients with BA compared with 6.5% and 14.9% in the general population, respectively). Ten patients had the B8/DR3 haplotype. Our results support the hypothesis that genetic factors may play a role in susceptibility to BA.

HLA-DR3 and DR4 and their relation to the incidence and progression of diabetic retinopathy.

PURPOSE: Cross-sectional data from the Wisconsin Epidemiologic Study of Diabetic Retinopathy indicated that patients with HLA-DR4, but not DR3, were more likely to have prevalent proliferative retinopathy than those without both antigens. We describe the relation of HLA-DR3 and DR4 antigens to the 14-year incidence and progression of diabetic retinopathy and macular edema in this cohort. DESIGN: A population-based cohort study. PARTICIPANTS: A probability sample of male and female patients receiving primary care for diabetes in 11 counties of southern Wisconsin. METHODS: Participants were invited for a baseline examination in 1980 to 1982, with follow-up examinations at 4, 10, and 14 years later. At the 4-year examination, a random sample of participants (n = 428) diagnosed with diabetes before the age of 30 and taking insulin were selected for HLA-DR typing. MAIN OUTCOME MEASURES: Fourteen-year incidence and progression of diabetic retinopathy and macular edema based on masked stereoscopic fundus photographic grading. RESULTS: There was no relation between HLA-DR3 and DR4 status with the 14-year incidence and progression of diabetic retinopathy, progression to proliferative retinopathy, and incidence of macular edema. Patients with either HLA-DR3 or DR4 were less likely to progress to proliferative retinopathy compared with those who were negative for both, although these relations were not statistically significant. The associations did not vary after adjusting for hypertension status, baseline retinopathy, and glycosylated hemoglobin levels, or after stratifying by duration of diabetes (less than 10 years vs. 10 years or more) and age at diagnosis of diabetes (less than 15 years vs. 15 years or more). Furthermore, 10-year mortality and 14-year nephropathy rates did not differ by HLA-DR3 or DR4 status, suggesting that selective mortality did not explain the pattern of associations seen. CONCLUSIONS: In contrast to the initial cross-sectional findings, these data suggest that HLA-DR3 or DR4 status is unrelated to 14-year incidence and progression of diabetic retinopathy. The discrepancy may be related to increasing homogeneity of retinopathy and diminishing power to detect small differences, but it may also reflect the uncertain and inconsistent effects of HLA-DR3 or DR4 on the development and progression of diabetic retinopathy.

Rheumatoid factors in systemic lupus erythematosus: association with clinical and laboratory parameters. SLE study group.

The prevalence and clinical and laboratory associations of IgM, IgG and IgA rheumatoid factors (RF) were determined in 352 patients with systemic lupus erythematosus (SLE). IgM, IgG, and IgA class RF were detected in 17.9%, 20.5%, and 20.5% of the sera, respectively. RF were associated with sicca syndrome, hypergammaglobulinemia, high titer of antinuclear antibodies, anemia, SSA- and SSB-antibodies, and with the presence of HLA-DR3. RF correlated negatively with nephritis and livedo racemosa. Moreover, we observed an association of RF and parameters of inflammatory activity such as elevated erythrocyte sedimentation rate (ESR) and leukopenia. Analysis of immunoglobulin classes revealed that laboratory parameters of inflammatory activity, SSA- and SSB-antibodies and HLA-DR3 correlated with IgA RF only. IgA RF define a subgroup of SLE patients characterized by distinct autoimmune phenomena and high disease activity in the absence of nephritis.

[Diabetes mellitus type I, celiac disease and Imerslund-Gräsbeck syndrome: only an incidental combination of rare diseases?]. / Diabetes mellitus Typ I, Zöliakie und Imerslund-Gräsbeck-Syndrom: nur eine ungewöhnliche Kombination seltener Erkrankungen?

We describe the clinical course of a girl with onset of type I diabetes mellitus at the age of 3 years. At the age of 10, coeliac disease and shortly thereafter a vitamin B12 deficiency anemia (Imerslund-Gräsbeck-syndrome) was diagnosed. Her younger sister also suffered from Imerslund-Gräsbeck-syndrome when she was 11 year old. This unusual, so far not described association of rare diseases suggests a common autoimmune etiology.

Adult linear IgA disease and chronic bullous disease of childhood: the association with human lymphocyte antigens Cw7, B8, DR3 and tumour necrosis factor influences disease expression.

Linear IgA disease and chronic bullous disease of childhood are both subepidermal autoimmune blistering diseases. Class I and II major histocompatibility locus (MHC) antigen typing was performed on 60 patients (26 chronic bullous disease of childhood, 34 adult linear IgA disease), and the findings were correlated with the clinical course. The typing was performed using a lymphocyte microcytotoxicity assay, and the results were compared with a reference population of U.K. organ donors. Analysis of the tumour necrosis factor (TNF) locus was performed using sequence-specific oligonucleotides on a dot blot in 51 patients and compared with a random control population and human lymphocyte antigen (HLA) DR3 matched controls. The disease was found to be significantly associated with HLA Cw7 (chi2 = 19.24, P = 0.001), B8 (chi2 = 9.89, P = 0.04) and DR3 (chi2 = 10.47, P = 0.014), all components of the common Caucasian haplotype. There was also a close association between the disease and possession of HLA DR2 or 3 (chi2 = 16.34, P = 0.001). A reduction in the incidence of DR1 and DR4 (alleles carrying the rheumatoid motif) was observed, which is more marked in the children (chi2 = 8.34, P = 0.039). In the childhood group there was an increased frequency of B8, DR3 and DQ2 compared with the adults which included five of 26 who were homozygous for these antigens, a feature not seen in the adults, which may account for the differences seen between the two groups. Possession of HLA B8, DR3 and DQ2 probably facilitates earlier presentation of the disease as there is no evidence from our results that the adults and children differ fundamentally in their MHC associations. The rare TNF2 allele was found in 29 of 51 patients (expected 8.2, chi2 = 18. 3, P = 0.0001). This was more marked in the children (19 of 26). Patients with the TNF2 allele had a longer disease duration (5.3 years TNF2, 3.0 years TNF1).