Multidisciplinary studies - including clinical, immunologic, pathologic, epidemiologic and molecular genetic investigations - are being used to complement findings in each area and overcome limitations inherent in each approach. Current studies are focusing on: exploring possible environmental risk and protective factors; identifying genetic risk and protective factors by candidate gene and whole genome SNP analyses; defining the associations among clinical, laboratory and immunologic features of autoimmune diseases for diagnostic, prognostic and pathogenic purposes; and understanding differences in epigenetics, gene expression and proteomic patterns between monozygotic twins discordant for disease. Evaluation of exposures to silica, organic solvents, ultraviolet light, vaccinations, selected drugs and dietary supplements, hormones and pregnancy, tobacco smoke, stressful life events and infectious agents in the development of systemic autoimmune diseases are being conducted via the Twin-sibs study. ? ? A group of poorly-understood, life-threatening autoimmune muscle diseases called the idiopathic inflammtory myopathies (IIM) or myositis syndromes are defined by chronic muscle inflammation and weakness associated with specific autoantibodies. There appear to be many different types of myositis based on the clinical presentations, pathology and the specific autoantibodies that develop. Both our worldwide and U.S. studies suggest that ultraviolet radiation exposure may modulate the clinical and immunologic expression of myositis in different populations. Ultraviolet radiation exposure strongly correlated with the prevalence of dermatomyositis and associated anti-Mi-2 autoantibodies directed against a 220 kD member of the SNF2/RAD54 helicase family, which is a major component of the nucleosome remodeling and histone deacetylase (NuRD) complex. Studies in collaboration with Trevor Archer are ongoing to understand the molecular effects of ultraviolet radiation and estrogen on the expression and function of the Mi-2 target autoantigen.? ? In collaboration with Ira Targoff, we have identified a new myositis autoantibody directed against a 155 kD nuclear protein of unknown function as the most common autoantibody in juvenile-onset dermatomyositis and one common in adult dermatomyositis as well. Patients with anti-p155 have a unique HLA risk factor, DQA1*0301 and are clinically distinct from patients with anti-synthetases or anti-SRP autoantibodies. Studies to define the target autoantigen are underway.? ? To evaluate whether seasonal early environmental exposures might influence later development of autoimmune disease, we assessed distributions of birth dates in groups of patients with idiopathic inflammatory myopathies (IIM). We assessed birth patterns in groups of patients with IIM and controls. Birth dates were analyzed as circular data. Seasonal clustering was assessed by the Rayleigh test, and differences between groups by a rank-based uniform scores test. We found that the overall birth distributions among patients with juvenile IIM and among patients with adult IIM did not differ significantly from those among juvenile and adult controls, respectively. Some subgroups of patients with juvenile IIM had seasonal birth distributions. Hispanic patients with juvenile-onset IIM had a seasonal birth pattern (mean birth date October 16) significantly different from that of Hispanic controls, who had a uniform birth distribution, and from that of non-Hispanic patients with juvenile-onset IIM, who had a mean birth date of May 2. Juvenile dermatomyositis patients with p155 autoantibody had a birth distribution that differed significantly from that of p155 antibody-negative juvenile dermatomyositis patients. Juvenile IIM patients with the HLA risk factor allele DRB1*0301 had a birth distribution significantly different from those without the allele (P = 0.021). Similar results were observed for juvenile and adult IIM patients with the linked allele DQA1*0501, versus juvenile and adult IIM patients without DQA1*0501, respectively. No significant patterns in birth season were found in other subgroups. We conclude that birth distributions appear to have stronger seasonality in juvenile than in adult IIM subgroups, suggesting greater influence of perinatal exposures on childhood-onset illness. Seasonal early-life exposures may influence the onset of some autoimmune diseases later in life.? ? We have also defined new genetic risk and protective factors for myositis in African Americans and children. Molecular genetic analyses of HLA-A, B, Cw, DRB1, and DQA1 polymorphisms were performed in a large population of African American patients with IIM in whom the major clinical and autoantibody subgroups were represented. These data were compared with similar information previously obtained from European American patients with IIM. In contrast to European American patients with IIM, African American patients with IIM, in particular those with polymyositis, had no strong disease associations with HLA alleles of the 8.1 ancestral haplotype; however, African Americans with dermatomyositis or with anti-Jo-1 autoantibodies shared the risk factor HLA-DRB1*0301 with European Americans. We detected novel HLA risk factors in African American patients with myositis overlap (DRB1*08) and in African American patients producing anti-signal recognition particle (DQA1*0102) and anti-Mi-2 autoantibodies (DRB1*0302). DRB1*0302 and the European American-, anti-Mi-2-associated risk factor DRB1*0701 were found to share a 4-amino-acid sequence motif, which was predicted by comparative homology analyses to have identical 3-dimensional orientations within the peptide-binding groove. These data demonstrate that North American IIM patients from different ethnic groups have both shared and distinct immunogenetic susceptibility factors, depending on the clinical phenotype. These findings, obtained from the largest cohort of North American minority patients with IIM studied to date, add additional support to the hypothesis that the myositis syndromes comprise multiple, distinct disease entities, perhaps arising from divergent pathogenic mechanisms and/or different gene-environment interactions.? ? In children with dermatomyositis (DM), we defined the relative importance (RI) of class II major histocompatibility complex (MHC) alleles and peptide binding motifs as risk or protective factors. Random Forests classification and multiple logistic regression were used to assess the RI of the HLA associations. The HLA-DRB1*0301 allele was a primary risk factor, while DQA1*0301, DQA1*0501 and homozygosity for DQA1*0501 were additional risk factors for juvenile DM. These risk factors were not present in patients with adult DM without defined autoantibodies. DQA1 alleles *0201, *0101 and *0102 were identified as novel protective factors for juvenile DM, the latter 2 also being protective factors in adult DM. The peptide binding motif DRB1 (9)EYSTS(13) was a risk factor, and DQA1 motifs F(25), S(26), and (45)(V/A)W(R/K)(47) were protective. Random Forests classification analysis revealed that among the identified risk factors for juvenile DM, DRB1*0301 had a higher RI (100%) than DQA1*0301 (RI 57%), DQA1*0501 (RI 42%), or the peptide binding motifs. In a logistic regression model, DRB1*0301 and DQA1*0201 were the strongest risk and protective factors, respectively, for juvenile DM. Thus, we identified DRB1*0301 as the primary genetic risk factor for juvenile DM.? ? Studies are now focusing on whole genome SNP scans in myositis, which will be facilitated by the International Myositis Genetic Consortium (MYOGEN) that we have formed to define additional genetic risk and protective factors in adults and children with these incurable and life-threatening diseases.
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