Environmental/genetic Risk Factors and Pathogenesis of Autoimmune Disease

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Multidisciplinary studies, including immunologic, pathologic, epidemiologic and molecular genetic investigations, are being used. 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 and sequencing analyses; defining the associations among clinical, laboratory and immunologic features of autoimmune diseases for diagnostic, prognostic and pathogenic purposes; and understanding differences in gene expression and proteomic patterns between monozygotic twins discordant for disease. Evaluation of exposures to silica, organic solvents and other xenobiotics, ultraviolet light, vaccinations, selected drugs, hormones and pregnancy, tobacco smoke, stressful life events and infectious agents in the development of systemic autoimmune diseases are being conducted. A group of poorly-understood, life-threatening autoimmune muscle diseases called the myositis syndromes or idiopathic inflammatory myopathies (IIM) are defined by chronic muscle inflammation and weakness and are associated with specific autoantibodies. The major forms of myositis are polymyositis (PM), in which multiple muscles are affected by inflammation, and dermatomyositis (DM), in which patients also develop skin inflammation. Yet there appear to be other types of myositis based on the clinical presentations, pathology and autoantibodies. We are studying both the adult and juvenile (JIIM) forms of these diseases to understand possible differences in pathogenesis and risk factors. One area of investigation in which we have made recent advances involves identifying new genetic associations with juvenile and adult IIM. To accomplish this goal, we formed collaborations with investigators around the world, called the Myositis Genetic Consortium (MYOGEN). We performed a genome-wide association study (GWAS) of adult and juvenile myositis patients of European ancestry. Single-nucleotide polymorphisms showing strong associations in GWAS were identified in the major histocompatibility complex (MHC) region, specifically the 8.1 ancestral haplotype (AH8.1), for all myositis, as well as for the four clinical and autoantibody phenotypes. Although the HLA DRB1*03:01 allele showed stronger associations with adult and juvenile DM, and HLA B*08:01 with PM and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for full risk. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations. These studies have found that genes associated with other autoimmune diseases are also seen in myositis phenotypes. Low copy numbers of C4T, C4L, and C4A, that result in C4A deficiency, were found to be present in IIM. C4A deficiency was found to be a risk factor for IIM, including for all subgroups (DM, JDM, PM, IBM) and for those with IIM autoantibodies. For DM and JDM, C4A deficiency was independent of the presence of HLA-DRB1*03, while in PM and IBM there was an interaction of C4A deficiency with HLA-DRB1*03 that increased risk. From a larger study of 2565 IIM patients involving more detailed genome-wide imputations using the Immunochip array, the HLA region was re-confirmed as the most significant risk factor. Additionally, STAT4 and DGKQ were confirmed as risk factors in all IIM. New risk factors were identified, including SDK2 and LINC00924, as well as subgroup specific associations of NAB1 and FAM167A-BLK in PM, and CCR5 in IBM. A number of these loci were intergenic, but associated with active transcription within B and T cells. These loci overlap with risks for other autoimmune disease, including RA, SLE, and systemic sclerosis. We have examined environmental factors as risk factors for myositis. Tobacco smoking has been associated with clinical and autoantibody myositis phenotypes in Caucasians. Caucasian ever-smokers were more likely to have PM (adjusted odds ratio, OR=2.24), and anti-Jo-1 autoantibodies (adjusted OR=1.94) and less likely to have anti-p155/140 autoantibodies. In Caucasians, ever-smokers with HLA-DRB1*03:01 allele had the highest odds of PM, ILD, and anti-Jo-1 autoantibodies. In a national myositis patient registry, differences in the prevalence of myositis subgroups was evident across the continental United States, with higher concentrations of patients with DM and IBM in the Northeast, with lung disease in the East and one pocket in the South, and of PM in the Southeast. There was a trend of higher prevalence near major roadways, esp in IBM, possibly due to air pollution exposure. From data in this registry, ambient UV radiation and a history of sunburn prior to diagnosis was associated with DM compared by PM and IBM. Antibody reactivity to flagellin, seen in gut bacteria, was frequent in JDM, especially in younger children who are anti-TIF1g antibody-positive. We have found through national surveillance data, NHANES, that the prevalence of a positive anti-nuclear autoantibody (ANA), as a common precursor and surrogate for autoimmune disease, has risen in recent years: 11.0% of the population sample had a positive ANA in 1998-1991, and 15.9% are positive in 2011-2012, corresponding to 22 million and 41 million affected individuals in the United States. ANA prevalence notably increased among adolescents ages 12-19 years, in older adults and non-Hispanic whites. Trends in obesity, smoking and alcohol usage did not explain the rise in ANA prevalence over this period of time. Further investigation has supported associatitons of ANA with dioxin-like compounds, including certain polychlorinated biphenyls. Further investigation is ongoing to determine factors underlying these increases in ANA prevalence, which may enable the development of preventable measures for autoimmune diseases. In examining gene expression and proteomic data in the blood of patients with adult and juvenile DM/JDM, we found a subset of interferon-stimulated genes was elevated. Innate immune markers specific to neutrophil granules and NETs were up-regulated in both DM and JDM. Pathway analysis revealed up-regulation of PI3K/AKT, ERK, and p38 MAPK signaling, whose central components were broadly up-regulated in DM, while peripheral upstream and downstream components were differentially regulated in both DM and JDM. Up-regulated components shared by DM and JDM included several cytokine:receptor pairs, Bcl-2 components, and glycolytic enzymes. Pathways unique to DM included sirtuin signaling, aryl hydrocarbon receptor signaling, protein ubiquitination, and granzyme B signaling. The combination of proteomics and transcript expression by multi-enrichment analysis broadened the identification of dysregulated pathways in DM/JDM. From a proteomics study of JDM patient urine, cathepsin D and galectin-3 binding protein were confirmed as candidate biomarkers of JDM disease activity and damage. We also found frequent presence of autoantibodies to Sp4, a transcription factor, in patients with JDM with anti-TIF1g autoantibodies. This autoantibody was protective for cancer in adult DM, and here associated with Raynaud's and milder weakness. Anti-TPM4 autoantibodies were found to be associated with vasculopathic features in JDM.