Autoimmune diseases are acquired, incurable disorders that result in great costs to our society and appear to be increasing in prevalence in the population. These disorders are thought to be the result of chronic immune activation by selected environmental exposures in genetically susceptible individuals. The reasons for the reported increases in autoimmune diseases are unclear, although our increasing exposure to novel immune-altering foods, drugs, occupational exposures and air, water and other environmental constituents may play a role in this phenomenon.
The aims of this project are to uncover pathogenic mechanisms, and environmental/genetic risk factors, that lead to these diseases that result in high morbidity and mortality. We are focusing on both the adult and juvenile forms of systemic rheumatic diseases as prototypic autoimmune diseases from which we hope that principles learned in these disorders may be applied generally to other diseases. Multidisciplinary studies -- including clinical, laboratory, immunologic, pathologic, epidemiologic, molecular and genetic investigations -- are being used to complement findings in each area and attempt to overcome limitations inherent in each approach. Disorders now under study include: rheumatoid arthritis, systemic lupus erythematosus, scleroderma and myositis. Current studies are focusing on: defining the associations among clinical, laboratory and immunologic features of these autoimmune diseases for diagnostic, prognostic and pathogenic purposes; understanding genetic risk and protective factors by candidate gene analyses and TdT approaches; exploring the roles of maternal-fetal and fetal-maternal microchimerism in these human diseases and animal models; beginning to define differences in gene expression patterns between monozygotic twins discordant for disease; using the natural variation in genes and environments around the world to decipher the ethnogeography of myositis; and exploring possible environmental risk and protective factors for these diseases. A new protocol, Pathogenic Studies in Families with Twins or Siblings Discordant for Systemic Rheumatic Disorders (NIH protocol 03-E-0099, The Twin-sib Study), was initiated and adult and pediatric subject enrollment and recruitment is ongoing to complete enrollment of 400 families over the next three years. This protocol will enroll 100 families in which twins or close siblings are discordant for each of the four major disorders above under study ? about half will be subjects with juvenile-onset disease and half will be subjects with adult-onset disease. Regarding the ethnogeography of autoimmune disease, we found that global UV radiation as measured from NOAA/NASA satellites best predicts the proportion of dermatomyositis patients and anti-Mi-2 autoantibodies (directed at an SNF2 helicase) around the world. Altogether, 913 consecutive patients from populations at 15 global locations were studied. Univariate and multivariate analyses demonstrated that of the 12 geoclimatic variables evaluated, surface ultraviolet radiation intensity (irradiance) most strongly contributed to the relative proportion of dermatomyositis, and was strongly related to the proportion of anti-Mi-2 autoantibodies (weighted r = 0.93, P = 7 X 10-7; and r = 0.69, P = 0.02, respectively). Published ethnogeographic MHC allele frequencies imply that the striking differences in the proportion of dermatomyositis and dermatomyositis-specific autoantibodies observed around the world are not the result of inherent global variations in known genetic risk factors. These data suggest that ultraviolet radiation exposure may modulate the clinical and immunologic expression of an autoimmune disease in different populations around the world. Our and others data suggest that microchimerism (the finding of cells from one individual in another person) may play a role in the pathogenesis of several autoimmune diseases. Both peripheral blood cells (CD4+ and CD8+ cells) and target tissues (muscle and skin) from juvenile myositis patients have been shown to contain maternal cells by FISH and HLA-C PCR in higher proportions compared to controls, suggesting graft-versus-host-like pathogenic mechanisms and possible new approaches to the treatment of myositis. We recently were unable to confirm genetic associations of microchimerism with HLA DQA1*0501 in all diseases as proposed by others, but rather discovered that HLA genes confer susceptibility to or protection from microchimerism only in selected autoimmune disease subsets, and do not appear to have a role in the persistence of microchimerism in healthy individuals. Dr. Sarkar is assessing the role of maternal-fetal and fetal-maternal microchimerism in the development of systemic rheumatic disease by evaluating 400 families with twins and close siblings discordant for disease. Microchimerism is being assessed by highly sensitive, complementary methods including HLA-C PCR, SYR-RT-PCR and FISH using validated molecular probes for X and Y chromosomes. An animal model of myositis -- Experimental Autoimmune Myositis or EAM, induced by subcutaneous injection of myosin and complete Freund?s adjuvant -- is being developed in mice transgenic for green fluorescent protein (GFP) by Dr. Sarkar to assess the role of microchimerism in the development of autoimmunity. We are a completing cohort control study to identify additional genetic risk and protective factors for adult and juvenile myositis and their clinical and serologic subsets. Candidate polymorphic loci being studied include HLA A, B, C, DRB1 and DQA1, killer cell immunoglobulin-like receptor (KIR) and chemokine receptors, immunoglobulin Gm and Km markers, and TNF alpha and IL1 alpha and beta regulatory non-coding regions. Studies of a major complication of myositis and other related diseases, the development of dystrophic calcification in muscle and subcutaneous tissues, are underway to understand the immunopathology and unique gene expressions relating to bone morphogenic proteins, in hopes of understanding pathogenesis of this currently untreatable and sometimes life-threatening manifestation of autoimmune diseases. Preliminary data suggest that the myositis that develops after silicone implants may be associated with unique HLA, Gm and Km markers and we are completing a matched case control study comparing the clinical, immunologic and genetic features of myositis developing after silicone implants with idiopathic myositis and with normal subjects with silicone implants.
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