Autoimmune diseases are often incurable, 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 these 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 contaminants 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 systemic rheumatic diseases as prototypic autoimmune diseases from which we hope that principles learned in these disorders may be applied generally to other autoimmune diseases. In this area our accomplishments this year include: - Sera and cell banks and databases of clinical and genetic data have been developed from idiopathic myositis patients around the world, both adult and juvenile, to compare the environmentally-related cases to this population and to gain an understanding of possible pathogenetic mechanisms in these disorders in different populations. Recent studies suggest that the phenotypic expression and genetic risk and protective factors for myositis differ in different ethnogeographic groups at four chromosomal loci in different geographic environments. - We found that global UV radiation as measured from satellite data 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 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. - Recent data suggest that microchimerism 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. - The genomic organization, transcriptional mapping, and evolutionary implications of the novel human bi-directional histidyl-tRNA synthetase locus (HARS/HARSL) have been reported. HARS is the most common autoantigen in myositis patients and information about its transcriptional and translational control may aid in understanding the mechanisms for the immune targeting of this protein involved in translational regulation. The HARS and HARSL genes each contain 13 exons with strong structural and sequence homology over exons 3-12. HARS transcripts originate from two distinct promoters; a cluster of short transcripts map 15-65 bp upstream of the HARS ORF while a single, longer transcript (352 bp 5'-UTR) maps to a distal promoter. Similarly, multiple HARSL transcripts (mapping 10-198 bp upstream of its ORF) are produced by the shared bi-directional prom ARSL loci are homologous and support a model of inverted gene duplication to explain the emergence of HARSL during mammalian evolution. Future studies will define the regulatory control regions and modulators of this bidirectional promotor. - In FY2002, we completed recruitment of the EAG staff, formally established our clinics, and planned the initiation of a number of new hypothesis-testing and hypothesis-generating clinical studies. Specific investigations now underway include: - Case control studies to identify additional genetic risk factors for adult and juvenile myositis and their clinical and serologic subsets are ongoing with collaborators. 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 and IL1 alpha and beta regulatory non-coding regions. - A hypothesis-testing case control study of genetic risk factors for myositis following silicone implants is ongoing. Preliminary data suggest that the myositis that develops after silicone implants differs from idiopathic myositis in frequencies of HLA DRB1 and DQA1 alleles. Subjects meeting myositis criteria following silicone implants or injections are being enrolled and are being matched 1:2 with two control groups: age-, gender-, race-, and silicone-exposure matched controls and age-, gender-, race-matched IIM patients without silicone implant exposure. - A hypothesis-generating case control study of phenotypes and genetic risk/protective factors associated with myositis following vaccinations is nearing completion. Numerous case reports and case series, as well as biologic plausibility from animal models, support the concept that certain foreign antigens in vaccines may trigger harmful immune responses in genetically susceptible individuals. Subjects who developed myositis within 6 months of vaccination have been enrolled in this protocol and are being matched with two control groups: age-, race-, and vaccine-exposure matched controls and age- and race-matched IIM patients without vaccine exposure within 6 months of disease onset. - Genetic risk factors for the development of microchimerism are being defined. Although other investigators have reported HLA DQA1*0501 as risk factor for microchimerism, preliminary data from our collaborative studies with Carol Artlett suggest that this allele is not a risk factor in all autoimmune diseases and that certain alleles may be protective. Cohort control studies are being planned to confirm these findings in other autoimmune diseases and on other alleles. - Determination of the identity, clinical associations and genetic risk factors for new disease-specific target autoantigens, including a recently identified 155kD protein of unknown function, targeted more commonly in juvenile dermatomyositis than adult IIM.
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