Autoimmune diseases are acquired, incurable disorders, affect up to 22 million Americans, are among the leading causes of death of young and middle-aged women, 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 dramatic increases in some autoimmune diseases remain unclear, although our increasing exposure to novel immune disrupters -- including foods, drugs, occupational exposures and air, water and other environmental constituents -- may play a role in this phenomenon. The evidence supporting the concept that autoimmune diseases have an environmental component includes: ? Less than 50% concordance rates in monozygotic twins for all autoimmune diseases studied; ? Strong temporal associations between certain exposures and the development of some autoimmune diseases; ? Documented dechallenge (disease improvement in certain individuals after removing a suspect environmental agent) and rechallange (disease worsening or recurrence after re-exposure to the suspect agent) data for dozens of drugs, biologics and other environmental agents; ? Seasonality and geographic clustering in disease onset in many disorders; ? Significant increases in the incidence and prevalence of many autoimmune diseases in recent decades; ? Associations of certain diseases or subgroups with birth dates; ? Strong biologic plausibility from a large variety of environmental agent-induced animal models of autoimmune diseases; and ? Epidemiologic associations, which have been confirmed in replication studies, between smoking, occupational exposure to silica dust, ultraviolet radiation, estrogens, selected infectious agents (especially Epstein Barr and Herpes zoster viruses) and certain autoimmune diseases. In addition to their role as initiators of autoimmunity, many lines of evidence suggest that environmental factors may also alter the rate of progression to clinical disease, the specific manifestations of disease expression and the course of illness. Based on these compelling data, and especially because of the recent dramatic increases in the incidence and prevalence of many autoimmune diseases for unknown reasons, we are focusing our efforts on the understudied area of environmental aspects of autoimmune diseases.
The aims of this project are to uncover environmental risk factors and pathogenic mechanisms that lead to these diseases that result in high morbidity and mortality. We are studying both the adult and juvenile forms of systemic autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, scleroderma and myositis) 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, environmental and genetic investigations -- are being used to complement findings in each area and attempt to overcome limitations inherent in each approach. Current studies are focusing on: exploring possible environmental risk and protective factors for these diseases; understanding genetic risk and protective factors by candidate gene analyses and other approaches; defining the associations among clinical, laboratory and immunologic features of these autoimmune diseases for diagnostic, prognostic and pathogenic purposes; exploring the roles of maternal-fetal and fetal-maternal microchimerism in human diseases and animal models; beginning to define differences in gene expression and proteomic patterns between monozygotic twins discordant for disease; and using the natural variation in genes and environments around the world to decipher the ethnogeography of autoimmune disorders. 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 rheumatoid arthritis, lupus, scleroderma and myositis are being conducted via the NIEHS Twin-sibs study. This study, which is recruiting 400 pairs of twins or close siblings discordant for these systemic autoimmune diseases, will also allow us to further assess the seasonal associations with disease onset and to determine if they might relate to specific infectious or non-infectious exposures. It is interesting that many of the environmental associations we have found to date in autoimmune diseases were only seen in specific phenotypes or genotypes. This point may have direct relevance to studies of other illnesses where confounding is likely when heterogeneous syndromes with different etiologies are grouped together as a common disorder. Recent discoveries include the finding that global UV radiation as measured from NOAA/NASA satellites best predicts the proportion of dermatomyositis patients and those with anti-Mi-2 autoantibodies (directed at chromodomain helicase DNA binding protein 4) around the world and in the U.S. In both worldwide and U.S. studies, analyses demonstrated that of the 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. 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. Studies are ongoing on understanding the molecular effects of ultraviolet radiation and estrogen on the expression and function of the Mi-2 target autoantigen. Reports of spatial clustering and seasonal associations with myositis onset, or with increased disease activity, in small series of patients are another line of evidence suggesting environmental triggers for myositis. We found that while there were no significant seasonal patterns of disease onset in myositis patients as a whole or in the polymyositis or dermatomyositis populations, such associations did occur in the serologically defined groups. Myositis onset in the non-African American patients with anti-synthetase autoantibodies peaked in March/April (P=0.03). Among the anti-synthetase patients, the seasonal association in onset was predominantly seen in those with polymyositis (P<0.05) and males (P=0.042). In contrast, patients without myositis-specific autoantibodies showed a significant peak in onset in June/July (P=0.03). Among them, women showed this seasonal association (P=0.005) while there was no seasonal pattern of myositis onset in men (P>0.9). These findings, taken together with other data, suggest that diverse environmental agents, acting upon different immunogenetic backgrounds, result in distinct immune responses and clinical syndromes in the myositis syndromes. Although the specific environmental agents responsible for these seasonal trends remain unclear, it is intriguing that a number of infectious agents peak in the spring and that ultraviolet light exposure peaks in the summer. Our data also emphasize the importance of considering more homogeneous disease groups based on clinicopathologic features, immune responses, ethnicity and gender in attempts to decipher the pathogeneses of autoimmune disorders.
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