Autoimmune diseases are acquired, incurable disorders, affect up to 22 million Americans, are among the leading causes of death of women and are increasing in prevalence in the population. These disorders likely result from 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. ? ? Evidence supporting the concept that autoimmune diseases have an environmental component includes: ? ? Less than 50% concordance rates in monozygotic twins;? ? 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 agents; ? ? Seasonality and geographic clustering in disease onset; ? ? 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 independent 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, environmental factors may also alter the rate of progression to clinical disease, the specific manifestations of disease and the course of illness. Because of the evidence above, 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, which 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 principles learned in these disorders may be applied to other diseases. ? ? 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; understanding 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 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.? ? Another myositis-specific autoantibody binds to components of the signal recognition particle (SRP). Since we previously discovered that other myositis autoantibodies inhibit the function of their targets, we collaborated with Dr. Steve High to confirm that human anti-SRP antibodies, in contrast to mouse antibodies, bind the 54 kDa protein of the SRP and block its function at multiple stages. This finding implies a unique pathway for the development of human autoantibodies and a novel mechanism by which these diagnostic immunoglobulins may result in pathology. ? ? 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 myositis. 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. ? ? Reports of spatial clustering and seasonal associations with autoimmune disease onset suggest environmental triggers. 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 clinical groups, such associations did occur in the serological groups. Myositis onset in the non-African American patients with anti-synthetase autoantibodies peaked in March/April. Among the anti-synthetase patients, the seasonal association in onset was predominantly seen in polymyositis and males. In contrast, patients without myositis-specific autoantibodies showed a peak in onset in June/July. Among them, women showed this seasonal association while there was no seasonal pattern of myositis onset in men. These findings suggest that diverse environmental agents, acting upon different genetic backgrounds, result in distinct immune responses and clinical syndromes in the myositis syndromes. 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.? ? We also assessed whether different types of myositis were the result of different genetics and if some genes could increase risk while others might actually decrease risk for the development of disease. HLA DRB1 and DQA1 alleles were defined in the largest population of adult and juvenile myositis patients ever studied, along with a large number of normal controls. We found that although some genes that regulate the immune system are risk factors for all types of myositis, other immune-modifying genes are risk factors for only certain forms. Additionally, in some of the subgroups, selected genes protect persons from the development of myositis. While some similarities exist in the genetics of childhood-onset and adult-onset forms, certain risk and protective factors are unique to either children or adults. Also, genes for myositis in non-whites differ from those in whites at these loci. Taken together with other information, these findings suggest that immune response genes are important in the development of myositis and that different combinations of risk and protective genes, along with environmental exposures, result in the myositis syndromes. These findings have important diagnostic implications and could allow for a better understanding of the mechanisms that lead to chronic immune-mediated muscle destruction.
Showing the most recent 10 out of 37 publications
