Immunogenetic and environmental risk factors for scleroderma and lupus

Systemic sclerosis (SSc; scleroderma) and systemic lupus erythematosus (SLE; lupus) are autoimmune rheumatic diseases. While the etiologies of SSc and SLE are unknown, both genetic and environmental factors are thought to be important. Cytotoxic T lymphocyte antigen-4 (CTLA-4; CD 152), a negative co-stimulatory molecule on activated T cells, plays a pivotal role in immune homeostasis. The cytokine interleukin-10 (IL-10) has diverse immune modulating activities, such as promoting B cell survival and class switching and inhibiting fibroblast proliferation. Particular genetic variants of CTLA-4 and IL-10 are associated with levels of these proteins and susceptibility to autoimmune diseases. Environmental exposure to the organic solvent trichloroethylene (TCE) is a risk factor for SSc and SLE. Infection with the Epstein-Barr virus (EBV) is also implicated in SLE etiology. Activation of microchimeric (allogeneic) cells is postulated to play a role in the etiology of SLE and SSc, in part because they are found in increased numbers in disease-affected tissues.; To determine the role of CTLA-4 and IL-10 genotypes in SLE and SSc, patients and controls were genotyped for four CTLA-4 and three IL-10 single nucleotide polymorphisms (SNPs), and patients' sera were characterized for disease-associated autoantibodies. SLE patient sera was also characterized for antibodies to EBV and other viruses. Genotype frequencies were compared between groups using the Chi square or Fisher's exact test. To determine if TCE can initiate autoimmune disease and fibrosis in microchimeric mice, female retired breeders were sub-acutely exposed to TCE and examined for pathology and microchimeric (male) DNA.; In this dissertation, evidence that particular IL-10 and CTLA-4 genotypes are risk factors for the development of SLE and SSc is presented. Additionally, to our knowledge, data presented in this thesis are the first report of an association between humoral autoimmune responses in SSc patients and IL-10 genotypes, and between CTLA-4 genotypes and humoral immunity to EBV. Administration of TCE to microchimeric mice did not result in major pathology, activated T cells in the skin, or production of antibodies to topoisomerase I (topo I; Scl-70) or anti-nuclear antibodies (ANA).