Xenobiotics, Lipid Peroxidation and Autoimmunity

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DESCRIPTION (provided by applicant): Autoimmune diseases (ADs) such as systemic lupus erythematosus (SLE) and scleroderma are serious pathological conditions in which immune responses against autoantigens cause structural and/or functional damage. The etiology of these diseases is largely unknown, although genetic, hormonal, nutritional and environmental factors may contribute to their pathogenesis. Lipid peroxidation (LPO), a major contributor to cellular damage, is also implicated in the pathogenesis of ADs. Our long-term goal is to elucidate the role of LPO in the development of ADs induced and/or exacerbated by chemical exposure. LPO-derived reactive aldehydes (LPDAs) such as malondialdehyde (MDA), 4-hydroxynonenal (HNE) and 4-hydroxyhexenal (HHE), covalently modify proteins to form LPDA-protein adducts, but their potential to elicit an autoimmune response has not been elucidated. We hypothesize that covalent binding of LPDAs cause structural alterations to endogenous macromolecules, including proteins, resulting in the formation of neoantigens. After antigen processing, these neoantigens (LPDA-modified proteins) elicit autoimmune responses by stimulating T and B-lymphocytes and leading to diseases like SLE and scleroderma. Further, persistent increases in antibodies to LPDA-protein adducts may lead to formation of immune complexes whose deposition in tissues could be a pathogenic mechanism of ADs. This hypothesis will be tested by pursuing three Specific Aims: 1) To study the kinetics of formation of LPDA-protein adducts in autoimmunity-prone (MRL+/+) and -resistant (B6C3F1) mice treated with environmental chemicals (trichloroethene and paraquat) known to cause lipid peroxidation; 2) To establish a link between increased LPDAs and the development of autoimmunity, by quantitating specific antibodies (to LPDA-protein adducts) and various autoantibodies, circulating immune complexes and by morphological assessment of major tissues, including liver, kidney, spleen and skin; and 3) To begin to establish the mechanism(s) of autoimmunity resulting from LPO. Experiments will be performed to elucidate the role of T cells in LPDA-induced autoimmunity. Our studies with autoimmune-prone and -resistant mice and the model chemicals should establish LPO as pathogenic mechanism of ADs, and open important avenues for clinical intervention, medical surveillance through the development of disease markers, and risk assessment.