Systemic lupus erythematosus (SLE) is a complex disease that has a spectrum of clinical manifestations thought to be the consequence of a dysfunctional immune system. The prominent serological feature of SLE is the presence of anti-DNA antibodies. While these antibodies are useful diagnostically, neither their etiology nor their precise role in the autoimmune pathology is clear. The investigator's objectives are to define the cellular and molecular interactions that influence autoantibody expression in both healthy and autoimmune states, first, by determining how healthy animals regulate the expression of autoantibodies, and second, by defining the critical lesion(s) in these processes that lead to autoimmunity. The investigators will use immunoglobulin (Ig) transgenic (tg) mice to follow the fate of autoreactive B cells. Because anti-DNA Igs that are present in SLE are heterogeneous in terms of their apparent specificity for single-stranded (ss) versus double-stranded (ds) DNA, the investigators will use a variety of anti-DNA Ig tgs to recapitulate these different autospecificities.
Specific aims are as follows: 1. Determine the relative fates of anti-ssDNA and anti-dsDNA tg B cells when they are a part of a diverse B-cell repertoire as is the case in autoimmune individuals. Evaluate how the presence of different anti-DNA Ig tgs affects the kinetics of autoantibody expression and influences the severity of renal pathology in MRL-lpr/lpr mice. 2. Examine the role of two regulators of cell death, Fas and Bcl-2, whose altered expression has been associated with the occurrence of SLE-associated autoantibodies. 3. Identify and compare cellular antigens that are recognized by autoantibodies for which the investigators have evidence of B cell tolerance and by antibodies which have been isolated from autoimmune mice. Examine the role that apoptosis plays in generating autoantigens targeted in SLE by determining if anti-nuclear antibodies from MRL-lpr/lpr mice bind to antigens exposed on apoptotic cells.
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