(Verbatim) - Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease caused by immune complex deposition in target organs, such as the kidney, and characterized by the production of marker autoantibodies, including anti-double stranded (ds) DNA, anti-Sm, and anti-ribosomal P. It is not known why these autoantibodies are so highly specific for SLE or how they are generated. The pathogenesis of SLE involves an interplay between endogenous (genetic) and exogenous (environmental) factors. Our laboratory is interested in the role of exogenous factors. We have reported that the isoprenoid alkane, pristane, induces both autoimmune disease (nephritis) and a variety of autoantibodies characteristic of SLE in non-autoimmune mice. These include anti-dsDNA, -Sm, -ribosomal P and others. Autoantibody production is highly dependent on IL-6 and IFNgamma and/or IL-12. Microbial stimulation is a co-factor. Unexpectedly, the injection of pristane in NZB X NZW F1 mice altered the autoantibody phenotype from anti-DNA/chromatin and anti-RNA helicase A (Th2 cytokine dependent) to anti-nRNP/Sm and Su (Th1 dependent). At the same time, IL-12 production increased, IL-4 decreased, and renal disease was accelerated dramatically. We hypothesize that pristane causes a defect in antigen presenting cells (APCs), mimicking genetic defects predisposing to SLE. Further, we hypothesize that differences in the cytokines induced by pristane may account for inter-strain differences in the autoantibodies produced.
Four specific aims are proposed.
Aim 1 is to identify the cells producing IL-6 and IL-12, which appear to drive the autoimmune process, using a combination of depletion experiments, mixing studies, and immunohistochemistry.
Aim 2 is to define the role of microbial stimulation by treating mice in germ-free conditions with pristane.
Aim 3 is to determine how pristane alters the immune function of APCs. These studies focus on a) identifying cellular receptors for pristane that appear to transmit a signal promoting lupus susceptibility and b) determining the mechanism.
Aim 4 is to examine the basis for the exquisite antigen-selectivity of autoantibody responses in pristane treated mice. We will look at the role of CD40-CD40 ligand interactions and germinal center formation. Finally, exploratory studies will begin to define how cytokines influence autoantibody phenotypes. These studies may provide a basis for understanding how defective APC function can predispose to SLE, the role of exogenous """"""""triggers"""""""" in the disease process, and the mechanisms for generating different autoantibody phenotypes under the influence of different cytokines.
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