Class I Molecules and Autoimmunity

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DESCRIPTION (provided by applicant): IgG is the major antibody isotype responsible for a wide diversity of autoimmune diseases. A major goal would thus be to understand how one controls the levels of pathogenic IgG antibodies in individuals with autoimmune disease. Studies culminating in our recent gene targeting and transgenic experiments have suggested that the MHC class I-like IgG protection receptor, FcRn, plays a key role in maintaining endogenous IgG concentrations in mammals of all ages. Our studies indicate that FcRn is a key control point for IgG-mediated immune responses. The overall goal of the proposed studies is thus to elucidate the biology and function of FcRn in normal and autoimmune states. Our new results provide the first direct evidence that FcRn is an important molecule for humoral autoimmunity. Aim 1 will determine which autoimmune diseases are ameliorated (or exacerbated) by an FcRn deficiency in a variety of autoimmune diseases. The results will suggest the diseases in which increased serum IgG concentrations are deleterious or protective. In doing so, it should define the autoimmune diseases that might be amenable to anti-FcRn therapeutic strategies. While FcRn protein is detected only at low levels in healthy adult mice, our new results indicate that FcRn protein increases substantially as mice develop SLE. Aim 2 will thus determine whether an increased level of FcRn expression contributes to autoimmune disease. These results should provide important insights into why FcRn is upregulated and whether FcRn upregulation is a major factor in establishing and maintaining hypergammaglobulinemia. While the IgG conserving function of FcRn is well established, the difficulties in monitoring FcRn in vivo have impeded the resolution of major issues concerning its in vivo biology. To determine the tissue sites in which FcRn expresses and operates to protect IgG from catabolism under normal and autoimmune situations, Aim 3 will thus employ Cre-Lox technology to replace the normal FcRn gene with an FcRn-GFP fusion construct. The expression of this construct under normal regulation and under tissue specific regulation will clarify the anatomy of FcRn-mediated protection of IgG, and, more generally, will facilitate many other aspects of investigation into the physiology of FcRn.