The overall goal of these studies is to define the structure/function relationship of a recently identified Fc receptor for IgA and IgM (Fcalpha/muR). The Ig-like domain at the amino terminus of the predicted Fcalpha/muR glycoprotein contains a sequence motif that is conserved in the polymeric Ig receptor of various species and is predicted to be the binding site for IgM and IgA. The Fcalpha/muR gene is expressed in both hematopoietic (B and monocyte/macrophages) and non-hematopoietic (kidney and intestine) tissues in both humans and mice. Preliminary studies of Fcalpha/muR expression in humans indicate an interesting cellular distribution: germinal centers with the appearance of follicular dendritic cells (FDC) in tonsil, proximal tubular epithelial cells in kidney and Paneth cells in small intestinal crypts. Unlike the mouse Fcalpha/muR, the human receptor is expressed only by the B cells that reside in secondary lymphoid tissues rather than those present in the circulation. A novel splice variant that is predicted to encode a soluble form of Fcalpha/muR has been identified in the kidney. These findings have led to the hypothesis that Fcalpha/muR plays multiple functional roles depending upon the cell types expressing it. Fcalpha/muR on FDC may trap IgM or IgA immune complexes and present the intact antigens to B cells in germinal centers. Fcalpha/muR expression by B cells may be closely linked with cellular activation. On the other hand, Fcalpha/muR in renal tubular epithelial cells and intestinal Paneth cells may play a protective role at portals of entry for antigens and microorganisms. These hypotheses will be tested through the following Specific Aims: 1) Determine the cellular distribution and molecular nature of Fcalpha/muR by using receptor-specific antibodies and Ig-ligands; 2) Define the newly identified Fcalpha/muR splice variant as a soluble form of receptor; 3) Determine the function of the membrane-bound Fcalpha/muR; and 4) Employ an Fcalpha/muR-deficient mouse model to explore the in vivo function of the Fca/alphaR.
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