IgA, which is mostly produced in relation to mucous membranes, is biosynthetically the body's major Ig. The proposed research is designed to provide new insights into key aspects of mucosal IgA host defense functions. Topics to be studied include how IgA and its receptor, the polymeric Ig receptor, are transported across polarized epithelial cells, the outcome(s) of IgA-mediated uptake of virus by epithelial cells, and the effects of complement activation on the epithelial transport of immune complexes.
Aim 1 focuses on proteins in epithelial cells that interact with specific sorting signals in the cytoplasmic domain of the polymeric Ig receptor and direct its movement initially to the basolateral cell surface and subsequently to the apical cell surface. These trafficking events are critical to the epithelial transport of IgA and indirectly any antigens complexed to IgA antibodies.
Aim 2 addresses the fate of virus that is endocytosed into an epithelial cell as a consequence of binding by IgA antibody. Is the virus neutralized intracellularly, does it instead replicate, or is it transcytosed and excreted from the apical surface? These experiments will be done with measles virus and IgA monoclonal antibodies to be made against its surface proteins.
Aim 3 seeks to understand the evolutionary significance of IgA's limited ability to activate complement. Immune complexes prepared with IgM antibodies, which also bind to the polymeric Ig receptor, or mixtures of IgA and IgG antibodies will be employed to pursue the hypothesis that activation products of complement bound to immune complexes inhibit their epithelial transport (excretion). The research overall is relevant to (a) vaccination strategies that are designed to stimulate the production of IgA antibodies in mucous membranes, which are the locus of or portal of entry for most infections, and (b) the clinical use of monoclonal antibodies for prophylaxis and treatment of mucosal infections.
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