Fc receptors (FcgammaR) on mononuclear cells are potent signalling molecules that trigger the activation of microbicidal and phagocytic machinery. Recent studies have shown that ligation of FcgammaRIII on NK cells also results in secretion of cytokines such as TNF-alpha. We have recently discovered that sera of autoimmune mice contain substantial amounts of anti-FcgammaR Ig, as much as 2% of total IgM in the NZB mouse strain. We suggest that this anti-FcgammaR Ig triggers the release of cytokines from mononuclear cells, resulting in the proliferation fibroblasts and the production of collagen, and thus may play a central role in autoimmune fibrosis. The proposal has 5 related aims. 1) We will construct recombinant huFcgammaRII (CD32) and FcgammaRIII (CD16) molecules and express them in CHO or insect cells. The recombinant receptors will be used for screening clones secreting human anti-FcgammaR Ig and for purification of polyclonal anti-FcgammaR Ig. 2) Polyclonal anti-FcgammaR Ig will be isolated by affinity chromatography of sera with high titers of anti-FcgammaR Ig on FcgammaR columns. Peripheral leukocytes from such patients will be transformed with Epstein Barr Virus, and clones screened by ELISA on FcgammaR-coated wells. Positive clones will be immortalized by fusion with SP2/0 cells. 3) The effects of the polyclonal and monoclonal anti-FcgammaR antibodies on mononuclear cell differentiation and secretion of cytokines and acidic and natural hydrolases will studied. 4) The effect of the secreted cytokines on fibroblast proliferation and synthesis of both collagen and collagenase, and morphology will be assessed. 5) We will determine if a restricted set of idiotypes are present in anti-FcgammaR Ig. Anti-Id antibody will be tested to block mononuclear cell stimulation by anti-FcgammaR Ig. These experiments address a possible mechanism of fibrosis, and are designed to test the hypothesis that the anti-FcgammaR Ig is a pathologic antibody, primarily by virtue of its ability to stimulate cytokine release from mononuclear cells.
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