? In the systemic vasculitides, recent genetic and mechanism-based observations have emphasized the role of antineutrophil cytoplasmic autoantibodies (ANCA) as phlogistic, pro-inflammatory, pathogenic mediators. ANCA can activate neutrophils and mononuclear phagocytes, which are critical in the development of tissue injury in vasculitis. While the generation of ANCA autoantibodies and the process of vascular injury in vivo is no doubt complex, new insights into the genetics, structure and function of human Fc? receptors which interact with ANCA have brought critical new areas of research into clear focus. Fc?R-mediated triggering is important in initiating cell functions including adhesion, synthesis and release of cytokines and release of both granule contents (including ANCA targets) and inflammatory mediators (reactive oxygen intermediates). Our work presented in Progress and Preliminary Data clearly establishes the contributions of each activating FcyR in ANCA-mediated neutrophil activation and we have shown the quantitative importance of allelic variants in these receptors to ANCA-mediated neutrophil activation. We have also shown expression of the inhibitory FcyR on neutrophils and we have defined a novel inhibitory activity of CR1 (CD35) on ANCA-mediated neutrophil activation. Each of these activating and inhibitory receptors is polymorphic in humans. ? ? Therefore, as supported by Progress and Preliminary Data, the specific aims of this proposal are 1) to establish Fc?RIIb and CR1 as negative regulators of ANCA induced phagocyte activation in vitro, to characterize the cell programs affected and to identify the mechanism(s)of action. 2) to test our ANCA hypothesis by establishing the contribution to ANCA-induced murine vasculitis of each Fc? receptor type in vivo using mice deficient in individual ligand-binding a-chains (both activators and inhibitor) and to test the role of neutrophils in vivo using mice deficient in granule contents. 3) to test our ANCA hypothesis in humans by using functionally significant, polymorphisms in target molecules identified in Progress and in Aims 1 and 2 (FcyR, CR1 and adhesion molecules modulated by ANCA) to establish a correlation between these variants and the human disease phenotype and 4) to establish the basis for novel interventions with peptides that interrupt the activation of phagocytes by ANCA and with inducers of FcyRIIb expression to downregulate ANCA-mediated activation. ? ? Given our current data on the unique functional and genetic profile of key receptors in the ANCA-PMN activation pathway, and the clear potential for targeted intervention, these studies may define important risk factors predisposing for disease and lead to the development of targeted therapeutic strategies. ? ?
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