In the systemic vasculitides, recent genetic and mechanism-based observations have emphasized the role of immune complexes (IC) and anti-neutrophil cytoplasmic autoantibodies (ANCA) as two major pathogenic mediators. Both play a central role in the recruitment and activation of neutrophils and mononuclear phagocytes, which is critical in the tissue injury in vasculitis. While the process of vascular injury in vivo is no doubt complex, new insights into the genetics, structure, and function of human Fc-gamma receptors (Fc-gamma R), which interact with IC and ANCA and into the cell programs initiated by these receptors on phagocytes have brought critical new areas of research into clear focus. These new areas provide an opportunity to define genetic risk factors for disease predisposition and to develop targeted therapeutic strategies. The molecular complexity of human Fc-gamma R includes allelic polymorphisms that are genetically distinct. For example, the Fc-gamma RIIa-H131 allele is the only human Fc-gamma R that recognizes human IgG2 efficiently, thus establishing the precedent for interaction between the qualitative and quantitative nature of the humoral immune response and defined Fc-gamma R genotypes. This molecula complexity also includes distinct receptor isoforms that, on neutrophils, engage different signal transduction pathways. These observations, coupled with new insights into complement receptor 1 (CR1; CD35), provide 1) a genetic basis for individual differences in patient responses in vasculitis; 2) a framework for understanding how the properties of autoantibodies, such as IC or ANCA antibodies, interplay with Fc-gamma R in phagocytes to lead to tissue damage, and 3) a potential strategy for selective modulation of receptor function. It is hypothesized that: 1) Fc-gamma RIIIb expressed on neutrophils engages a distinct signal transduction pathway and elicits a unique cell program; 2) that, like KIR in NK cells, Fc-gamma RIIb and CR1 function as important negative regulators of Fc-gamma R-initiated programs in myeloid cells; 3) that participation of these negative regulators may explain the different biologies of ANCA and IC for neutrophils and mononuclear phagocytes, and 4) that allelic polymorphisms in expression and function will play an important role in disease risk and phenotype. Studies are proposed to characterize the pathways of neutrophil activation by the two neutrophil Fc-gamma R (Fc-gamma RIIIb and Fc-gamma RIIa) and define this differential activation at the levels of gene transcription and integrated cell programs. In addition, studies are proposed to characterize the mechanisms through which CR1 and Fc-gamma RIIb function as negative regulators in phagocytes, and these findings will be related to the representation of Fc-gamma R alleles, CR1 alleles, adhesion molecule alleles (E-selectin, ICAM-1) and clinical manifestations in two prototypic paradigms of systemic vasculitis; ANCA positive vasculitis (Wagener's granulomatosis, microscopic polyangiitis) and cryoglobulinemic leukocytoclastic vasculitis. These studies may identify risk factors for disease predisposition and new approaches for targeted therapeutics.
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