In the systemic vasculitides, immune complexes and anti-neutrophil cytoplasmic autoantibodies (ANCA) are the two major pathogenic mechanisms for recruitment of neutrophils which play a critical pathogenic role. No longer considered cells with a limited program of effector functions, neutrophils participate actively in intercellular adhesive events, synthesize and release a range of cytokines important for inflammatory cascades, and secrete both degradative enzymes and short-lived inflammatory mediators. This new appreciation for the molecular and cell biology of neutrophils, coupled with new insights into the structural genetics and function of Fcgamma receptors which interact with immune complexes and ANCA so characteristics of systemic vasculitis, highlights the critical importance of understanding the determinants which initiate these cell programs. The molecular complexity of human Fcgamma receptors includes allelic polymorphisms which are functionally distinct. For example, the FcgammaRIIA/LR allele expressed on neutrophils is the only human Fcgamma receptor which recognizes human IgG2 efficiently, --thus establishing the precedent for interaction between the qualitative and quantitative nature of the humoral immune response and defined Fcgamma receptor genotypes. This molecular complexity also includes distinct receptor isoforms which on neutrophils engage different signal transduction pathways. These observations provide (1) a genetic basis for individual differences in patient responses in vasculitis, (2) a framework for understanding how the properties of autoantibodies, -- as immune complexes or as ANCA antibodies, -- interplay with Fcgamma receptors on neutrophils to lead to tissue damage, and (3) a potential strategy for selective modulation of receptor function. We hypothesize (1) that autoantibodies bind Fcgamma receptors and trigger neutrophils, and (2) that Fcgamma receptor-mediated neutrophil triggering is important in initiating neutrophil functions including homo- and heterotypic adhesion, synthesis and release of cytokines (eg, IL-1, 1L- 1ra, IL-8, TNFalpha), and release of both granular enzymes and short- lived inflammatory mediators. Furthermore, we hypothesize that (1) the two different FcgammaR expressed on neutrophils engage different signal transduction pathways, and (2) these pathways are amenable to differential pharmacological modulation. Accordingly, we will characterize the pathways of neutrophil activation by the two different neutrophil FcgammaR (FcgammaRIIIB and FcgammaRIIA) and define the properties of this differential activation at the levels of gene transcription and integrated cell programs; investigate the capacity of cryoglobulin immune complexes and ANCA to preferentially engage these two receptor systems and to be blocked by specific pharmacologic and recombinant molecules; and relate these findings to the expression of FcgammaR alleles and clinical manifestations in two prototypic paradigms of systemic vasculitis: Wegener's granulomatosis with ANCA and cryoglobulinemic leukocytoclastic vasculitis. These studies may identify genetic risk factors for disease predisposition and important new approaches for targeted therapeutics in vasculitis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR042476-01A1
Application #
2081769
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1994-09-15
Project End
1998-08-31
Budget Start
1994-09-15
Budget End
1995-08-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Hospital for Special Surgery
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10021
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