In the past five years there has been a marked increase in our knowledge of human Fc-gamma receptors which we now understand as three families of related, but richly diverse, molecules. The various FC-gammaR forms, isoforms and allelic forms, -- have different functional capacities. These advances bring into focus our hypotheses: 1) that abnormal Fc-gammaR function (both genetically determined and disease-acquired) is a contributory factor in autoimmune immune complex disease pathogenesis; 2) that the presence/ expression of different FC-gammaR structural forms is both genetically determined (at the level of allelic forms) and under differential regulational control (at the level of family and isoform expression); 3) that the different capacities of the Fc-gammaR forms preferentially associated with or expressed in immunogenetically defined normals and in SLE patients contributes substantially to the abnormal Fc- gammaR function. Preliminary data indicate that the Fc-gammaRI is a compelling candidate responsible for Fc-gammaR dysfunction in immunogenetically defined normals and SLE. Receptor specific studies have shown that Fc-gammaRI is uniquely associated with this Fc-gammaR abnormality which may be related to newly discovered Fc-gammaRI isoforms and allelic forms. Therefore, the specific aims of this proposal are: 1. to define the different structural isoforms and allelic forms of Fc- gamma receptors, focussing on FC-gammaRI; 2. to define the functional capacities of each of these structural forms; 3. to define the mechanisms mediating these different functional capacities; 4. to define the relative expression of the families and their isoforms in, and to determine the association of allelic forms with, Fc-y receptor dysfunction in immunogenetically defined normals and in autoimmune diseases such as SLE. The efficiency of handling immune complexes by Fc-gamma receptors is critical in determining the predisposition to immune complex disease. Thus, genetically associated abnormalities in Fc-gamma receptor specific function may be a significant risk factor for SLE. This proposal will focus on fundamental Fc-gamma receptor structure-function relationships, emphasizing the Fc-mediated defects in phagocyte function, so that we can assess the impact of Fe-gamma receptor polymorphisms on immune complex interactions. Identification of genetic risk factors for SLE and appropriate regulation of specific Fc-gamma receptor isoform expression with cytokines or other agents will allow novel and effective therapy in SLE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR033062-12
Application #
2078900
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1984-09-30
Project End
1996-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
12
Fiscal Year
1995
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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