Defective mononuclear phagocyte system (MPS) function in vivo occurs endogenously in immunologic diseases such as systemic lupus erythematosus (SLE) and can be induced exogenously by administration of gammaglobulin in idiopathic thrombocytopenic purpura (ITP). MPS dysfunction in SLE is associated with nephritis reflecting greater tissue deposition of immune complexes. This same modulation of immune clearance is used to advantage for ITP in which intravenous gammaglobulin delays clearance of IgG-sensitized platelets and increases the circulating platelet count. The overall goal of this proposal is to determine the nature of the defect(s) in mononuclear phagocytes in human models in which modulation of MPS function is either endogenously or exogenously derived so that a more rational therapeutic approach can be devised. Our data suggest that defective Fc receptor-mediated clearance reflects the composite of several factors: altered FcGamma receptor binding, genetically determined differences in phagocytic capacity and superimposed acquired differences in phagocytic rates in disease states.
The specific aims are 1) to analyze in vivo kinetic data by computer simulation to define specific abnormalities which can be tested in vitro; 2) to delineate the nature of the defect in phagocytosis in SLE, ITP and immunogenetically defined normals with regard to specificity, dependence on lymphocyte products and role of monocyte subpopulations; 3) to define in biochemical terms the nature of the FcGamma receptor in SLE and ITP where there are divergent changes and in DR2 normals; 4) to examine the early membrane events involved in """"""""Fc"""""""" signal transduction associated with altered receptors and/or phagocytosis. In vivo clearance kinetic data are derived from the clearance of IgG-sensitized autologous erythrocytes; phagocytosis by blood monocytes of Fc specific and non-specific probes is assessed by radiometric incorporation; two dimensional gel electrophoresis and Western blotting of affinity-isolated Fc receptor are used to define Mr, isoelectric point, lectin-binding and epitope maps; tetraphenylphosphonium cation partioning, 45Calcium fluxes and quin 2 fluorescence define early Fc-initiated events. These studies will define the mechanisms underlying altered MPS function which have implications for immune clearance, monocyte receptor-ligand interactions and phagocytosis. Delineation of these mechanisms will allow for a more rational therapeutic approach in rheumatic and immunologic disease such as SLE and ITP.
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