FcGamma receptor (FcR) dependent in vivo mononuclear phagocyte system (MPS) clearance is markedly abnormal in systemic lupus erythematosus (SLE). Our preliminary in vitro studies of FcR-mediated monocyte function in SLE patients suggest that phagocytosis is impaired in SLE, without a decrease in the number of FcR on blood monocytes. The goal of this proposal is to investigate the basis of phagocytic dysfunction in SLE. Studies of murine macrophages have demonstrated subpopulations of FcR defined by differential affinities to specific IgG subclasses and by trypsin sensitivity, with varying functions. It is hypothesized that there subpopulations of FcR on human monocytes and that the defects observed in SLE are due to an imbalance in the expression of the different subpopulations.
Three specific aims will be addressed: 1) To establish if subpopulations of FcR on human monocytes can be distinguished by their binding properties to different ligands and if their distribution is different in SLE. Monocytes from SLE and controls will be compared with regard to a) FcR number and affinity as defined by saturable binding of monomeric subclass-specific IgG species after incubation at 37 degrees and centrifugation through phthalate oils, b) effect of trypsin treatment of monocytes on binding, c) ability of protein A complexed with IgG1, IgG2 and IgG4 to bind monocyte FcR, d) binding of a monoclonal antibody recognizing the human 3G8 FcR antigen as determined by immunofluorescence. 2) To detect the presence of subpopulations of FcR based on the differential ability of various ligands to initiate FcR-mediated functions. Monocytes from SLE patients and controls will be compared as to a) the ability of subclass-specific IgG species to stimulate PGE2 production, as determined by radioimmunoassay, b) the relative rate of phagocytosis of 51Cr-labeled erythrocytes with subclass-specific IgG coupled to the surface, c) the effects of subclass-specific IgG binding to FcR on monocyte membrane potential as determined by distribution of the lipophilic cation trimethylphosphonium. 3) To determine whether the differences observed in SLE can be normalized by long-term culturing of monocytes. Since MPS dysfunction correlates with disease activity in SLE and may contribute to the pathogenesis of disease, understanding the cellular basis for this abnormality may lead to therapeutic manipulations.
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| Salmon, J E; Kimberly, R P (1986) Phagocytosis of concanavalin A-treated erythrocytes is mediated by the Fc gamma receptor. J Immunol 137:456-62 |
| Salmon, J E; Kimberly, R P; Gibofsky, A et al. (1986) Altered phagocytosis by monocytes from HLA-DR2 and DR3-positive healthy adults is Fc gamma receptor specific. J Immunol 136:3625-30 |
