Cell surface receptors for the Fc portion of IgG (designated FcGR) play fundamental roles in the normal functions of leukocytes. Altered FcGR function is related to a wide variety of autoimmune diseases. and to glucocorticoid therapy of these diseases. Recent work from this and other laboratories has led to identification of three distinct FcGR types on human leukocytes, designated FcGRI, II and III. The expression of one of these (FcGRI) is increased 10-to 20-fold by gamma interferon (IFN- gamma). Glucocorticoids also regulate FcGRI, through their inhibition of IFN-gamma production and their enhancement of IFN-gamma augmentation of FcGRI expression. A detailed analysis of hormonal and lymphokine regulation of FcGRI, II, and III, and the role of each in FcGR-dependent functions are the focus of this proposal. Monoclonal antibodies (MAbs) specific for each FcGR, and for a unique set of macrophage """"""""activation"""""""" antigens will be used, in conjunction with flow cytometry, to define the phenotypic changes which result from hormone and lymphokine treatment of monocytes, macrophages, neutrophils, and human leukocyte cell lines. The enhancement of FcGRI expression by IFN-gamma will serve as the prototype for these studies. Target cell-specific and hapten-specific mouse IgG MAbs and heteroantibodies will be used to determine which of the three FcGR can mediate immune phagocytosis, immune pinocytosis and antibody-dependent cellular cytotoxicity (ADCC). Interactive effects between FcGR and activation antigens will also be examined. In an attempt to extrapolate these studies to a clinical situation in which FcGR play a central role, FcGRI, II and III expression on leukocytes from patients who have systemic lupus erythematosus (SLE) will be studied. The mechanism for deficient IFN-gamma production and IFN-gamma augmentation of FcGRi in SLE will also be explored. Since glucocorticoids have varied in vitro effects on different leukocytes, the relationship between myeloid differentiation and regulation of FcGR by IFN-gamma and dexamethasone will also be tested. These studies should increase our understanding of the role of each FcGR in normal homeostasis, and in diseases in which FcGR plays a role.
| Backman, K A; Guyre, P M (1994) Gamma-interferon inhibits Fc receptor II-mediated phagocytosis of tumor cells by human macrophages. Cancer Res 54:2456-61 |
