Monocyte and macrophage receptors for the Fc portion of IgG(FcRG) are essential for optimal phagocytosis of opsonized particulate antigens and for antibody-dependent cellular cytotoxicity (ADCC). FcRG thus play a beneficial role in clearing the body of bacterial infections and probably of malignancies. They also participate in the clearance of antibody-coated erythrocytes in autoimmune hemolytic anemia, a disease in which the number of FcRG on circulating monocytes has recently been shown to be elevated. Conversely, a functional FcRG defect is present in several diseases, most notably systemic lupus erythematosus (SLE). However, FcRG levels on circulating monocytes of SLE patients appear to be normal, and no mechanism has been identified to explain the functional defect. The studies proposed will apply the recent finding that recombinant human immune (Gamma)interferon (but not Alpha- or Beta-interferons) increases 10-fold the number of FcRG sites on human monocytes, monocyte derived and alveolar macrophages, and leukocyte cell lines. The potential physiological significance of the unexpected finding that glucocorticoids can augment the Gamma-interferon-induced increase in FcRG will also be investigated. While glococorticoids are highly effective for treating immune-complex diseases, little is known about the precise mechanisms by which these steroids are beneficial. Using a highly efficient technique, newly developed by the applicant, monocytes will be prepared and their in vitro maturation and response to Gamma-interferon and glucocorticoids will be examined. Flow cytometry, radioligand binding and assays of effector function will be employed to define (i) the relationship between density of FcRG on the cell surface and FcRG-dependent functions following treatment in vitro with Gamma-interferon and/or glucocorticoids, and (ii) phenotypic changes which accompany altered expression of FcRG. An additional aim is to use these parameters of the normal monocyte/macrophage response to glococorticoids and Gamma-interferon to evaluate monocytes from patients with systemic lupus erythematosus. The results of thes studies should help clarify the physiologic, pathophysiologic and therapeutic potential of Gamma-interferon, and its interplay with other factors such as glococorticoids, in modulating the immune response.
