ALLELIC POLYMORPHISMS OF HUMAN FC-GAMMA RECEPTOR IIA AND FC-GAMMA RECEPTOR-IIIB - INDEPENDENT MECHANISMS FOR DIFFERENCES IN HUMAN PHAGOCYTE FUNCTION

Two different allelic polymorphisms among the isoforms of human Fc-gamma receptors have been defined: the low-responder (LR)-high-responder (HR) polymorphism of huFc-gamma-RIIA expressed on both PMN and monocytes and the NA1-NA2 polymorphism of the neutrophil Fc-gamma-RIII (huFc-gamma-RIIIB). To address the issues of whether the LR-HR polymorphism has a significant impact on Fc-gamma-R-mediated functions in human blood cells and whether any differences in LR-HR might be related to higher Fc-gamma-R-mediated phagocytosis in NA1 donors, we examined Fc-gamma-R-specific binding and internalization by donors homozygous for the two huFc-gamma-RIIA alleles. PMN from LR homozygotes showed consistently higher levels of internalization of erythrocytes opsonized with pooled human IgG (E-hIgG). The absence of an LR-HR phagocytic difference with erythrocytes opsonized with either anti-Fc-gamma-RIIA MAb IV.3 or rabbit IgG, as opposed to E-hIgG, suggested that the Fc piece of the opsonin might be important for this LR-HR difference. Accordingly, we studied HR and LR homozygotes with human IgG subclass-specific probes. Both PMN (independent of huFc-gamma-RIIIB phenotype) and monocytes from LR donors bound and internalized erythrocytes coated with human IgG2 (E-hIgG2) efficiently, whereas phagocytes from HR donors did so poorly. E-hIgG2 internalization was completely abrogated by blockade of the ligand binding site of huFc-gamma-RIIA with IV.3 Fab, indicating that huFc-gamma-RIIA is essential for the handling of hIgG2 and that the mechanism of the LR-HR phagocytic difference is at the level of ligand binding to huFc-gamma-RIIA. In contrast, the difference in internalization of E-hIgG between NA1 and NA2 homozygous donors was independent of the huFc-gamma-RIIA phenotype and did not manifest differences in ligand binding. Thus, the two known allelic polymorphisms of human Fc-gamma-R have distinct and independent mechanisms for altering receptor function, which may influence host defense and immune complex handling.