Mouse FcγRII is a negative regulator of FcγRIII in IgG immune complex-triggered inflammation but not in autoantibody-induced hemolysis

Murine low-affinity receptors for IgG, FcγRII and FcγRIII, differ by their distinct capacities in mediating down-regulation or activation of cellular effector functions, respectively. In this study, antibodies detecting the mouse Ly-17.1/2 alloantigen system are demonstrated to be specific for FcγRII with no cross-reactivities to other FcγR, including FcγRIII. Using these FcγRII-specific monoclonal antibodies (mAb), the significance of FcγRII inhibition of FcγRIII was examined in two models of autoantibody [autoimmune hemolytic anemia (AIHA)]- and IgG immune complex-induced (Arthus reaction) inflammation in C57BL/6 mice in comparison with FcγRII(-/-) and FcγRIII(-/-) mice. Our results demonstrate that both FcγRIII and FcγRII contributed to the binding of erythrocytes opsonized with the pathogenic IgG1 autoreactive anti-murine red blood cell antibody 105-2H. However, the functional blocking with anti-FcγRII mAb in C57BL/6 mice and the lack of FcγRII expression in FcγRII(-/-) mice, which both lowered the threshold level of FcγRIII-triggered phagocytosis in vitro, did not results in enhanced disease development of 105-2H mAb-induced AIHA in vivo. This was in sharp contrast to cutaneous Arthus reaction, where FcγRIII-mediated activation was inhibited by FcγRII. Together these results show that murine AIHA is markedly different from other FcγR-dependent inflammatory diseases where FcγRIII is normally counterregulated by FcγRII.