Differential contribution of three activating IgG Fc receptors (FcγRI, FcyRIII, and FcγRIV) to IgG2a- and IgG2b-induced autoimmune hemolytic anemia in mice

Murine phagocytes express three different activating IgG Fc gamma R: Fc gamma RI is specific for IgG2a; Fc gamma RIII for IgG1, IgG2a, and IgG2b; and Fc gamma RIV for IgG2a and IgG2b. Although the role of Fc gamma RIII in IgG1 and IgG2a anti-RBC-induced autoimmune hemolytic anemia (AIHA) is well documented, the contribution of Fc gamma RI and Fc gamma RIV to the development of IgG2a- and IgG2b-induced anemia has not yet been defined. In the present study, using mice deficient in Fc gamma RI, Fc gamma RIII, and C3, in combination with an Fc gamma RIV-blocking mAb, we assessed the respective roles of these three Fc gamma R in the development of mild and severe AIHA induced by two different doses (50 and 200 mu g) of the IgG2a and IgG2b subclasses of the 34-3C anti-RBC monoclonal autoantibody. We observed that the development of mild anemia induced by a low dose of 34-3C IgG2a autoantibody was highly dependent, on Fc gamma RIII, while Fc gamma RI and Fc gamma RIV additionally contributed to the development of severe anemia induced by a high dose of this subclass. In contrast, the development of both mild and severe anemia induced by 34-3C IgG2b was dependent on Fc gamma RIII and Fc gamma RIV. Our results indicate differential roles of the three activating Fc gamma R in IgG2a- and IgG2b-mediated AIHA.