Markedly different pathogenicity of four immunoglobulin G isotype-switch variants of an antierythrocyte autoantibody is based on their capacity to interact in vivo with the low-affinity Fcγ receptor III

Using three different Fc gamma receptor (Fc gamma R)-deficient mouse strains, we examined the induction of autoimmune hemolytic anemia by each of the four immunoglobulin (Ig)G isotype-switch variants of a 4C8 IgM antierythrocyte autoantibody and its relation to the contributions of the two Fc gamma R, Fc gamma RI, and Fc gamma RIII, operative in the phagocytosis of opsonized particles. We found that the four IgG isotypes of this antibody displayed striking differences in pathogenicity, which were related to their respective capacity to interact in vivo with the two phagocytic Fc gamma Rs, defined as follows: IgG2a > IgG2b > IgG3/IgG1 for Fc gamma RI, and IgG2a > IgG1 > IgG2b > IgG3 for Fc gamma RIII. Accordingly, the IgG2a autoantibody exhibited the highest pathogenicity, similar to 20-100-fold more potent than its IgG1 and IgG2b variants, respectively, while the IgG3 variant, which displays little interaction with these Fc gamma Rs, was not pathogenic at all. An unexpected critical role of the low-affinity Fc gamma RIII was revealed by the use of two different IgG2a anti-red blood cell autoantibodies, which displayed a striking preferential utilization of Fc gamma RIII, compared with the high-affinity Fc gamma RI. This demonstration of the respective roles in vivo of four different IgG isotypes, and of two phagocytic Fc gamma Rs, in autoimmune hemolytic anemia highlights the major importance of the regulation of IgG isotype responses in autoantibody-mediated pathology and humoral immunity.