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 Fc gamma receptor III

Using three different Fc gamma receptor (Fc gamma R)-deficient mouse strain s, we examined the induction of autoimmune hemolytic anemia by each of the four immunoglobulin (Ig)G isotype-switch variants of a 4C8 IgM antierythroc yte 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 opsoniz ed particles. We found that the four IgG isotypes of this antibody displaye d striking differences in pathogenicity, which were related to their respec tive capacity to interact in vivo with the two phagocytic Fc gamma Rs, defi ned as follows: IgG2a > IgG2b > IgG3/IgG1 for Fc gamma RI, and IgG2a > IgG1 > IgG2b > IgG3 for Fc gamma RIII. Accordingly, the IgG2a autoantibody exhi bited the highest pathogenicity, similar to 20-100-fold more potent than it s IgG1 and IgG2b variants, respectively, while the IgG3 variant, which disp lays 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 w ith the high-affinity Fc gamma RI. This demonstration of the respective rol es in vivo of four different IgG isotypes, and of two phagocytic Fc gamma R s, in autoimmune hemolytic anemia highlights the major importance of the re gulation of IgG isotype responses in autoantibody-mediated pathology and hu moral immunity.