Original Article

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 Receptor III

Correspondence to: Shozo Izui, Department of Pathology, Centre Médical Universitaire, 1 rue Michel-Servet, Geneva 4, 1211, Switzerland. Tel:41-22-70-25-741 Fax:41-22-70-25-746 E-mail:shozo.izui{at}medecine.unige.ch.

Using three different Fc receptor (FcR)-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 FcR, FcRI, and FcRIII, 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 FcRs, defined as follows: IgG2a > IgG2b > IgG3/IgG1 for FcRI, and IgG2a > IgG1 > IgG2b > IgG3 for FcRIII. Accordingly, the IgG2a autoantibody exhibited the highest pathogenicity, ~20–100-fold more potent than its IgG1 and IgG2b variants, respectively, while the IgG3 variant, which displays little interaction with these FcRs, was not pathogenic at all. An unexpected critical role of the low-affinity FcRIII was revealed by the use of two different IgG2a anti–red blood cell autoantibodies, which displayed a striking preferential utilization of FcRIII, compared with the high-affinity FcRI. This demonstration of the respective roles in vivo of four different IgG isotypes, and of two phagocytic FcRs, in autoimmune hemolytic anemia highlights the major importance of the regulation of IgG isotype responses in autoantibody-mediated pathology and humoral immunity.

Key Words: autoantibody, autoimmune hemolytic anemia, Fc receptor, IgG isotype, knockout mouse

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