FcγRIII (CD16)-deficient mice show IgG isotype-dependent protection to experimental autoimmune hemolytic anemia

D Meyer, C Schiller, J Westermann… - Blood, The Journal …, 1998 - ashpublications.org
D Meyer, C Schiller, J Westermann, S Izui, WLW Hazenbos, JS Verbeek, RE Schmidt…
Blood, The Journal of the American Society of Hematology, 1998ashpublications.org
In autoimmune hemolytic anemia (AIHA), there is accumulating evidence for an involvement
of FcγR expressed by phagocytic effector cells, but demonstration of a causal relationship
between individual FcγRs and IgG isotypes for disease development is lacking. Although the
relevance of IgG isotypes to human AIHA is limited, we could show a clear IgG isotype
dependency in murine AIHA using pathogenic IgG1 (105-2H) and IgG2a (34-3C)
autoreactive anti–red blood cell antibodies in mice defective for FcγRIII, and comparing the …
Abstract
In autoimmune hemolytic anemia (AIHA), there is accumulating evidence for an involvement of FcγR expressed by phagocytic effector cells, but demonstration of a causal relationship between individual FcγRs and IgG isotypes for disease development is lacking. Although the relevance of IgG isotypes to human AIHA is limited, we could show a clear IgG isotype dependency in murine AIHA using pathogenic IgG1 (105-2H) and IgG2a (34-3C) autoreactive anti–red blood cell antibodies in mice defective for FcγRIII, and comparing the clinical outcome to those in wild-type mice. FcγRIII-deficient mice were completely resistent to the pathogenic effects of 105-2H monoclonal antibody, as shown by a lack of IgG1-mediated erythrophagocytosis in vitro and in vivo. In addition, the IgG2a response by 34-3C induced a less severe but persistent AIHA in FcγRIII knock-out mice, as documented by a decrease in hematocrit. Blocking studies indicated that the residual anemic phenotype induced by 34-3C in the absence of FcγRIII reflects an activation of FcγRI that is normally coexpressed with FcγRIII on macrophages. Together these results show that the pathogenesis of AIHA through IgG1-dependent erythrophagocytosis is exclusively mediated by FcγRIII and further suggest that FcγRI, in addition to FcγRIII, contributes to this autoimmune disease when other IgG isotypes such as IgG2a are involved.
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