FC-GAMMA-RIII (CD16)-DEFICIENT MICE SHOW IGG ISOTYPE-DEPENDENT PROTECTION TO EXPERIMENTAL AUTOIMMUNE HEMOLYTIC-ANEMIA

In autoimmune hemolytic anemia (AIHA), there is accumulating evidence for an involvement of Fc gamma R expressed by phagocytic effector cell s, but demonstration of a causal relationship between individual Fc ga mma Rs and IgG isotypes for disease development is lacking. Although t he relevance of IgG isotypes to human AIHA is limited, we could show a clear IgG isotype dependency in murine AIHA using pathogenic IgG1 (10 5-2H) and lgG2a (34-3C) autoreactive anti-red brood cell antibodies in mice defective for Fc gamma RIII, and comparing the clinical outcome to those in wild-type mice. Fc gamma RIII-deficient mice were complete ly resistent to the pathogenic effects of 105-2H monoclonal antibody, as shown by a lack of IgG1-mediated erythrophagocytosis in vitro and i n vivo. In addition, the lgG2a response by 34-3C induced a less severe but persistent AIHA in Fc gamma RIII knock-out mice, as documented by a decrease in hematocrit. Blocking studies indicated that the residua l anemic phenotype induced by 34-3C in the absence of Fc gamma RIII re flects an activation of Fc gamma RI that is normally coexpressed with Fc gamma RIII on macrophages. Together these results show that the pat hogenesis of AIHA through IgG1-dependent erythrophagocytosis is exclus ively mediated by Fc gamma RIII and further suggest that Fc gamma RI, in addition to Fc gamma RIII, contributes to this autoimmune disease w hen other IgG isotypes such as IgG2a are involved. (C) 1998 by The Ame rican Society of Hematology.