Cell-derived anaphylatoxins as key mediators of antibody-dependent type II autoimmunity in mice
Varsha Kumar, Syed R. Ali, Stephanie Konrad, Jörg Zwirner, J. Sjef Verbeek, Reinhold E. Schmidt, J. Engelbert Gessner
Varsha Kumar, Syed R. Ali, Stephanie Konrad, Jörg Zwirner, J. Sjef Verbeek, Reinhold E. Schmidt, J. Engelbert Gessner
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Research Article Immunology

Cell-derived anaphylatoxins as key mediators of antibody-dependent type II autoimmunity in mice

Abstract

Complement C5a, a potent anaphylatoxin, is a candidate target molecule for the treatment of inflammatory diseases, such as myocardial ischemia/reperfusion injury, RA, and the antiphospholipid syndrome. In contrast, up until now, no specific contribution of C5a and its receptor, C5aR, was recognized in diseases of antibody-dependent type II autoimmunity. Here we identify C5a as a novel key mediator of autoimmune hemolytic anemia (AIHA) and show that mice lacking C5aR are partially resistant to this IgG autoantibody–induced disease model. Upon administration of anti-erythrocyte antibodies, upregulation of activating Fcγ receptors (FcγRs) on Kupffer cells, as observed in WT mice, was absent in C5aR-deficient mice, and FcγR-mediated in vivo erythrophagocytosis was impaired. Surprisingly, in mice deficient in FcγRI and FcγRIII, anti-erythrocyte antibody–induced C5 and C5a production was abolished, demonstrating the existence of a previously unidentified FcγR-mediated C5a-generating pathway. These results show that the development of a full-blown antibody-dependent autoimmune disease requires C5a — produced by and acting on FcγR — and may suggest therapeutic benefits of C5 and/or C5a/C5aR blockade in AIHA and other diseases closely related to type II autoimmune injury.

Authors

Varsha Kumar, Syed R. Ali, Stephanie Konrad, Jörg Zwirner, J. Sjef Verbeek, Reinhold E. Schmidt, J. Engelbert Gessner

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34-3C mAb–induced C5a production in primary cultures of Kupffer cells bu...
34-3C mAb–induced C5a production in primary cultures of Kupffer cells but not SECs. Cultured Kupffer cells (A) and SECs (B) from WT mice were incubated with rbcs opsonized with 34-3C mAb (20 μg) or with rbcs alone (0 μg). After 3 hours of incubation, culture supernatants were assayed for C5a-dependent chemotactic activity on PMNs derived from WT mice (black bars) or C5aR–/– mice (gray bars). (A and B) Results are expressed as mean values ± SD obtained from 2 individual experiments performed in duplicate. Significant differences were determined by Student’s t test (*P < 0.05).