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- Title
Cell-derived anaphylatoxins as key mediators of antibody-dependent type II autoimmunity in mice.
- Authors
Kumar, Varsha; Ali, Syed R.; Konrad, Stephanie; Zwirner, Jörg; Verbeek, J. Sjef; Schmidt, Reinhold E.; Gessner, J. Engelbert
- 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 Fc receptors (FcRs) on Kupffer cells, as observed in WT mice, was absent in C5aR-deficient mice, and FcR-mediated in vivo erythrophagocytosis was impaired. Surprisingly, in mice deficient in FcRI and FcRIII, anti-erythrocyte antibody-induced C5 and C5a production was abolished, demonstrating the existence of a previously unidentified FcR-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 FcR - and may suggest therapeutic benefits of C5 and/or C5a/C5aR blockade in AIHA and other diseases closely related to type II autoimmune injury.
- Subjects
AUTOIMMUNE diseases; IMMUNOGLOBULIN G; CELL receptors; KUPFFER cells; HEMOLYTIC anemia; PHAGOCYTOSIS
- Publication
Journal of Clinical Investigation, 2006, Vol 116, Issue 2, p512
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI25536