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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 Fcgamma receptors (FcgammaRs) on Kupffer cells, as observed in WT mice, was absent in C5aR-deficient mice, and FcgammaR-mediated in vivo erythrophagocytosis was impaired. Surprisingly, in mice deficient in FcgammaRI and FcgammaRIII, anti-erythrocyte antibody-induced C5 and C5a production was abolished, demonstrating the existence of a previously unidentified FcgammaR-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 FcgammaR--and may suggest therapeutic benefits of C5 and/or C5a/C5aR blockade in AIHA and other diseases closely related to type II autoimmune injury.
AuthorsVarsha Kumar, Syed R Ali, Stephanie Konrad, Jörg Zwirner, J Sjef Verbeek, Reinhold E Schmidt, J Engelbert Gessner
JournalThe Journal of clinical investigation (J Clin Invest) Vol. 116 Issue 2 Pg. 512-20 (Feb 2006) ISSN: 0021-9738 [Print] United States
PMID16453025 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibodies, Monoclonal
  • Immunoglobulin G
  • Receptor, Anaphylatoxin C5a
  • Receptors, IgG
  • Complement C5a
Topics
  • Anemia, Hemolytic, Autoimmune (genetics, immunology)
  • Animals
  • Antibodies, Monoclonal (immunology)
  • Autoimmunity (physiology)
  • Complement C5a (genetics, immunology)
  • Erythrocytes (metabolism)
  • Immunoglobulin G (immunology)
  • Kupffer Cells (cytology, metabolism)
  • Macrophages, Peritoneal (immunology)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Phagocytosis (physiology)
  • Receptor, Anaphylatoxin C5a (genetics, immunology)
  • Receptors, IgG
  • Survival Rate

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