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.
|
Authors | Varsha Kumar, Syed R Ali, Stephanie Konrad, Jörg Zwirner, J Sjef Verbeek, Reinhold E Schmidt, J Engelbert Gessner |
Journal | The Journal of clinical investigation
(J Clin Invest)
Vol. 116
Issue 2
Pg. 512-20
(Feb 2006)
ISSN: 0021-9738 [Print] United States |
PMID | 16453025
(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
|