Cell-derived anaphylatoxins as key mediators of antibody-dependent type II autoimmunity in mice.
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.
Kumar
Varsha
V
Department of Clinical Immunology, Medical School Hannover, Hannover, Germany.
Ali
Syed R
SR
Konrad
Stephanie
S
Zwirner
Jörg
J
Verbeek
J Sjef
JS
Schmidt
Reinhold E
RE
Gessner
J Engelbert
JE
D000744:Anemia, Hemolytic, Autoimmune / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015551:Autoimmunity / Q000502:physiology*; D015936:Complement C5a / Q000235:genetics / Q000276:immunology*; D004912:Erythrocytes / Q000378:metabolism; D007074:Immunoglobulin G / Q000276:immunology*; D007728:Kupffer Cells / Q000166:cytology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D010587:Phagocytosis / Q000502:physiology; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000276:immunology*; D017452:Receptors, IgG; D015996:Survival Rate
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D044087:Receptor, Anaphylatoxin C5a; D017452:Receptors, IgG; D015936:Complement C5a