Cell-derived anaphylatoxins as key mediators of antibody-dependent type II autoimmunity in mice
Varsha Kumar, … , Reinhold E. Schmidt, J. Engelbert Gessner
Varsha Kumar, … , Reinhold E. Schmidt, J. Engelbert Gessner
Published February 1, 2006
Citation Information: J Clin Invest. 2006;116(2):512-520. https://doi.org/10.1172/JCI25536.
View: Text | PDF
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

×

Figure 6

Options: View larger image (or click on image) Download as PowerPoint
FcγR-dependent C5a production and induction of C5 mRNA synthesis in Kupf...
FcγR-dependent C5a production and induction of C5 mRNA synthesis in Kupffer cells but not SECs in anemia. (A and B) Supernatants of liver homogenates from WT mice collected at different time points (A) or from WT, C5aR–/–, and FcγRI/III–/– mice collected 24 hours after AIHA induction (B) were assayed for C5a-dependent chemotactic activity on PMNs derived from WT mice (black bars) or C5aR–/– mice (negative control, gray bars). (C and D) Kupffer cell and SEC C5 mRNA levels of the indicated WT, FcγRI/III–/–, and C5aR–/– mice at 4 hours after injection of 34-3C mAb (black bars) as compared with mice not receiving 34-3C mAb (gray bars). (A–D) Results are expressed as mean values ± SD obtained from 3–5 mice in each group. Significant differences were determined by Student’s t test (**P < 0.001).