C5aR activation in the absence of C5a: A new disease mechanism of autoimmune hemolytic anemia in mice

Eur J Immunol. 2018 Apr;48(4):696-704. doi: 10.1002/eji.201747238. Epub 2018 Jan 15.


IgG Fc receptors (FcγRs) and the C5a anaphylatoxin receptor (C5aR) were identified as key regulators of type II autoimmune injury in mice. However, and with respect to C5aR, the relative importance of C5a for IgG autoantibody-induced cellular destruction remained unclear. Using an experimental model of autoimmune hemolytic anemia (AIHA), we here report marked differences in the development of AIHA between mice lacking C5aR and C5-deficient (Hc0 ) strain, indicating a limited role of C5 in this type of C5aR-regulated disease. Ex-vivo-analyses of liver homogenates from anemic Hc0 mice demonstrate C5a-independent C5aR activation, upregulation of FcγR expression and amplification of erythrophagocytosis by macrophages. As assessed by pharmacological inhibition studies, targeting of C5aR, but not of C5, is effective in treating experimental AIHA. Collectively, these results define a previously unrecognized disease mechanism of C5aR activation in AIHA that does not necessarily involve C5 and C5a.

Keywords: Complement; Complement receptor; Erythrophagocytosis; Fc receptors; Red blood cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anemia, Hemolytic, Autoimmune / immunology*
  • Animals
  • Autoimmunity / immunology*
  • Complement C5a / deficiency*
  • Erythrocytes / immunology
  • Kupffer Cells / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phagocytosis / immunology
  • Receptor, Anaphylatoxin C5a / antagonists & inhibitors
  • Receptor, Anaphylatoxin C5a / genetics
  • Receptor, Anaphylatoxin C5a / metabolism*
  • Receptors, IgG / biosynthesis
  • Receptors, IgG / immunology*


  • C5ar1 protein, mouse
  • Receptor, Anaphylatoxin C5a
  • Receptors, IgG
  • Complement C5a