Abrogation of immune complex glomerulonephritis by native carboxypeptidase and pharmacological antagonism of the C5a receptor

Cell Mol Immunol. 2016 Sep;13(5):651-7. doi: 10.1038/cmi.2015.45. Epub 2015 Jul 13.


Activation of complement generates C5a which leads to signaling through C5aR1. This is tightly controlled, including by the plasma proteins factor H (FH) and carboxypeptidase N. Here we studied a chronic serum sickness (CSS) model of glomerulonephritis (GN) in which there is an active humoral immune response, formation of glomerular immune complexes (ICs), and resulting glomerular inflammation. The antibody response, glomerular IC deposition, the degree of GN, and consequent renal functional insufficiency in CSS were all worse in FH-/- mice compared to wild-type FH+/+ animals. This was ameliorated in the former by giving a C5aR1 antagonist for the final 3 weeks of the 5-week protocol. In contrast, blocking CP-mediated inactivation of C5a increased these disease measures. Thus, complement regulation by both plasma FH and CP to limit the quantity of active C5a is important in conditions where the humoral immune response is directed to a continuously present foreign antigen. Signaling through C5aR1 enhances the humoral immune response as well as the inflammatory response to ICs that have formed in glomeruli. Both effects are relevant even after disease has begun. Thus, pharmacological targeting of C5a in IC-mediated GN has potential clinical relevance.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigen-Antibody Complex / metabolism*
  • Apoferritins / metabolism
  • Carboxypeptidases / metabolism*
  • Complement C5a / metabolism
  • Complement Factor H / deficiency
  • Complement Factor H / metabolism
  • Glomerulonephritis / immunology*
  • Glomerulonephritis / pathology
  • Immunity, Humoral
  • Immunoglobulin G / metabolism
  • Kidney / pathology
  • Kidney / physiopathology
  • Kidney Function Tests
  • Male
  • Mice, Inbred C57BL
  • Receptor, Anaphylatoxin C5a / antagonists & inhibitors*
  • Receptor, Anaphylatoxin C5a / metabolism


  • Antigen-Antibody Complex
  • Immunoglobulin G
  • Receptor, Anaphylatoxin C5a
  • Complement C5a
  • Complement Factor H
  • Apoferritins
  • Carboxypeptidases