The C5a receptor has a key role in immune complex glomerulonephritis in complement factor H-deficient mice.

Abstract

Chronic serum sickness leads to the formation of glomerular immune complexes; however, C57BL/6 mice do not develop glomerulonephritis unless complement factor H (CFH) is absent from the plasma. Here we studied the role for C5a receptor (R) in this setting. The exaggerated humoral immune response in CFH(-/-) mice was normalized in CFH(-/-)C5aR(-/-) double knockout mice, highlighting the C5aR dependence. The CFH knockout mice developed proliferative glomerulonephritis with endocapillary F4/80+ macrophage infiltration, a process reduced in the double knockout mice. There was no interstitial inflammation by histologic criteria or flow cytometry for F4/80+ Ly6C(hi)CCR2(hi) inflammatory macrophages. There were, however, more interstitial CD3+ CD4+ T lymphocytes in CFH knockout mice with chronic serum sickness, while double knockout mice had greater than 5-fold more Ly6C(lo)CCR2(lo) anti-inflammatory macrophages compared to the CFH knockout mice. Mice lacking C5aR were significantly protected from functional renal disease as assessed by blood urea nitrogen levels. Thus, IgG- and iC3b-containing immune complexes are not inflammatory in C57BL/6 mice. Yet when these mice lack CFH, sufficient C3b persists in glomeruli to generate C5a and activate C5aR.