Anti-C1q autoantibodies deposit in glomeruli but are only pathogenic in combination with glomerular C1q-containing immune complexes
Leendert A. Trouw, … , Cees van Kooten, Mohamed R. Daha
Leendert A. Trouw, … , Cees van Kooten, Mohamed R. Daha
Published September 1, 2004
Citation Information: J Clin Invest. 2004;114(5):679-688. https://doi.org/10.1172/JCI21075.
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Categories: Article Autoimmunity

Anti-C1q autoantibodies deposit in glomeruli but are only pathogenic in combination with glomerular C1q-containing immune complexes

Abstract

Anti-C1q autoantibodies are present in sera of patients with several autoimmune diseases, including systemic lupus erythematosus (SLE). Strikingly, in SLE the presence of anti-C1q is associated with the occurrence of nephritis. We have generated mouse anti–mouse C1q mAb’s and used murine models to investigate whether anti-C1q autoantibodies actually contribute to renal pathology in glomerular immune complex disease. Administration of anti-C1q mAb JL-1, which recognizes the collagen-like region of C1q, resulted in glomerular deposition of C1q and anti-C1q autoantibodies and mild granulocyte influx, but no overt renal damage. However, combination of JL-1 with a subnephritogenic dose of C1q-fixing anti–glomerular basement membrane (anti-GBM) antibodies enhanced renal damage characterized by persistently increased levels of infiltrating granulocytes, major histological changes, and increased albuminuria. This was not observed when a non–C1q-fixing anti-GBM preparation was used. Experiments with different knockout mice showed that renal damage was dependent not only on glomerular C1q and complement activation but also on Fcγ receptors. In conclusion, anti-C1q autoantibodies deposit in glomeruli together with C1q but induce overt renal disease only in the context of glomerular immune complex disease. This provides an explanation why anti-C1q antibodies are especially pathogenic in patients with SLE.

Authors

Leendert A. Trouw, Tom W.L. Groeneveld, Marc A. Seelen, Jacques M.G.J. Duijs, Ingeborg M. Bajema, Frans A. Prins, Uday Kishore, David J. Salant, J. Sjef Verbeek, Cees van Kooten, Mohamed R. Daha

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In vitro characterization of mouse anti–mouse C1q mAb. (A) Anti-C1q dete...
In vitro characterization of mouse anti–mouse C1q mAb. (A) Anti-C1q detection ELISA for anti-C1q mAb’s JL-1, JL-2, and JL-3 and control mAb IgG2b under 0.5 M NaCl buffer conditions. OD415, OD at 415 nm. (B) Epitope competition ELISA showing inhibition of binding of DIG-labeled anti-C1q mAb to mouse C1q by unlabeled anti-C1q mAb or control mAb IgG2b. (C) Immunohistochemistry of WT or C1q–/– mouse spleen stained with anti-C1q mAb or controls. Original magnification, ×250. Poly, polyclonal antibody. (D) C1q head domains of the human A, B, and C chains or the control maltose-binding protein (MBP), CLRs, and intact human C1q were coated, and mAb JL-1 binding was analyzed. (E) Anti-C1q tail ELISA using human CLRs and serum of autoimmune MRL-lpr mice (MRL-lpr) or nonautoimmune normal mouse serum (NMS) for binding.