期刊
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
卷 27, 期 5, 页码 1413-1425出版社
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2015020212
关键词
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资金
- German Research Foundation (DFG) [Zi432, SK 46]
- International Leibniz Research School (Jena, Germany)
- Jena School for Microbial Communication
- excellence initiative of the DFG
- European Community [2012-305608]
C3 glomerulopathy (C3G) is a severe kidney disease for which no specifictherapy exists. The causes of C3G are heterogeneous, and defective complement regulation is often linked to C3G pathogenesis. Copy number variations in the complement factor H-related (CFHR) gene cluster on chromosome 1q32 and CFHR5 mutant proteins associate with this disease. Here, we identified CFHR5 as a pattern recognition protein that binds to damaged human endothelial cell surfaces and to properdin, the human complement activator. We found the two N-terminal short consensus repeat domains of CFHR5 contact properdin and mediate dimer formation. These properdin-binding segments are duplicated in two mutant CFHR5 proteins, CFHR2-CFHR5(Hyb) from German patients with C3G and CFHR5(Dup) from Cypriot patients with C3G. Each of these mutated proteins assembled into large multimeric complexes and, compared to CFHR5, bound damaged human cell surfaces and properdin with greater intensity and exacerbated local complement activation. This enhanced surface binding and properdin recruitment was further evidenced in the mesangia of a transplanted and explanted kidney from a German patient with a CFHR2-CFHR5(Hyb) protein. Enhanced properdin staining correlated with local complement activation with C3b and C5b-9 deposition on the mesangial cell surface in vitro. This gain of function in complement activation for two disease-associated CFHR5 mutants describes a new disease mechanism of C3G, which is relevant for defining appropriate treatment options for this disorder.
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