期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 21, 页码 8761-8766出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1019338108
关键词
inflammation; infection
资金
- Medical Research Council, United Kingdom [G0701298]
- Spanish Ministerio de Educacion y Cultura [SAF2008-00226]
- Ciber de Enfermedades Raras
- Fundacion Renal Inigo Alvarez de Toledo
- Medical Research Council [G0701298] Funding Source: researchfish
- MRC [G0701298] Funding Source: UKRI
Common polymorphisms in complement alternative pathway (AP) proteins C3 (C3(R102G)), factor B (fB(R32Q)), and factor H (fH(V62I)) are associated with age-related macular degeneration (AMD) and other pathologies. Our published work showed that fB(R32Q) influences C3 convertase formation, whereas fH(V62I) affects factor I cofactor activity. Here we show how C3(R102G) (C3S/F) influences AP activity. In hemolysis assays, C3(102G) activated AP more efficiently (EC50 C3(102G): 157 nM; C3(102R): 191 nM; P < 0.0001). fB binding kinetics and convertase stability were identical, but native and recombinant fH bound more strongly to C3b(102R) (K-D C3b(102R): 1.0 mu M; C3b(102G): 1.4 mu M; P < 0.0001). Accelerated decay was unaltered, but fH cofactor activity was reduced for C3b(102G), favoring AP amplification. Combining disease risk variants (C3(102G), fB(32R), and fH(62V)) in add-back assays yielded sixfold higher hemolytic activity compared with protective variants (C3(102R), fB(32Q), and fH(62I); P < 0.0001). These data introduce the concept of a functional complotype (combination of polymorphisms) defining complement activity in an individual, thereby influencing susceptibility to AP-driven disease.
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