Common polymorphisms in C3, factor B, and factor H collaborate to determine systemic complement activity and disease risk

Heurich, Meike; Martı́nez-Barricarte, Rubén; Francis, Nigel J.; Roberts, Dawn; Córdoba, Santiago Rodrı́guez de; Morgan, B. Paul; Harris, Claire L.

doi:10.1073/pnas.1019338108

Cited by 201 publications

(192 citation statements)

References 47 publications

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“…Current concepts are that common allelic variants in complement regulators present in the general population confer a complotype that predisposes to disease (96) and that additional immune insults unmask complement regulatory deficiencies. As one illustration supporting this concept, poststreptococcal GN, generally a self-limited disease, resulted in progressive C3 nephropathy in a patient with a complement regulator mutation (97).…”

Section: Kidney Injury Mediated By Serum Complement In the Absence Ofmentioning

confidence: 99%

Molecules Great and Small

Mathern

Heeger

2015

Clinical Journal of the American Society of Nephrology

233

192

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The complement cascade, traditionally considered an effector arm of innate immunity required for host defense against pathogens, is now recognized as a crucial pathogenic mediator of various kidney diseases. Complement components produced by the liver and circulating in the plasma undergo activation through the classical and/or mannose-binding lectin pathways to mediate anti-HLA antibody-initiated kidney transplant rejection and autoantibody-initiated GN, the latter including membranous glomerulopathy, antiglomerular basement membrane disease, and lupus nephritis. Inherited and/or acquired abnormalities of complement regulators, which requisitely limit restraint on alternative pathway complement activation, contribute to the pathogenesis of the C3 nephropathies and atypical hemolytic uremic syndrome. Increasing evidence links complement produced by endothelial cells and/or tubular cells to the pathogenesis of kidney ischemia-reperfusion injury and progressive kidney fibrosis. Data emerging since the mid-2000s additionally show that immune cells, including T cells and antigen-presenting cells, produce alternative pathway complement components during cognate interactions. The subsequent local complement activation yields production of the anaphylatoxins C3a and C5a, which bind to their respective receptors (C3aR and C5aR) on both partners to augment effector T-cell proliferation and survival, while simultaneously inhibiting regulatory T-cell induction and function. This immune cell-derived complement enhances pathogenic alloreactive T-cell immunity that results in transplant rejection and likely contributes to the pathogenesis of other T cell-mediated kidney diseases. C5a/C5aR ligations on neutrophils have additionally been shown to contribute to vascular inflammation in models of ANCA-mediated renal vasculitis. New translational immunology efforts along with the development of pharmacologic agents that block human complement components and receptors now permit testing of the intriguing concept that targeting complement in patients with an assortment of kidney diseases has the potential to abrogate disease progression and improve patient health.

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Section: Kidney Injury Mediated By Serum Complement In the Absence Ofmentioning

confidence: 99%

Molecules Great and Small

Mathern

Heeger

2015

Clinical Journal of the American Society of Nephrology

233

192

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“…22,23 Likewise, all affected members carried SNPs in C3 (R102G [C3 slow/fast polymorphism] 24 /P314L), which have previously been shown to bind fH less strongly, and thus, C3b is less efficiently inactivated. 25,26 Both these SNPs, which result in increased AP activity, have been associated with an increased risk of DDD. 20 It is interesting to note that, in addition to a functionally significant mutation in CFH and functionally significant SNPs, C3Nef was also detected.…”

mentioning

confidence: 99%

Characterization of a Factor H Mutation That Perturbs the Alternative Pathway of Complement in a Family with Membranoproliferative GN

Wong¹,

Anderson²,

Herbert³

et al. 2014

Journal of the American Society of Nephrology

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Complement C3 activation is a characteristic finding in membranoproliferative GN (MPGN). This activation can be caused by immune complex deposition or an acquired or inherited defect in complement regulation. Deficiency of complement factor H has long been associated with MPGN. More recently, heterozygous genetic variants have been reported in sporadic cases of MPGN, although their functional significance has not been assessed. We describe a family with MPGN and acquired partial lipodystrophy. Although C3 nephritic factor was shown in family members with acquired partial lipodystrophy, it did not segregate with the renal phenotype. Genetic analysis revealed a novel heterozygous mutation in complement factor H (R83S) in addition to known risk polymorphisms carried by individuals with MPGN. Patients with MPGN had normal levels of factor H, and structural analysis of the mutant revealed only subtle alterations. However, functional analysis revealed profoundly reduced C3b binding, cofactor activity, and decay accelerating activity leading to loss of regulation of the alternative pathway. In summary, this family showed a confluence of common and rare functionally significant genetic risk factors causing disease. Data from our analysis of these factors highlight the role of the alternative pathway of complement in MPGN.

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“…Thus, other interactions between the TED-CUB domains and the MG1-MG8 domains in C4b may play a role in disease, although these will relate more closely to the complement regulators than with C4b itself. The well-characterised Arg 102 -Glu 1032 salt bridge is crucial for C3b and the Factor H SCR-1/4 domains [47]. The C3b polymorphism R102G that affects the Arg 102 -Glu 1032 bridge is linked to AMD and aHUS [10].…”

Section: Discussionmentioning

confidence: 99%

Domain structure of human complement C4b extends with increasing NaCl concentration: implications for its regulatory mechanism

Fung

Wright

Gor

et al. 2016

Biochemical Journal

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During the activation of complement C4 to C4b, the exposure of its thioester domain (TED) is crucial for the attachment of C4b to activator surfaces. In the C4b crystal structure, TED forms an Arg 104 -Glu 1032 salt bridge to tether its neighbouring macroglobulin (MG1) domain. Here, we examined the C4b domain structure to test whether this salt bridge affects its conformation. Dual polarisation interferometry of C4b immobilised at a sensor surface showed that the maximum thickness of C4b increased by 0.46 nm with an increase in NaCl concentration from 50 to 175 mM NaCl. Analytical ultracentrifugation showed that the sedimentation coefficient s 20,w of monomeric C4b of 8.41 S in 50 mM NaCl buffer decreased to 7.98 S in 137 mM NaCl buffer, indicating that C4b became more extended. Small angle X-ray scattering reported similar R G values of 4.89-4.90 nm for C4b in 137-250 mM NaCl. Atomistic scattering modelling of the C4b conformation showed that TED and the MG1 domain were separated by 4.7 nm in 137-250 mM NaCl and this is greater than that of 4.0 nm in the C4b crystal structure. Our data reveal that in low NaCl concentrations, both at surfaces and in solution, C4b forms compact TED-MG1 structures. In solution, physiologically relevant NaCl concentrations lead to the separation of the TED and MG1 domain, making C4b less capable of binding to its complement regulators. These conformational changes are similar to those seen previously for complement C3b, confirming the importance of this salt bridge for regulating both C4b and C3b.

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Common polymorphisms in C3, factor B, and factor H collaborate to determine systemic complement activity and disease risk

Cited by 201 publications

References 47 publications

Molecules Great and Small

Molecules Great and Small

Characterization of a Factor H Mutation That Perturbs the Alternative Pathway of Complement in a Family with Membranoproliferative GN

Domain structure of human complement C4b extends with increasing NaCl concentration: implications for its regulatory mechanism

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