Deletion of Lys224 in regulatory domain 4 of Factor H reveals a novel pathomechanism for dense deposit disease (MPGN II)

Licht, Christoph; Heinen, Stefan; Józsi, Mihály; Löschmann, Ina; Saunders, Rebecca E.; Perkins, Stephen J.; Waldherr, R; Skerka, Christine; Kirschfink, Michael; Höppe, Bernd; Zipfel, Peter F.

doi:10.1038/sj.ki.5000269

Cited by 187 publications

(153 citation statements)

References 46 publications

Supporting

Mentioning

145

Contrasting

Unclassified

Order By: Relevance

“…Infusions of fresh frozen plasma containing fH may benefit patients deficient in fH (88), and therapy targeting C5 showed some success in patients with forms of C3 nephropathies (89,90).…”

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

View full text Add to dashboard Cite

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.

show abstract

“…Infusions of fresh frozen plasma containing fH may benefit patients deficient in fH (88), and therapy targeting C5 showed some success in patients with forms of C3 nephropathies (89,90).…”

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

View full text Add to dashboard Cite

show abstract

“…Among these correlations, mutations that alter the C-terminal region of FH are prototypical of aHUS, 7-9 whereas the Y402H polymorphism in SCR7 of FH is a unique risk factor for AMD [10][11][12][13] and complete FH deficiency or homozygous mutations in the N-terminal region of FH associate with C3G. 14,15 In this context, the association of the C-terminal FH-R1210C mutation with aHUS, 16 AMD, [17][18][19] and C3G 2 0 challenges these genotypephenotype correlations, suggesting previously unrecognized pathogenic links between these disorders. Here, we performed experiments to reveal the molecular basis of these associations and to identify what determines the disease outcome in FH-R1210C carriers.…”

mentioning

confidence: 99%

“…activators, galactose-deficient IgA1-containing immune complexes, or AMD risk polymorphisms will trigger C3G, IgA nephropathy, or AMD, 14,[27][28][29][30] respectively. Additional genetic and/or environmental factors altering host surfaces, depositing activating molecules (i.e., C-reactive protein, malondialdehyde), or removing FH ligands (i.e., heparan sulfate, sialic acid) might also influence the pathologic outcome in these individuals.…”

mentioning

confidence: 99%

Molecular Basis of Factor H R1210C Association with Ocular and Renal Diseases

Recalde

Tortajada

Subias

et al. 2015

JASN

View full text Add to dashboard Cite

The complement factor H (FH) mutation R1210C, which was described in association with atypical hemolytic uremic syndrome (aHUS), also confers high risk of agerelated macular degeneration (AMD) and associates with C3 glomerulopathy (C3G). To reveal the molecular basis of these associations and to provide insight into what determines the disease phenotype in FH-R1210C carriers, we identified FH-R1210C carriers in our aHUS, C3G, and AMD cohorts. Disease status, determined in patients and relatives, revealed an absence of AMD phenotypes in the aHUS cohort and, vice versa, a lack of renal disease in the AMD cohort. These findings were consistent with differences in the R1210C-independent overall risk for aHUS and AMD between mutation carriers developing one pathology or the other. R1210C is an unusual mutation that generates covalent complexes between FH and HSA. Using purified FH proteins and surface plasmon resonance analyses, we demonstrated that formation of these FH-HSA complexes impairs accessibility to all FH functional domains. These data suggest that R1210C is a unique C-terminal FH mutation that behaves as a partial FH deficiency, predisposing individuals to diverse pathologies with distinct underlying pathogenic mechanisms; the final disease outcome is then determined by R1210C-independent genetic risk factors.

show abstract

“…Plasma exchange may be effective at removing autoantibodies or dysfunctional complement components, while also enhancing CFH function through the infusion of plasma. Plasma exchange was reported to be effective in two affected sisters who had a factor H mutation and C3 nephritic factor [61]. The role of immunosuppressive agents in dense deposit disease is uncertain.…”

Section: Mpgn Type Ii/dense Deposit Diseasementioning

confidence: 99%