Defective complement control of Factor H (Y402H) and FHL-1 in age-related macular degeneration

Skerka, Christine; Lauer, Nadine; Weinberger, Andreas A W A; Keilhauer, Claudia N.; Sühnel, Jürgen; Smith, Richard J.H.; Schlötzer‐Schrehardt, Ursula; Fritsche, Lars G.; Heinen, Stefan; Hartmann, Andrea; Weber, Bernhard H. F.; Zipfel, Peter F.

doi:10.1016/j.molimm.2007.02.012

Cited by 177 publications

(121 citation statements)

References 37 publications

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“…No binding of fH was detected (negative results not shown), eliminating the possibility that the different results were due to the source of CRP. We next coated plates with natural human CRP using the non-physiological alkaline and Ca 2ϩ -free buffers described in previous reports (8,(15)(16)(17). We confirmed using anti-CRP that a similar amount of CRP became immobilized as in the presence of Ca 2ϩ (Fig.…”

Section: Resultssupporting

confidence: 67%

“…Attention has focused on defining the functional differences between the fH-Y402H variants that might influence C regulation and predispose to disease (13)(14)(15)(16). fH binds multiple ligands, and differences between the variants in ligand binding properties have been sought.…”

Section: Discussionmentioning

confidence: 99%

“…CRP bound to its natural ligands binds C1q and is a potent activator of the classical C pathway (35); CRP in drusen may, therefore, drive C activation and inflammation. Recent reports that the AMD-linked fH-H402 variant binds to CRP with lower affinity than fH-Y402 (13)(14)(15)36) have attracted enormous interest because they suggest a mechanism for the association. Binding of fH to CRP in the retina could, by regulating the alternative pathway amplification loop, restrict CRP-triggered local C activation.…”

Section: Discussionmentioning

confidence: 99%

“…When a fH polymorphism, resulting in a single amino acid change (Y402H) in SCR7 was implicated as a powerful risk factor for age-related macular degeneration (AMD) (10 -12), there was immediately intense interest in exploring differences in ligand binding between these polymorphic variants that might explain the disease association. Several groups have lately reported that the fH Y402 and H402 variants show differential binding affinity for CRP (13)(14)(15)(16)(17). Each used similar methods with CRP directly immobilized on a surface (ELISA plate or surface plasmon resonance chip) and either intact fH variants or recombinant fragments in the fluid phase.…”

Section: Complement (C)mentioning

confidence: 99%

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Complement Factor H Binds to Denatured Rather than to Native Pentameric C-reactive Protein

Hakobyan

Harris

Berg

et al. 2008

Journal of Biological Chemistry

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Binding of the complement regulatory protein, factor H, to C-reactive protein has been reported and implicated as the biological basis for association of the H402 polymorphic variant of factor H with macular degeneration. Published studies utilize solid-phase or fluid-phase binding assays to show that the factor H Y402 variant binds C-reactive protein more strongly than H402. Diminished binding of H402 variant to C-reactive protein in retinal drusen is posited to permit increased complement activation, driving inflammation and pathology. We used well validated native human C-reactive protein and pure factor H Y402H variants to test interactions. When factor H variants were incubated with C-reactive protein in the fluid phase at physiological concentrations, no association occurred. When C-reactive protein was immobilized on plastic, either non-specifically by adsorption in the presence of Ca 2؉ to maintain its native fold and pentameric subunit assembly or by specific Ca 2؉ -dependent binding to immobilized natural ligands, no specific binding of either factor H variant from the fluid phase was observed. In contrast, both factor H variants reproducibly bound to C-reactive protein immobilized in the absence of Ca 2؉ , conditions that destabilize the native fold and pentameric assembly. Both factor H variants strongly bound C-reactive protein that was denatured by heat treatment before immobilization, confirming interaction with denatured but not native C-reactive protein.We conclude that the reported binding of factor H to C-reactive protein results from denaturation of the C-reactive protein during immobilization. Differential binding to C-reactive protein, thus, does not explain association of the Y402H polymorphism with macular degeneration.

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Section: Resultssupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Complement (C)mentioning

confidence: 99%

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Complement Factor H Binds to Denatured Rather than to Native Pentameric C-reactive Protein

Hakobyan

Harris

Berg

et al. 2008

Journal of Biological Chemistry

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“…AMD is a chronic inflammatory disease associated with the replacement of tyrosine (Y) by histidine (H) at CCP7 position 402 [Y(402)H]. This exchange results in inappropriate ACP regulation in the retina, ultimately leading to the formation of drusen and vision loss (Skerka et al , 2007; reviewed in Skerka and Zipfel, 2008; Zipfel et al , 2010). Another FH polymorphism associated with AMD is the substitution of isoleucine with valine at position 62 [I(62)V], which results in and increased binding affinity for C3b and enhanced cofactor activity (Tortajada et al , 2009).…”

Section: Discussionmentioning

confidence: 99%

ThePlasmodium falciparumblood stages acquire factor H family proteins to evade destruction by human complement

Rosa

Flammersfeld

Ngwa

et al. 2015

Cellular Microbiology

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SummaryThe acquisition of regulatory proteins is a means of blood‐borne pathogens to avoid destruction by the human complement. We recently showed that the gametes of the human malaria parasite Plasmodium falciparum bind factor H (FH) from the blood meal of the mosquito vector to assure successful sexual reproduction, which takes places in the mosquito midgut. While these findings provided a first glimpse of a complex mechanism used by Plasmodium to control the host immune attack, it is hitherto not known, how the pathogenic blood stages of the malaria parasite evade destruction by the human complement. We now show that the human complement system represents a severe threat for the replicating blood stages, particularly for the reinvading merozoites, with complement factor C3b accumulating on the surfaces of the intraerythrocytic schizonts as well as of free merozoites. C3b accumulation initiates terminal complement complex formation, in consequence resulting in blood stage lysis. To inactivate C3b, the parasites bind FH as well as related proteins FHL‐1 and CFHR‐1 to their surface, and FH binding is trypsin‐resistant. Schizonts acquire FH via two contact sites, which involve CCP modules 5 and 20. Blockage of FH‐mediated protection via anti‐FH antibodies results in significantly impaired blood stage replication, pointing to the plasmodial complement evasion machinery as a promising malaria vaccine target.

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Reducing the Genetic Risk of Age-Related Macular Degeneration With Dietary Antioxidants, Zinc, and ω-3 Fatty Acids

Ho¹

2011

Arch Ophthalmol

187

131

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To investigate whether dietary nutrients can reduce the genetic risk of early age-related macular degeneration (AMD) conferred by the genetic variants CFH Y402H and LOC387715 A69S in a nested case-control study.Methods: For 2167 individuals (Ն55 years) from the population-based Rotterdam Study at risk of AMD, dietary intake was assessed at baseline using a semiquantitative food frequency questionnaire and genetic variants were determined using TaqMan assay. Incident early AMD was determined on fundus photographs at 3 follow-up visits (median follow-up, 8.6 years). The synergy index was used to evaluate biological interaction between risk factors; hazard ratios were calculated to estimate risk of early AMD in strata of nutrient intake and genotypes.Results: Five hundred seventeen participants developed early AMD. Significant synergy indices supported the possibility of biological interaction between CFH Y402H and zinc, ␤-carotene, lutein/zeaxanthin, and eicosapentaenoic/docosahexaenoic acid (EPA/DHA) and between LOC387715 A69S and zinc and EPA/DHA (all P Ͻ.05). Homozygotes of CFH Y402H with dietary intake of zinc in the highest tertile reduced their hazard ratio of early AMD from 2.25 to 1.27. For intakes of ␤-carotene, lutein/zeaxanthin, and EPA/DHA, these risk reductions were from 2.54 to 1.47, 2.63 to 1.72, and 1.97 to 1.30, respectively. Carriers of LOC387715 A69S with the highest intake of zinc and EPA/DHA reduced their risk from 1.70 to 1.17 and 1.59 to 0.95, respectively (all P trends Ͻ.05).Conclusions: High dietary intake of nutrients with antioxidant properties reduces the risk of early AMD in those at high genetic risk. Therefore, clinicians should provide dietary advice to young susceptible individuals to postpone or prevent the vision-disabling consequences of AMD.

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Defective complement control of Factor H (Y402H) and FHL-1 in age-related macular degeneration

Cited by 177 publications

References 37 publications

Complement Factor H Binds to Denatured Rather than to Native Pentameric C-reactive Protein

Complement Factor H Binds to Denatured Rather than to Native Pentameric C-reactive Protein

ThePlasmodium falciparumblood stages acquire factor H family proteins to evade destruction by human complement

Reducing the Genetic Risk of Age-Related Macular Degeneration With Dietary Antioxidants, Zinc, and ω-3 Fatty Acids

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