Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations

Kumar, Vikrant; Pouw, Richard B.; Autio, Matias; Sagmeister, Manfred G.; Phua, Zai Y; Borghini, Lisa; Wright, Victoria J.; Hoggart, Clive; Pan, Bangfen; Tan, Antson Kiat Yee; Binder, A.; Brouwer, Mieke C.; Pinnock, Ellie; Groot, Ronald de; Hazelzet, Jan A.; Emonts, Marieke; Flier, Michiel van der; Reiter, Karl; Nöthen, Markus M.; Hoffmann, Per; Schlapbach, Luregn J.; Bellos, Evangelos; Anderson, Suzanne T.; Secka, Fatou; Martinón‐Torres, Federico; Salas, Antonio; Fink, Colin G.; Carrol, Enitan D.; Pollard, Andrew J.; Coin, Lachlan; Zenz, Werner; Wouters, Diana; Ang, Lay Teng; Hibberd, Martin L.; Levin, Michael; Kuijpers, Taco W.; Dávila, Sonia

doi:10.1016/j.ajhg.2022.08.001

Cited by 4 publications

(2 citation statements)

References 54 publications

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“…Reduced level of FH was found to be a protective factor from meningococcal disease and the lower FH concentration was associated with a single nucleotide polymorphism in the CFHR3 gene. Deletion of the corresponding gene segment in an engineered cell line elevated the FH level, thereby a direct regulatory role of this polymorphism was proved, although the exact mechanism is unclear ( 216 ). N. meningitidis and N. gonorrhoeae both bind FHR-5 by the same outer membrane protein PorB in the presence of sialylated lipopolysaccharide, and the addition of FHR-5 to sialylated N. gonorrhoeae caused enhanced complement-mediated lysis of the bacteria ( 217 ).…”

Section: What We Learned From Diseases/disease Associationsmentioning

confidence: 99%

The human factor H protein family – an update

Sándor,

Schneider,

Matola

et al. 2024

Front. Immunol.

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Complement is an ancient and complex network of the immune system and, as such, it plays vital physiological roles, but it is also involved in numerous pathological processes. The proper regulation of the complement system is important to allow its sufficient and targeted activity without deleterious side-effects. Factor H is a major complement regulator, and together with its splice variant factor H-like protein 1 and the five human factor H-related (FHR) proteins, they have been linked to various diseases. The role of factor H in inhibiting complement activation is well studied, but the function of the FHRs is less characterized. Current evidence supports the main role of the FHRs as enhancers of complement activation and opsonization, i.e., counter-balancing the inhibitory effect of factor H. FHRs emerge as soluble pattern recognition molecules and positive regulators of the complement system. In addition, factor H and some of the FHR proteins were shown to modulate the activity of immune cells, a non-canonical function outside the complement cascade. Recent efforts have intensified to study factor H and the FHRs and develop new tools for the distinction, quantification and functional characterization of members of this protein family. Here, we provide an update and overview on the versatile roles of factor H family proteins, what we know about their biological functions in healthy conditions and in diseases.

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Section: What We Learned From Diseases/disease Associationsmentioning

confidence: 99%

The human factor H protein family – an update

Sándor,

Schneider,

Matola

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…This might explain the prevalence of B/v1 fHbp expressing strains among disease isolates [ 38 ]. Furthermore, a protective CFHR3 SNP, rs75703017 was associated with lower CFH concentrations; evidence indicates that sequences around CFHR3 include a regulatory region that affects CFH transcription [ 39 ]. Of note, CFHR3 can be lost along with CFHR1 [ 40 ], with this deletion being common in individuals from Northern Nigeria [ 41 ], where epidemics of meningococcal disease can start [ 42 ].…”

Section: Fhbp Cfhrs and Host Susceptibilitymentioning

confidence: 99%