Complement-Regulator Factor H and Related Proteins in Otitis Media with Effusion

Närkiö-Mäkelä, Mervi; Hellwage, Jens; Tahkokallio, Olli; Meri, Seppo

doi:10.1006/clim.2001.5043

Cited by 44 publications

(18 citation statements)

References 24 publications

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“…We speculate that fine-tuning of complement activation (complement modulation) could be achieved by altering CFHR levels. It is notable that in otitis media with effusion, where complement is strongly activated in the middle ear effusion fluid, CFHR5 levels were noted to be high (17) and it was proposed that competition between CFHR5 and CFH might be relevant in this circumstance. This theory requires further study but our data would predict that a local increase in CFHR protein concentration would, through enhanced CFH deregulation, enable rapid enhancement of complement activation.…”

Section: Discussionmentioning

confidence: 99%

Dimerization of complement factor H-related proteins modulates complement activation in vivo

Jorge

Caesar

Malik

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

248

374

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The complement system is a key component regulation influences susceptibility to age-related macular degeneration, meningitis, and kidney disease. Variation includes genomic rearrangements within the complement factor H-related ( CFHR ) locus. Elucidating the mechanism underlying these associations has been hindered by the lack of understanding of the biological role of CFHR proteins. Here we present unique structural data demonstrating that three of the CFHR proteins contain a shared dimerization motif and that this hitherto unrecognized structural property enables formation of both homodimers and heterodimers. Dimerization confers avidity for tissue-bound complement fragments and enables these proteins to efficiently compete with the physiological complement inhibitor, complement factor H (CFH), for ligand binding. Our data demonstrate that these CFHR proteins function as competitive antagonists of CFH to modulate complement activation in vivo and explain why variation in the CFHRs predisposes to disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Dimerization of complement factor H-related proteins modulates complement activation in vivo

Jorge

Caesar

Malik

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

248

374

View full text Add to dashboard Cite

show abstract

“…Additionally, we tested patients suffering from autoimmune diseases for FHR-3 levels, as we assumed elevated systemic FHR-3 levels could be involved in inflammation (16). Complement activation is important in RA as immune complexes fix complement, resulting in the release of chemo-attractants for macrophages (55).…”

Section: Discussionmentioning

confidence: 99%

“…FHR-3 was also found in middle ear fluid following alternative complement pathway activation due to infections and was associated with pro-inflammatory activity (16). …”

Section: Introductionmentioning

confidence: 99%

Complement Regulator FHR-3 Is Elevated either Locally or Systemically in a Selection of Autoimmune Diseases

et al. 2016

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The human complement factor H-related protein-3 (FHR-3) is a soluble regulator of the complement system. Homozygous cfhr3/1 deletion is a genetic risk factor for the autoimmune form of atypical hemolytic-uremic syndrome (aHUS), while also found to be protective in age-related macular degeneration (AMD). The precise function of FHR-3 remains to be fully characterized. We generated four mouse monoclonal antibodies (mAbs) for FHR-3 (RETC) without cross-reactivity to the complement factor H (FH)-family. These antibodies detected FHR-3 from human serum with a mean concentration of 1 μg/mL. FHR-3 levels in patients were significantly increased in sera from systemic lupus erythematosus, rheumatoid arthritis, and polymyalgia rheumatica but remained almost unchanged in samples from AMD or aHUS patients. Moreover, by immunostaining of an aged human donor retina, we discovered a local FHR-3 production by microglia/macrophages. The mAb RETC-2 modulated FHR-3 binding to C3b but not the binding of FHR-3 to heparin. Interestingly, FHR-3 competed with FH for binding C3b and the mAb RETC-2 reduced the interaction of FHR-3 and C3b, resulting in increased FH binding. Our results unveil a previously unknown systemic involvement of FHR-3 in rheumatoid diseases and a putative local role of FHR-3 mediated by microglia/macrophages in the damaged retina. We conclude that the local FHR-3/FH equilibrium in AMD is a potential therapeutic target, which can be modulated by our specific mAb RETC-2.

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“…Levels of FH and FHRs in human plasma vary widely in the population. Interestingly, one report suggests that the concentrations of FHR proteins are increased upon infection, such as in the middle ear fluid of patients with otitis media with effusion (Närkiö-Mäkelä et al, 2001). We anticipate that unraveling physiological or pathological conditions that may alter the FH/FHRs ratio and sorting out how these changes occur will impact our understanding of the pathogenic mechanisms of several diseases associated with complement dysregulation.…”

Section: Mutations Involving the Fhrsmentioning

confidence: 96%

Complement genetics and susceptibility to inflammatory disease. Lessons from genotype–phenotype correlations

Córdoba

2016

Immunobiology

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Complement-Regulator Factor H and Related Proteins in Otitis Media with Effusion

Cited by 44 publications

References 24 publications

Dimerization of complement factor H-related proteins modulates complement activation in vivo

Dimerization of complement factor H-related proteins modulates complement activation in vivo

Complement Regulator FHR-3 Is Elevated either Locally or Systemically in a Selection of Autoimmune Diseases

Complement genetics and susceptibility to inflammatory disease. Lessons from genotype–phenotype correlations

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