Factor H-related 2 levels dictate FHR dimer composition

Factor H-related 2 levels dictate FHR dimer composition

Abstract Factor H-related (FHR) protein 1 and 2 form dimers resulting in FHR-1 and -2 homodimers, and FHR-1/2 heterodimers. Dimerization is hypothesized to further increase their antagonistic function with complement regulator factor H (FH). So far, only FHR-1 homodimers and FHR-1/2 heterodimers cou...

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Main Authors: Bert R. J. Veuskens, Mieke C. Brouwer, Gerard van Mierlo, Judy Geissler, Karin van Leeuwen, Maaike Derlagen, Nadia C. H. Keijzer, Mark Hoogenboezem, Taco W. Kuijpers, Richard B. Pouw
Format: Article
Language:English
Published: Nature Portfolio 2025-03-01
Series:Scientific Reports
Subjects:
Complement system
FHR-1
FHR-2
Dimerization
Online Access:https://doi.org/10.1038/s41598-025-94064-4
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Summary:Abstract Factor H-related (FHR) protein 1 and 2 form dimers resulting in FHR-1 and -2 homodimers, and FHR-1/2 heterodimers. Dimerization is hypothesized to further increase their antagonistic function with complement regulator factor H (FH). So far, only FHR-1 homodimers and FHR-1/2 heterodimers could be quantified in a direct way. With the reported genetic associations between CFHR2 and complement-related diseases such as age related macular degeneration and C3-glomerulopathy, direct assessment of FHR-2/2 levels determining the dimer distribution of FHR-1 and -2 is needed to further elucidate their role within complement regulation. Therefore, novel in-house generated FHR-2 antibodies were used to develop a specific ELISA to enable direct quantification of FHR-2 homodimers. Allowing for the first time the accurate measurement of all FHR-1 and -2 containing dimers in a large cohort of healthy donors. By using native FHR-1 and -2 or deficient plasma, we determined the stability, kinetics and distribution of FHR-1 and -2 dimers. Additionally, we show how genetic variants influence dimer levels. Our results confirm a rapid, dynamic, dimer formation in plasma and show FHR-1/2 dimerization rearches a distribution equilibrium that is limited by the relative low levels of FHR-2 in relation to its dimerization partner FHR-1.
ISSN:2045-2322

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