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Factor H-related 2 levels dictate FHR dimer composition.

Bert R J Veuskens^1,2, Mieke C Brouwer¹, Gerard van Mierlo¹

¹Sanquin Research and Landsteiner Laboratory of the Amsterdam University Medical Centers, University of Amsterdam, Plesmanlaan 125, 1066 CX, Amsterdam, The Netherlands.

Scientific Reports

|March 28, 2025

Summary

Factor H-related proteins 1 and 2 form dimers, influencing complement regulation. This study developed a new ELISA to quantify Factor H-related protein 2 homodimers, revealing insights into dimer distribution and disease associations.

Keywords:

Complement system Dimerization FHR-1 FHR-2

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Published on: June 10, 2025

Area of Science:

Immunology
Complement System Biology
Protein Biochemistry

Background:

Factor H-related (FHR) proteins 1 and 2 form homodimers and heterodimers.
Dimerization is thought to enhance their antagonistic function against complement regulator Factor H (FH).
Previous quantification methods could not directly measure FHR-2 homodimers, limiting understanding of FHR-1 and FHR-2 dimer distribution.

Purpose of the Study:

To develop a specific ELISA for direct quantification of FHR-2 homodimers.
To accurately measure all FHR-1 and FHR-2 containing dimers in a healthy donor cohort.
To elucidate the role of FHR-2 homodimers in complement regulation and disease.

Main Methods:

Development of novel in-house generated FHR-2 antibodies.
Creation of a specific ELISA assay for FHR-2 homodimer quantification.
Analysis of dimer stability, kinetics, and distribution using native and deficient plasma.

Main Results:

Enabled the first accurate measurement of all FHR-1 and FHR-2 containing dimers.
Confirmed rapid and dynamic dimer formation in human plasma.
Demonstrated that FHR-1/2 dimerization equilibrium is limited by low FHR-2 levels relative to FHR-1.

Conclusions:

The developed ELISA allows precise assessment of FHR-2 homodimer levels.
Understanding FHR dimer distribution is crucial given genetic links to complement-related diseases.
FHR-2 levels significantly impact the overall dimer distribution and complement regulatory function.