title: Complement Factor H-Related Protein 3 Serum Levels Are Low Compared to Factor H and Mainly Determined by Gene Copy Number Variation in CFHR3.
abstract: The major human complement regulator in blood, complement factor H (FH), has several closely related proteins, called FH-related (FHR) proteins. As all FHRs lack relevant complement regulatory activity, their physiological role is not well understood. FHR protein 3 (FHR-3) has been suggested to compete with FH for binding to Neisseria meningitidis, thereby affecting complement-mediated clearance. Clearly, the in vivo outcome of such competition greatly depends on the FH and FHR-3 concentrations. While FH levels have been established, accurate FHR-3 levels were never unequivocally reported to date. Moreover, CFHR3 gene copy numbers commonly vary, which may impact the FHR-3 concentration. Hence, we generated five anti-FHR-3 mAbs to specifically measure FHR-3 in human healthy donors of which we determined the gene copy number variation at the CFH/CFHR locus. Finally, we examined the acute-phase response characteristics of FHR-3 in a small sepsis cohort. We determined FHR-3 levels to have a mean of 19 nM and that under normal conditions the copy number of CFHR3 correlates to a very large extent with the FHR-3 serum levels. On average, FHR-3 was 132-fold lower compared to the FH concentration in the same serum samples and FHR-3 did not behave as a major acute phase response protein.
authors.affiliation: Department of Immunopathology, Sanquin Research and Landsteiner laboratory of the Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.|Department of Pediatric Hematology, Immunology & Infectious Diseases, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Pouw
authors.affiliation: Department of Immunopathology, Sanquin Research and Landsteiner laboratory of the Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Mieke C
authors.initials: MC
authors.lastname: Brouwer
authors.affiliation: Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory of the Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Judy
authors.initials: J
authors.lastname: Geissler
authors.affiliation: Department of Immunopathology, Sanquin Research and Landsteiner laboratory of the Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Laurens V
authors.initials: LV
authors.lastname: van Herpen
authors.affiliation: Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Sacha S
authors.initials: SS
authors.lastname: Zeerleder
authors.affiliation: Division of Hematology and Central Hematology Laboratory, Luzerner Kantonsspital and University of Berne, Berne, Switzerland.
authors.forename: Walter A
authors.initials: WA
authors.lastname: Wuillemin
authors.affiliation: Department of Immunopathology, Sanquin Research and Landsteiner laboratory of the Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Diana
authors.initials: D
authors.lastname: Wouters
authors.affiliation: Department of Pediatric Hematology, Immunology & Infectious Diseases, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands.|Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory of the Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
mesh_terms: D000210:Acute-Phase Reaction / Q000097:blood / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology; D001798:Blood Proteins / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D017242:Complement Factor H / Q000032:analysis / Q000235:genetics*; D003429:Cross Reactions; D056915:DNA Copy Number Variations; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D018805:Sepsis / Q000097:blood / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D001798:Blood Proteins; C105970:CFHR3 protein, human; D017242:Complement Factor H