title: Complement Regulator FHR-3 Is Elevated either Locally or Systemically in a Selection of Autoimmune Diseases.
abstract: The human complement factor H-related protein-3 (FHR-3) is a soluble regulator of the complement system. Homozygouscfhr3/1deletion 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.
authors.affiliation: Department of Ophthalmology, University Hospital Regensburg , Regensburg , Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schäfer
authors.affiliation: Institute of Human Genetics, University of Regensburg , Regensburg , Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Grosche
authors.affiliation: Institute of Functional Genomics, University of Regensburg , Regensburg , Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Reinders
authors.affiliation: Research Unit Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH) , Neuherberg , Germany.
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Hauck
authors.affiliation: Department of Immunopathology, Sanquin Research and Landsteiner Laboratory of the Academic Medical Center, University of Amsterdam , Amsterdam , Netherlands.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Pouw
authors.affiliation: Department of Pediatric Hematology, Immunology and Infectious Diseases, Academic Medical Center, Emma Children's Hospital, Amsterdam, Netherlands; Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory of the Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
authors.affiliation: Department of Immunopathology, Sanquin Research and Landsteiner Laboratory of the Academic Medical Center, University of Amsterdam , Amsterdam , Netherlands.
authors.forename: Diana
authors.initials: D
authors.lastname: Wouters
authors.affiliation: Klinik und Poliklinik für Rheumatologie und Klinische Immunologie, Asklepios Klinikum Bad Abbach , Bad Abbach , Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Ehrenstein
authors.affiliation: Department of Ophthalmology, Inselspital, University of Bern , Bern , Switzerland.
authors.forename: Volker
authors.initials: V
authors.lastname: Enzmann
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany; Friedrich Schiller University, Jena, Germany.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Zipfel
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology , Jena , Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Skerka
authors.affiliation: Department of Ophthalmology, University Hospital Regensburg , Regensburg , Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Pauly
keywords: FH competition; FHR-3/CFHR3; immune therapy; microglia/macrophage; retinal degeneration; rheumatic disease; specific antibody