title: An engineered construct combining complement regulatory and surface-recognition domains represents a minimal-size functional factor H.
abstract: Complement is an essential humoral component of innate immunity; however, its inappropriate activation leads to pathology. Polymorphisms, mutations, and autoantibodies affecting factor H (FH), a major regulator of the alternative complement pathway, are associated with various diseases, including age-related macular degeneration, atypical hemolytic uremic syndrome, and C3 glomerulopathies. Restoring FH function could be a treatment option for such pathologies. In this article, we report on an engineered FH construct that directly combines the two major functional regions of FH: the N-terminal complement regulatory domains and the C-terminal surface-recognition domains. This minimal-size FH (mini-FH) binds C3b and has complement regulatory functions similar to those of the full-length protein. In addition, we demonstrate that mini-FH binds to the FH ligands C-reactive protein, pentraxin 3, and malondialdehyde epitopes. Mini-FH was functionally active when bound to the extracellular matrix and endothelial cells in vitro, and it inhibited C3 deposition on the cells. Furthermore, mini-FH efficiently inhibited complement-mediated lysis of host-like cells caused by a disease-associated FH mutation or by anti-FH autoantibodies. Therefore, mini-FH could potentially be used as a complement inhibitor targeting host surfaces, as well as to replace compromised FH in diseases associated with FH dysfunction.
authors.affiliation: Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, 07745 Jena, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Hebecker
authors.forename: María
authors.initials: M
authors.lastname: Alba-Domínguez
authors.forename: Lubka T
authors.initials: LT
authors.lastname: Roumenina
authors.forename: Stefanie
authors.initials: S
authors.lastname: Reuter
authors.forename: Satu
authors.initials: S
authors.lastname: Hyvärinen
authors.forename: Marie-Agnès
authors.initials: MA
authors.lastname: Dragon-Durey
authors.forename: T Sakari
authors.initials: TS
authors.lastname: Jokiranta
authors.forename: Pilar
authors.initials: P
authors.lastname: Sánchez-Corral
authors.forename: Mihály
authors.initials: M
authors.lastname: Józsi
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002097:C-Reactive Protein / Q000378:metabolism; D003167:Complement Activation; D003179:Complement C3b / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D017242:Complement Factor H / Q000235:genetics* / Q000276:immunology*; D003170:Complement Pathway, Alternative; D042783:Endothelial Cells / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D008315:Malondialdehyde / Q000378:metabolism; D011485:Protein Binding; D015202:Protein Engineering; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism; D017422:Sequence Analysis, DNA; D000683:Serum Amyloid P-Component / Q000378:metabolism; D000099153:Pentraxins
chemical_list: D002097:C-Reactive Protein; D003179:Complement C3b; D017242:Complement Factor H; D008315:Malondialdehyde; D011994:Recombinant Proteins; D000683:Serum Amyloid P-Component; D000099153:Pentraxins