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Factor D Inhibition Blocks Complement Activation Induced by Mutant Factor B Associated With Atypical Hemolytic Uremic Syndrome and Membranoproliferative Glomerulonephritis

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dc.contributor Skrifstofa meðferðarsviðs
dc.contributor Landspitali- The National University Hospital of Iceland
dc.contributor.author Aradottir, Sigridur Sunna
dc.contributor.author Kristoffersson, Ann Charlotte
dc.contributor.author Roumenina, Lubka T.
dc.contributor.author Bjerre, Anna
dc.contributor.author Kashioulis, Pavlos
dc.contributor.author Palsson, Runolfur
dc.contributor.author Karpman, Diana
dc.date.accessioned 2021-10-07T01:02:08Z
dc.date.available 2021-10-07T01:02:08Z
dc.date.issued 2021
dc.identifier.citation Aradottir , S S , Kristoffersson , A C , Roumenina , L T , Bjerre , A , Kashioulis , P , Palsson , R & Karpman , D 2021 , ' Factor D Inhibition Blocks Complement Activation Induced by Mutant Factor B Associated With Atypical Hemolytic Uremic Syndrome and Membranoproliferative Glomerulonephritis ' , Frontiers in Immunology , vol. 12 , pp. 690821 . https://doi.org/10.3389/fimmu.2021.690821
dc.identifier.issn 1664-3224
dc.identifier.other PURE: 38428323
dc.identifier.other PURE UUID: 9c4f6b76-dc46-4ffa-924c-e4ecff79ded6
dc.identifier.other Scopus: 85109614915
dc.identifier.uri https://hdl.handle.net/20.500.11815/2687
dc.description Funding The Swedish Research Council (2017-01920), The Knut and Alice Wallenberg Foundation (Wallenberg Clinical Scholar 2015.0320), Skåne Centre of Excellence in Health, The IngaBritt and Arne Lundberg’s Research Foundation, Olle Engkvist Byggmästare Foundation (all to DK). Publisher Copyright: Copyright © 2021 Aradottir, Kristoffersson, Roumenina, Bjerre, Kashioulis, Palsson and Karpman.
dc.description.abstract Complement factor B (FB) mutant variants are associated with excessive complement activation in kidney diseases such as atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy and membranoproliferative glomerulonephritis (MPGN). Patients with aHUS are currently treated with eculizumab while there is no specific treatment for other complement-mediated renal diseases. In this study the phenotype of three FB missense variants, detected in patients with aHUS (D371G and E601K) and MPGN (I242L), was investigated. Patient sera with the D371G and I242L mutations induced hemolysis of sheep erythrocytes. Mutagenesis was performed to study the effect of factor D (FD) inhibition on C3 convertase-induced FB cleavage, complement-mediated hemolysis, and the release of soluble C5b-9 from glomerular endothelial cells. The FD inhibitor danicopan abrogated C3 convertase-associated FB cleavage to the Bb fragment in patient serum, and of the FB constructs, D371G, E601K, I242L, the gain-of-function mutation D279G, and the wild-type construct, in FB-depleted serum. Furthermore, the FD-inhibitor blocked hemolysis induced by the D371G and D279G gain-of-function mutants. In FB-depleted serum the D371G and D279G mutants induced release of C5b-9 from glomerular endothelial cells that was reduced by the FD-inhibitor. These results suggest that FD inhibition can effectively block complement overactivation induced by FB gain-of-function mutations.
dc.format.extent 1
dc.format.extent 690821
dc.language.iso en
dc.relation.ispartofseries Frontiers in Immunology; 12()
dc.rights info:eu-repo/semantics/openAccess
dc.subject Nýrnasjúkdómar
dc.subject Ónæmisfræði
dc.subject Nýrnalæknisfræði
dc.subject atypical hemolytic uremic syndrome
dc.subject C3 glomerulopathy
dc.subject complement
dc.subject danicopan
dc.subject factor B
dc.subject factor D
dc.subject Immunology and Allergy
dc.subject Immunology
dc.title Factor D Inhibition Blocks Complement Activation Induced by Mutant Factor B Associated With Atypical Hemolytic Uremic Syndrome and Membranoproliferative Glomerulonephritis
dc.type /dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article
dc.description.version Peer reviewed
dc.identifier.pmid 34177949
dc.identifier.doi https://doi.org/10.3389/fimmu.2021.690821
dc.relation.url http://www.scopus.com/inward/record.url?scp=85109614915&partnerID=8YFLogxK
dc.contributor.department Faculty of Medicine


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