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

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


Title: Factor D Inhibition Blocks Complement Activation Induced by Mutant Factor B Associated With Atypical Hemolytic Uremic Syndrome and Membranoproliferative Glomerulonephritis
Author: Aradottir, Sigridur Sunna
Kristoffersson, Ann Charlotte
Roumenina, Lubka T.
Bjerre, Anna
Kashioulis, Pavlos
Palsson, Runolfur   orcid.org/0000-0001-6763-1702
Karpman, Diana
Date: 2021
Language: English
Scope: 1
University/Institute: Skrifstofa meðferðarsviðs
Landspitali- The National University Hospital of Iceland
Department: Faculty of Medicine
Series: Frontiers in Immunology; 12()
ISSN: 1664-3224
DOI: https://doi.org/10.3389/fimmu.2021.690821
Subject: Nýrnasjúkdómar; Ónæmisfræði; Nýrnalæknisfræði; atypical hemolytic uremic syndrome; C3 glomerulopathy; complement; danicopan; factor B; factor D; Immunology and Allergy; Immunology
URI: https://hdl.handle.net/20.500.11815/2687

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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

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.

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.

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