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

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 the...

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Autores principales: Aradottir, Sigridur Sunna, Kristoffersson, Ann-Charlotte, Roumenina, Lubka T., Bjerre, Anna, Kashioulis, Pavlos, Palsson, Runolfur, Karpman, Diana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222914/
https://www.ncbi.nlm.nih.gov/pubmed/34177949
http://dx.doi.org/10.3389/fimmu.2021.690821
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author Aradottir, Sigridur Sunna
Kristoffersson, Ann-Charlotte
Roumenina, Lubka T.
Bjerre, Anna
Kashioulis, Pavlos
Palsson, Runolfur
Karpman, Diana
author_facet Aradottir, Sigridur Sunna
Kristoffersson, Ann-Charlotte
Roumenina, Lubka T.
Bjerre, Anna
Kashioulis, Pavlos
Palsson, Runolfur
Karpman, Diana
author_sort Aradottir, Sigridur Sunna
collection PubMed
description 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.
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spelling pubmed-82229142021-06-25 Factor D Inhibition Blocks Complement Activation Induced by Mutant Factor B Associated With Atypical Hemolytic Uremic Syndrome and Membranoproliferative Glomerulonephritis Aradottir, Sigridur Sunna Kristoffersson, Ann-Charlotte Roumenina, Lubka T. Bjerre, Anna Kashioulis, Pavlos Palsson, Runolfur Karpman, Diana Front Immunol Immunology 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. Frontiers Media S.A. 2021-06-10 /pmc/articles/PMC8222914/ /pubmed/34177949 http://dx.doi.org/10.3389/fimmu.2021.690821 Text en Copyright © 2021 Aradottir, Kristoffersson, Roumenina, Bjerre, Kashioulis, Palsson and Karpman https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Aradottir, Sigridur Sunna
Kristoffersson, Ann-Charlotte
Roumenina, Lubka T.
Bjerre, Anna
Kashioulis, Pavlos
Palsson, Runolfur
Karpman, Diana
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
title_full Factor D Inhibition Blocks Complement Activation Induced by Mutant Factor B Associated With Atypical Hemolytic Uremic Syndrome and Membranoproliferative Glomerulonephritis
title_fullStr Factor D Inhibition Blocks Complement Activation Induced by Mutant Factor B Associated With Atypical Hemolytic Uremic Syndrome and Membranoproliferative Glomerulonephritis
title_full_unstemmed Factor D Inhibition Blocks Complement Activation Induced by Mutant Factor B Associated With Atypical Hemolytic Uremic Syndrome and Membranoproliferative Glomerulonephritis
title_short Factor D Inhibition Blocks Complement Activation Induced by Mutant Factor B Associated With Atypical Hemolytic Uremic Syndrome and Membranoproliferative Glomerulonephritis
title_sort factor d inhibition blocks complement activation induced by mutant factor b associated with atypical hemolytic uremic syndrome and membranoproliferative glomerulonephritis
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222914/
https://www.ncbi.nlm.nih.gov/pubmed/34177949
http://dx.doi.org/10.3389/fimmu.2021.690821
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