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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
Pálsson, Runólfur
Karpman, Diana
Date: 2021-06-10
Language: English
Scope: 1
University/Institute: Landspitali - The National University Hospital of Iceland
Department: Faculty of Medicine
Office of Division of Clinical Services I
Series: Frontiers in Immunology; 12()
ISSN: 1664-3224
DOI: 10.3389/fimmu.2021.690821
Subject: Ónæmisfræði; Nýrnalæknisfræði; Nýrnasjúkdómar; atypical hemolytic uremic syndrome; C3 glomerulopathy; complement; danicopan; factor B; factor D; Complement Activation; Glomerulonephritis, Membranoproliferative/genetics; Endothelial Cells/immunology; Humans; Middle Aged; Erythrocytes; Infant; Male; Complement C3b/immunology; Atypical Hemolytic Uremic Syndrome/genetics; Complement C3-C5 Convertases/immunology; Female; Child; Complement Factor B/genetics; Hemolysis; Rabbits; Kidney Glomerulus/cytology; Phenotype; Animals; Complement Factor D/antagonists & inhibitors; Sheep; Mutation; 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 , Pálsson , 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 , 690821 , 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 Information: The authors wish to thank Dr Marina Noris and Dr Roberta Donadelli, Istituto di Ricerche Farmacologiche Mario Negri, Bergamo Italy for excellent technical advice for the assay of factor B cleavage by the C3 convertase. Dr Ravi Bhongir and Dr Sandra Jovic, Infection Medicine, Clinical Sciences Lund are acknowledged for their help with the surface plasmon resonance assays. The authors thank Drs Markus Heidenblad, Sofia Saal and Bj?rn Hallstr?m of the Center for Molecular Diagnostics, Region Sk?ne and Clinical Genomics Lund, SciLifeLab, Lund University for next-generation sequencing. Dr Henning Gong carried out part of the mutagenesis study as part of his master?s thesis. The kidney biopsies of Patient 3 were assessed by Dr. Melinda Raki, Department of Pathology, Oslo University Hospital, Oslo Norway, Dr. Sabine Leh, Department of Pathology, Haukeland Univeristy Hospital Bergen, Norway, Professor Sanjeev Sethi and Professor Fernando Fervenza of the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. This work was presented in preliminary poster form at the17th Congress of the International Pediatric Nephrology Association, Iguacu Brazil, September 20-24, 2016, at the 6th International Conference ?HUS & related diseases?, Innsbruck, Austria, June 11-13, 2017, the 16th European Meeting of Complement in Human Disease, Copenhagen, Denmark, September 8-12, 2017, the 18th Congress of the International Pediatric Nephrology Association, Venice, Italy October 17-21, 2019. Publisher Copyright: © Copyright © 2021 Aradottir, Kristoffersson, Roumenina, Bjerre, Kashioulis, Palsson and Karpman.

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