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

Frontiers in Immunology

Lubka T. Roumenina¹  Pavlos Kashioulis²  Sigridur Sunna Aradottir³  Ann-Charlotte Kristoffersson³  Diana Karpman³  Runolfur Palsson⁵  Anna Bjerre⁶ 

[1] Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France;Department of Molecular and Clinical Medicine/Nephrology, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden;Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway;Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavík, Iceland;Institute of Clinical Medicine, University of Oslo, Oslo, Norway;Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland;

关键词: complement;    factor B;    factor D;    danicopan;    atypical hemolytic uremic syndrome;    C3 glomerulopathy;   

DOI  :  10.3389/fimmu.2021.690821

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown