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https://hdl.handle.net/2445/208062
Title: | Complement alternative pathway determines disease susceptibility and severity in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis |
Author: | Lucientes Continente, Laura Fernández Juárez, Gema Márquez Tirado, Bárbara Jiménez Villegas, Laura Acevedo, Mercedes Cavero, Teresa Cámara, Luís Sánchez Draibe, Juliana Anton Pampols, Paula Caravaca Fontán, Fernando Praga, Manuel Villacorta, Javier Goicoechea de Jorge, Elena |
Keywords: | Vasculitis Immunogenètica Vasculitis Immunogenetics |
Issue Date: | 1-Jan-2024 |
Publisher: | Elsevier BV |
Abstract: | Activation of the alternative pathway (AP) of complement is involved in the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), although the underlying molecular mechanisms are unclear. To gain insight into the role of the AP, common gene variants in CFH/CFHR1-5, CFB, C3 and MCP, and longitudinal determinations of plasma C3, C4, FH, FHR-1, FHR-2, FHR-5, FB, properdin and sC5b-9 levels were analyzed in a Spanish AAV cohort consisting of 102 patients; 54 with active AAV (active cohort) and 48 in remission not receiving immunosuppressants or dialysis therapy (remission cohort). The validation cohort consisted of 100 patients with ANCA-associated glomerulonephritis. Here, we demonstrated that common genetic variants in complement components of the AP are associated with disease susceptibility (CFB32Q/W) or severity of kidney damage in AAV (CFH-H1, CFH1H2 and DCFHR3/1). Plasma levels of complement components were significantly different between active and remission cohorts. In longitudinal observations, a high degree of AP activation at diagnosis was associated with worse disease outcome, while high basal FHR-1 levels and lower FH/FHR-1 ratios determined severe forms of kidney associated AAV. These genetic and plasmatic findings were confirmed in the validation cohort. Additionally, autoantibodies against FH and C3 convertase were identified in one and five active patients, respectively. Thus, our study identified key genetic and plasma components of the AP that determine disease susceptibility, prognosis, and severity in AAV. Our data also suggests that balance between FH and FHR-1 is critical and supports FHR-1 as a novel AP -specific therapeutic target in AAV. Kidney International (2024) 105, 177-188; https://doi.org/10.1016/ j.kint.2023.10.013 |
Note: | Reproducció del document publicat a: https://doi.org/10.1016/j.kint.2023.10.013 |
It is part of: | Kidney International, 2024, vol. 105, num. 1, p. 177-188 |
URI: | https://hdl.handle.net/2445/208062 |
Related resource: | https://doi.org/10.1016/j.kint.2023.10.013 |
ISSN: | 0085-2538 |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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