Complement alternative pathway determines disease susceptibility and severity in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis

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,...

Descripción completa

Detalles Bibliográficos
Autores: 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
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/208062
Acceso en línea:https://hdl.handle.net/2445/208062
Access Level:acceso abierto
Palabra clave:Vasculitis
Immunogenètica
Immunogenetics
id ES_d1c0f63cadae9b88529bbc6134c1919d
oai_identifier_str oai:diposit.ub.edu:2445/208062
network_acronym_str ES
network_name_str España
repository_id_str
spelling Complement alternative pathway determines disease susceptibility and severity in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitisLucientes Continente, LauraFernández Juárez, GemaMárquez Tirado, BárbaraJiménez Villegas, LauraAcevedo, MercedesCavero, TeresaCámara, Luís SánchezDraibe, JulianaAnton Pampols, PaulaCaravaca Fontán, FernandoPraga, ManuelVillacorta, JavierGoicoechea de Jorge, ElenaVasculitisImmunogenèticaVasculitisImmunogeneticsActivation 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.2023.10.013Elsevier BV2024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/208062Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1016/j.kint.2023.10.013Kidney International, 2024, vol. 105, num. 1, p. 177-188https://doi.org/10.1016/j.kint.2023.10.013cc by-nc-nd (c) Lucientes Continente, Laura et al., 2024http://creativecommons.org/licenses/by-nc-nd/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2080622026-05-27T06:46:51Z
dc.title.none.fl_str_mv Complement alternative pathway determines disease susceptibility and severity in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis
title Complement alternative pathway determines disease susceptibility and severity in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis
spellingShingle Complement alternative pathway determines disease susceptibility and severity in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis
Lucientes Continente, Laura
Vasculitis
Immunogenètica
Vasculitis
Immunogenetics
title_short Complement alternative pathway determines disease susceptibility and severity in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis
title_full Complement alternative pathway determines disease susceptibility and severity in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis
title_fullStr Complement alternative pathway determines disease susceptibility and severity in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis
title_full_unstemmed Complement alternative pathway determines disease susceptibility and severity in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis
title_sort Complement alternative pathway determines disease susceptibility and severity in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis
dc.creator.none.fl_str_mv 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
author Lucientes Continente, Laura
author_facet 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
author_role author
author2 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
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Vasculitis
Immunogenètica
Vasculitis
Immunogenetics
topic Vasculitis
Immunogenètica
Vasculitis
Immunogenetics
description 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
publishDate 2024
dc.date.none.fl_str_mv 2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/208062
url https://hdl.handle.net/2445/208062
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1016/j.kint.2023.10.013
Kidney International, 2024, vol. 105, num. 1, p. 177-188
https://doi.org/10.1016/j.kint.2023.10.013
dc.rights.none.fl_str_mv cc by-nc-nd (c) Lucientes Continente, Laura et al., 2024
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by-nc-nd (c) Lucientes Continente, Laura et al., 2024
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier BV
publisher.none.fl_str_mv Elsevier BV
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869420290998534144
score 15.301603

Similares en LA Referencia