Cargando…

B cell OX40L supports T follicular helper cell development and contributes to SLE pathogenesis

OBJECTIVES: TNFSF4 (encodes OX40L) is a susceptibility locus for systemic lupus erythematosus (SLE). Risk alleles increase TNFSF4 expression in cell lines, but the mechanism linking this effect to disease is unclear, and the OX40L-expressing cell types mediating the risk are not clearly established....

Descripción completa

Detalles Bibliográficos
Autores principales: Cortini, Andrea, Ellinghaus, Ursula, Malik, Talat H, Cunninghame Graham, Deborah S, Botto, Marina, Vyse, Timothy James
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705841/
https://www.ncbi.nlm.nih.gov/pubmed/28818832
http://dx.doi.org/10.1136/annrheumdis-2017-211499
_version_ 1783282105280626688
author Cortini, Andrea
Ellinghaus, Ursula
Malik, Talat H
Cunninghame Graham, Deborah S
Botto, Marina
Vyse, Timothy James
author_facet Cortini, Andrea
Ellinghaus, Ursula
Malik, Talat H
Cunninghame Graham, Deborah S
Botto, Marina
Vyse, Timothy James
author_sort Cortini, Andrea
collection PubMed
description OBJECTIVES: TNFSF4 (encodes OX40L) is a susceptibility locus for systemic lupus erythematosus (SLE). Risk alleles increase TNFSF4 expression in cell lines, but the mechanism linking this effect to disease is unclear, and the OX40L-expressing cell types mediating the risk are not clearly established. Blockade of OX40L has been demonstrated to reduce disease severity in several models of autoimmunity, but not in SLE. We sought to investigate its potential therapeutic role in lupus. METHODS: We used a conditional knockout mouse system to investigate the function of OX40L on B and T lymphocytes in systemic autoimmunity. RESULTS: Physiologically, OX40L on both B and T cells contributed to the humoral immune response, but B cell OX40L supported the secondary humoral response and antibody affinity maturation. Our data also indicated that loss of B cell OX40L impeded the generation of splenic T follicular helper cells. We further show that in two models of SLE—a spontaneous congenic model and the H2-IA(bm12) graft-versus-host-induced model—loss of B cell OX40L ameliorates the autoimmune phenotype. This improvement was, in each case, accompanied by a decline in T follicular helper cell numbers. Importantly, the germline knockout did not exhibit a markedly different phenotype from the B cell knockout in these models. CONCLUSIONS: These findings contribute to a model in which genetically determined increased OX40L expression promotes human SLE by several mechanisms, contingent on its cellular expression. The improvement in pathology in two models of systemic autoimmunity indicates that OX40L is an excellent therapeutic target in SLE.
format Online
Article
Text
id pubmed-5705841
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher BMJ Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-57058412017-12-08 B cell OX40L supports T follicular helper cell development and contributes to SLE pathogenesis Cortini, Andrea Ellinghaus, Ursula Malik, Talat H Cunninghame Graham, Deborah S Botto, Marina Vyse, Timothy James Ann Rheum Dis Basic and Translational Research OBJECTIVES: TNFSF4 (encodes OX40L) is a susceptibility locus for systemic lupus erythematosus (SLE). Risk alleles increase TNFSF4 expression in cell lines, but the mechanism linking this effect to disease is unclear, and the OX40L-expressing cell types mediating the risk are not clearly established. Blockade of OX40L has been demonstrated to reduce disease severity in several models of autoimmunity, but not in SLE. We sought to investigate its potential therapeutic role in lupus. METHODS: We used a conditional knockout mouse system to investigate the function of OX40L on B and T lymphocytes in systemic autoimmunity. RESULTS: Physiologically, OX40L on both B and T cells contributed to the humoral immune response, but B cell OX40L supported the secondary humoral response and antibody affinity maturation. Our data also indicated that loss of B cell OX40L impeded the generation of splenic T follicular helper cells. We further show that in two models of SLE—a spontaneous congenic model and the H2-IA(bm12) graft-versus-host-induced model—loss of B cell OX40L ameliorates the autoimmune phenotype. This improvement was, in each case, accompanied by a decline in T follicular helper cell numbers. Importantly, the germline knockout did not exhibit a markedly different phenotype from the B cell knockout in these models. CONCLUSIONS: These findings contribute to a model in which genetically determined increased OX40L expression promotes human SLE by several mechanisms, contingent on its cellular expression. The improvement in pathology in two models of systemic autoimmunity indicates that OX40L is an excellent therapeutic target in SLE. BMJ Publishing Group 2017-12 2017-08-17 /pmc/articles/PMC5705841/ /pubmed/28818832 http://dx.doi.org/10.1136/annrheumdis-2017-211499 Text en © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted. This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/
spellingShingle Basic and Translational Research
Cortini, Andrea
Ellinghaus, Ursula
Malik, Talat H
Cunninghame Graham, Deborah S
Botto, Marina
Vyse, Timothy James
B cell OX40L supports T follicular helper cell development and contributes to SLE pathogenesis
title B cell OX40L supports T follicular helper cell development and contributes to SLE pathogenesis
title_full B cell OX40L supports T follicular helper cell development and contributes to SLE pathogenesis
title_fullStr B cell OX40L supports T follicular helper cell development and contributes to SLE pathogenesis
title_full_unstemmed B cell OX40L supports T follicular helper cell development and contributes to SLE pathogenesis
title_short B cell OX40L supports T follicular helper cell development and contributes to SLE pathogenesis
title_sort b cell ox40l supports t follicular helper cell development and contributes to sle pathogenesis
topic Basic and Translational Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705841/
https://www.ncbi.nlm.nih.gov/pubmed/28818832
http://dx.doi.org/10.1136/annrheumdis-2017-211499
work_keys_str_mv AT cortiniandrea bcellox40lsupportstfollicularhelpercelldevelopmentandcontributestoslepathogenesis
AT ellinghausursula bcellox40lsupportstfollicularhelpercelldevelopmentandcontributestoslepathogenesis
AT maliktalath bcellox40lsupportstfollicularhelpercelldevelopmentandcontributestoslepathogenesis
AT cunninghamegrahamdeborahs bcellox40lsupportstfollicularhelpercelldevelopmentandcontributestoslepathogenesis
AT bottomarina bcellox40lsupportstfollicularhelpercelldevelopmentandcontributestoslepathogenesis
AT vysetimothyjames bcellox40lsupportstfollicularhelpercelldevelopmentandcontributestoslepathogenesis