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

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Title: B cell OX40L supports T follicular helper cell development and contributes to SLE pathogenesis
Authors: Cortini, A
Ellinghaus, U
Malik, TH
Cunninghame Graham, DS
Botto, M
Vyse, TJ
Item Type: Journal Article
Abstract: 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.
Issue Date: 13-Nov-2017
Date of Acceptance: 1-Aug-2017
URI: http://hdl.handle.net/10044/1/51525
DOI: 10.1136/annrheumdis-2017-211499
ISSN: 0003-4967
Publisher: BMJ Publishing Group
Start Page: 2095
End Page: 2103
Journal / Book Title: Annals of the Rheumatic Diseases
Volume: 76
Issue: 12
Copyright Statement: © 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/
Keywords: B cells
OX40L
T follicular helper cells
autoantibodies
systemic lupus erythematosus
Science & Technology
Life Sciences & Biomedicine
Rheumatology
SYSTEMIC-LUPUS-ERYTHEMATOSUS
CHEMOKINE RECEPTOR
LIGAND INTERACTION
DENDRITIC CELL
CHRONIC GRAFT
EXPRESSION
CD4
DIFFERENTIATION
ASSOCIATION
SUSCEPTIBILITY
B cells
OX40L
T follicular helper cells
autoantibodies
systemic lupus erythematosus
Animals
Autoantibodies
Autoimmunity
B-Lymphocytes
Lupus Erythematosus, Systemic
Membrane Glycoproteins
Mice
Mice, Knockout
OX40 Ligand
T-Lymphocytes, Helper-Inducer
Tumor Necrosis Factors
B-Lymphocytes
T-Lymphocytes, Helper-Inducer
Animals
Mice, Knockout
Mice
Lupus Erythematosus, Systemic
Tumor Necrosis Factors
Membrane Glycoproteins
Autoantibodies
Autoimmunity
OX40 Ligand
1103 Clinical Sciences
1107 Immunology
1117 Public Health and Health Services
Arthritis & Rheumatology
Publication Status: Published
Online Publication Date: 2017-08-17
Appears in Collections:Department of Immunology and Inflammation
Faculty of Medicine