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Basic and translational research
Extended report
B cell OX40L supports T follicular helper cell development and contributes to SLE pathogenesis
  1. Andrea Cortini1,
  2. Ursula Ellinghaus1,
  3. Talat H Malik2,
  4. Deborah S Cunninghame Graham1,
  5. Marina Botto2,
  6. Timothy James Vyse1
  1. 1Division of Medical and Molecular Genetics and Immunology, Infection and Inflammatory Disease, King’s College London, London, UK
  2. 2Department of Medicine, Centre for Complement and Inflammation Research, Imperial College London, London, UK
  1. Correspondence to Professor Timothy James Vyse, Division of Medical and Molecular Genetics and Division of Immunology, Infection, and Inflammatory Disease, King’s College London, London, UK; timothy.vyse{at}kcl.ac.uk

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-IAbm12 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.

  • systemic lupus erythematosus
  • B cells
  • OX40L
  • T follicular helper cells
  • autoantibodies

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/

https://doi.org/10.1136/annrheumdis-2017-211499

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    Footnotes

    • Handling editor Tore K Kvien

    • Contributors AC designed, performed and analysed experiments and wrote the manuscript. UE performed experiments, helped with the statistical analysis and discussed the data. THM performed experiments. DSCG discussed the data and edited the manuscript. MB and TJV designed experiments, discussed the data and wrote the manuscript.

    • Funding This work was financed by the Wellcome Trust programme grant 17966/Z/2008. DSCG and TJV were awarded an Arthritis Research UK Project Grant (20265).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement There are no additional unpublished data. The mouse model described in this study is available to other researchers on request and has already been shared with other investigators.

    • Correction notice This article has been corrected since it published Online First. The fourth author’s name has been corrected to Deborah S Cunninghame Graham.