The role of OX40 ligand/OX40 axis signalling in atopic dermatitis

Emma Guttman-Yassky, Michael Croft, Bob Geng et al. British Journal of Dermatology, Volume 191, Issue 4, October 2024, Pages 488–496, https://doi.org/10.1093/bjd/ljae230

Abstract

Atopic dermatitis (AD) is a heterogeneous inflammatory condition involving multiple immune pathways mediated by pathogenic T cells. OX40 ligand (OX40L) and OX40 are costimulatory immune checkpoint molecules that regulate effector and memory T-cell activity and promote sustained immune responses in multiple immunological pathways, including T helper (Th)2, Th1, Th17 and Th22. As such, OX40L/OX40 signalling between antigen-presenting cells (APCs) and activated T cells postantigen recognition promotes pathogenic T-cell proliferation and survival.

Under inflammatory conditions, OX40L is upregulated on APCs, enhancing the magnitude of antigen-specific T-cell responses and secretion of proinflammatory cytokines. In AD, OX40L/OX40 signalling contributes to the amplification and chronic persistence of T-cell-mediated inflammation. Recent therapeutic success in clinical trials has highlighted the importance of the OX40L/OX40 axis as a promising target for the treatment of AD. Here, we discuss the many factors that are involved in the expression of OX40L and OX40, including the cytokine milieu, antigen presentation, the inflammatory environment in AD, and the therapeutic direction influenced by this costimulatory pathway.

Lay Summary

Atopic dermatitis (AD) (also known as atopic eczema) is a common skin disease caused by inflammation, and affects 2–3 of every 10 people worldwide. AD affects people of all ages and can cause a range of symptoms, including dry thickened skin, itchiness, rashes and pain. Despite the recent addition of new targeted treatment options, there is still a need for new treatments for people with moderate-to-severe AD.

New drugs are being studied that target two important signalling molecules in the immune system, called OX40 ligand (OX40L) and OX40. OX40L and OX40 bind together to continue the cycle of immune system activation, leading to increasing symptoms of AD. Blocking the OX40L and OX40 interaction may ease or stop symptoms of AD.

This review outlines what is currently known about the causes of AD, including the role played by the immune system and specifically the role of OX40L and OX40. We also highlight the development of new treatments that target the OX40L and OX40 interaction to treat AD, and suggest what the future may hold for managing AD.

Graphical Abstract

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