Investigating shared immunological mechanisms linking joint and ocular pathology in inflammatory arthritis and autoimmune uveitis

Abstract

Inflammatory arthritis and sight-threatening uveitis are clinically linked, with approximately 30% of patients with juvenile idiopathic arthritis and spondyloarthropathies developing uveitis. Although CD4⁺ T cells are implicated in both conditions, the shared immune mechanisms driving joint and ocular inflammation remain poorly defined.

Assessment of the ocular microenvironment during antigen-induced arthritis (AIA) by optical coherence tomography and flow cytometry revealed subclinical leukocyte infiltration comprising CD4⁺ and CD8⁺ T cells, CD11b⁺ myeloid cells, and Ly6G⁺ neutrophils. Perturbations in the ocular immune microenvironment were coupled to flares of arthritis, which, rather than systemic antigen challenge, required to drive AIA. The magnitude of leukocyte infiltration mirrored the severity of joint inflammation, with interleukin-27 receptor (IL-27R)-deficient mice with exacerbated arthritis displaying increased ocular leukocyte infiltrates and IL-6R-deficient mice with reduced arthritis showing negligible infiltration. Combining an adoptive transfer model of uveitis with AIA resulted in enhanced CD4⁺ T cells with pathogenic potential infiltrating the eye, suggesting that inflammatory arthritis may increase vulnerability to uveitis.

Parallel investigations utilised RNA-sequencing to identify effector characteristics shared by joint- and ocular-infiltrating CD4⁺ T cells in AIA and experimental autoimmune uveitis (EAU). The gene encoding galectin-3 was upregulated in CD4+ T cells infiltrating eyes and joints, and its clinical significance was confirmed in datasets from patient cohorts. In vitro studies revealed that galectin-3 was selectively expressed in CD4+ T cells undergoing differentiation into T helper 17 (Th17) cells. Galectin-3 inhibition impaired Th17 cell expansion and suppressed expression of genes associated with pathogenic responses (e.g., Il17a, Il17f, Rorc Rora, Ccr6) while enhancing expression of genes associated with regulatory T cell functions (e.g., Klf2, Ikzf3, Prdm1).

These findings demonstrate that established arthritis models offer a platform for exploring mechanisms underpinning joint-ocular comorbidities and support a pathogenic role for CD4+ T cell-derived galectin-3 in both tissues. Targeting galectin-3 has translational potential for treating arthritis, uveitis and their co-existence as multimorbidities.

Date of Award	20 Jan 2026
Original language	English
Awarding Institution	University of Bristol
Sponsors	Fight for Sight & Versus Arthritis
Supervisor	Gareth Jones (Supervisor) & Lindsay B Nicholson (Supervisor)