Jebson, Bethany-rose; (2025) Defining the role of B cells in the pathogenesis of juvenile idiopathic arthritis-associated uveitis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Juvenile idiopathic arthritis (JIA) is the most common autoimmune rheumatic disease in children. In some cases, it is accompanied by uveitis (JIA-Uveitis), a serious complication that can cause permanent vision loss if uncontrolled. Known risk factors, such as positive antinuclear autoantibody (ANA) status, suggest a role for B cell dysregulation in JIA-Uveitis pathology, which remains underexplored. In a large cohort of JIA patients, I identified that there is a significant expansion of CD19+IgD-CD27-CD11c- double-negative (DN) B cells in the peripheral blood of JIA-Uveitis patients compared to those with JIA alone. A LASSO regression model also revealed that, alongside increased CD11c- DN B cells, increased memory B cells, ANA status, JIA subtype, and decreased Th2 B cells distinguished JIA-Uveitis from JIA-alone patients with an AUC of 0.82, outperforming traditional risk factors (AUC 0.74). Despite these strong phenotypic changes, transcriptional changes within bulk CD19+ B cells were limited. However, analysis of the B-cell-receptor (BCR) repertoire using the same dataset highlighted reduced BCR diversity in JIA-Uveitis patients which is highly suggestive of altered B cell activation. In severe cases of JIA-Uveitis, B cells infiltrating the eye displayed a similar antigen-activated phenotype to those in inflamed JIA joints. Mirroring these findings in the gold-standard preclinical uveitis model, experimental autoimmune uveitis (EAU), I identified that there is evidence of altered B cell activation, including increased splenic GC B cells, plasmablasts, and class-switched B cells compared to controls, and ocular infiltration of B cells in mice with severe disease. Preliminary experiments in B cell-deficient mice showed that the absence of B cells resulted in less severe uveitis, suggesting a direct contribution to uveitis pathology. These findings set the scene for future research exploring the therapeutic potential of targeting altered B cell activation in JIA-Uveitis, a disease still in need of novel therapeutics to prevent lifelong sight loss.

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