Title: Defining the contribution of B cell immunopathology to the development of juvenile idiopathic arthritis associated uveitis
Funder: Versus Arthritis

Abstract: Juvenile Idiopathic Arthritis (JIA) is an umbrella term that encompasses a group of arthritides that develop under 16 years old. In the most common forms (rheumatoid factor (RF)negoligo-articular and poly-articular JIA) of disease, up to 30% of patients can develop chronic anterior uveitis1 . The connection between uveitis and JIA remains unclear1 . Response to therapy is heterogenous and some children develop a treatment refractory form of disease, leading to life-long loss of sight. Childhood visual disability has significant negative impact on quality of life and global developmental outcomes2 .There is a major unmet need for therapeutics that target specific uveitic pathogenic mechanisms and better strategies to identify at-risk children as screening for all JIA-patients is costly and timewasting for the majority of patients. Current treatment strategies are based around treatment with local steroids, methotrexate and agents that block TNFa1 . However, there is evidence that JIA-uveitis is a B-cell-driven disease. The primary risk factors for JIA_x0002_uveitis development are anti-nuclear autoantibody (ANA) production3 (and within our preliminary cohort Figure 1A), a hallmark for the breakdown in B-cell tolerance4 , and early age at disease onset, which is associated with a prominent B-cell transcriptional signature within total peripheral blood mononuclear cells (PBMC) compared to children with later disease onset5 . Using a discovery data-set (n=44), we have recently identified a significant increase in antibody-producing plasmablast frequency and significant reduction in immature B-cell frequency, which have been previously ascribed a regulatory phenotype6 , within PBMCs from JIA-uveitis patients compared to JIA-patients without uveitis suggesting that B-cell compartment is skewed to an ‘inflammatory phenotype’ (Figure 1B). Furthermore, an alteration in the proportion of memory B-cells and mature naïve B-cells suggests that normal B-cell development may be aberrant in JIA-uveitis (Figure 1B). Further evidence for B-cell-driven pathology in JIA-uveitis is provided by case studies demonstrating that rituximab, a B-cell depleting monoclonal antibody, has some efficacy in patients refractory to first-line therapies7,8 . Despite this, there are no available studies that compare B-cell phenotype in JIA-uveitis patients compared to JIA-patients without uveitis. Furthermore, whilst experimental models of uveitis have established that monocytes/macrophages and T cells contribute to experimental autoimmune uveitis, there is a paucity of studies that investigate B-cell driven immunopathology9 . Notably, there is one study that has demonstrated that a population IL-35 induced regulatory B-cells can suppress experimental autoimmune uveitis on adoptive transfer10 . Here, the student would build upon preliminary data to formally address the role of B-cells in JIA-uveitis by accessing already stored samples from a world-unique JIA biobank and by using an experimental model of uveitis. By assessing B-cell function and phenotype during uveitis development using mouse models and JIA patient samples, evidence for the correct application of B-cell targeting therapies to this devastating disease could be developed.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM