Bethany R. Jebson, Benjamin Ingledow, Vicky Alexiou, Jakub Kubiak, Persephone Jenkins, Yuxuan Meng, Melissa Kartawinata, Restuadi Restuadi, Wei-Yu Lin, Chris Wallace, Colin J. Chu, Ameenat Lola Solebo, Lucy R. Wedderburn, Elizabeth C. Rosser, Lucy R. Wedderburn, Zoe Wanstall, Fatjon Dekaj, Aline Kimonyo, Eileen Hahn, Genevieve Gottschalk, Freya Luling Feilding, Alyssia McNeece, Fatema Merali, Elizabeth Ralph, Emily Robinson, Emma Sumner, Andrew Dick, Michael W. Beresford, Emil Carlsson, Joanna Fairlie, Jenna F. Gritzfeld, Oliver McClurg, Karen Rafferty, Athimalaipet V. Ramanan, Teresa Duerr, Michael Barnes, Sandra Ng, Kimme Hyrich, Stephen Eyre, Soumya Raychaudhuri, Wendy Thomson, John Bowes, Jeronee Jennycloss, Saskia Lawson-Tovey, Paul Martin, Andrew Morris, Stephanie Shoop-Worrall, Samantha Smith, Michael Stadler, Damian Tarasek, Melissa Tordoff, Annie Yarwood, Wei-Yu Lin, Nophar Geifman, Sarah Clarke
Abstract In Juvenile Idiopathic Arthritis (JIA), the most common childhood rheumatic disease, many patients also develop uveitis (JIA-uveitis), risking life-long vision loss. The mechanisms driving uveitis development in JIA remain understudied. Here, we demonstrate that peripheral blood CD19 + IgD - CD27 - double negative type 1 (DN1) B cells are elevated in JIA-uveitis compared to JIA patients without eye disease (JIA). The B cell receptor (BCR) repertoire was also more clonal and somatically hypermutated in JIA-uveitis and antigen-activated B cells infiltrated chronically inflamed JIA-uveitis eyes. Features of heightened B cell activation were recapitulated in experimental autoimmune uveoretinitis (EAU) and disrupting B and T cell interactions using monoclonal antibodies and transgenic mice suppresses uveitis. Together, these findings support a conceptual shift that uveitis is a primarily T cell driven disease and provide evidence for potential new therapeutic strategies that also consider B cells as drivers in disease pathology.