Clinicomolecular Identification of Conserved and Individualized Features of Granulomatous Uveitis

PURPOSE: To identify molecular features that distinguish individuals with shared clinical features of granulomatous uveitis. DESIGN: Cross-sectional observational study. PARTICIPANTS: Four eyes from patients with active granulomatous uveitis. METHODS: We performed single-cell RNA sequencing with antigen-receptor sequence analysis to obtain an unbiased gene expression survey of ocular immune cells and to identify clonally expanded lymphocytes. MAIN OUTCOMES MEASURES: For each inflamed eye, we measured the proportion of distinct immune cell types, the amount of B- or T-cell clonal expansion, and the transcriptional profile of T and B cells. RESULTS: Each individual showed robust clonal expansion arising from a single T- or B-cell lineage, suggesting distinct, antigen-driven pathogenic processes in each patient. This variability in clonal expansion was mirrored by individual variability in CD4 T-cell populations, whereas ocular CD8 T cells and B cells were more similar transcriptionally among patients. Finally, ocular B cells displayed evidence of class switching and plasmablast differentiation within the ocular microenvironment, providing additional support for antigen-driven immune responses in granulomatous uveitis. CONCLUSIONS: Collectively, our study identified both conserved and individualized features of granulomatous uveitis, illuminating parallel pathophysiologic mechanisms and suggesting that future personalized therapeutic approaches may be warranted.