Clinicomolecular Identification of Conserved and Individualized Features of Granulomatous Uveitis
Lynn M. Hassman, Michael Paley, Ekaterina Esaulova, Grace Paley, Philip A. Ruzycki, Nicole Linskey, Jennifer Laurent, Lacey Feigl‐Lenzen, Luke E. Springer, Cynthia L. Montana, Karen Hong, Jennifer M. Enright, Hayley R. James, Maxim N. Artyomov, Wayne M. Yokoyama
Abstract
Objective: 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 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 had 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 transcriptionally similar between 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.