Abstract
Purpose :
Non-infectious uveitis is a heterogeneous group of blinding ocular inflammatory diseases whose pathophysiologic mechanisms are poorly understood. This results in empiric treatments that are ineffective for many patients. We therefore set out to identify immunologic mechanisms that would differentiate uveitis subtypes and reveal therapeutic targets.
Methods :
We performed single-cell V(D)J sequencing to identify clonally expanded lymphocytes, an indication of antigen-driven immune responses, in parallel with single-cell RNA sequencing in order 1)identify antigen-expanded lymphocytes and 2) characterize the gene expression of aqueous fluid and peripheral blood immune cells from 18 patients with diverse types of uveitis.
Results :
We identified clonal CD4 T cell expansion in aqueous samples from a subset of patients with uveitis, suggesting that these ocular immune cells had responded to an antigen. Furthermore, we found that patients with robust CD4 clonal expansion tended to have granulomatous features and prolonged disease courses. Furthermore, these patients’ CD4 T cells were enriched in expression of genes associated with the effector memory cell state, a group of antigen-experienced T cells that drive chronic or recurrent inflammatory disease. These patients also had more type 1 conventional dendritic cells (DC1s) enriched in expression of genes required for activating T effector memory cells, and fewer type 2 conventional dendritic cells (DC2s).
Conclusions :
This suggests that antigen-driven immune responses may be a distinguishing feature in uveitis patients with granulomatous features and prolonged disease courses. Furthermore, the correlation between increased frequencies of DC1s and CD4 clonal expansion suggests that DC1s may activate CD4 T effector memory cells to drive chronic granulomatous uveitis.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.