W38 - Antigen-driven Ocular Immune Responses Distinguish Granulomatous and Non-granulomatous Uveitis

Purpose

Non-infectious uveitis is a heterogeneous group of blinding ocular inflammatory diseases in which pathophysiologic mechanisms are poorly understood, resulting 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 in parallel with single-cell RNA sequencing in order identify antigen-expanded T cells and characterize the gene expression of ocular immune cells from 18 patients with diverse types of uveitis.

Results

We identified clonal expansion of ocular CD4 T cells and gene expression consistent with IFNg response and effector memory cell state in a subset of patients with granulomatous clinical features, suggesting that antigen triggered ocular immune responses in these patients. Clonal CD4 T cell expansion was also associated with more type 1 conventional dendritic cells (DC1s), but fewer type 2 conventional dendritic cells (DC2s), suggesting that DC1 may direct antigen-driven ocular immune responses in granulomatous uveitis.

In the subset of patients without granulomatous features or clonal expansion, CD4 T cells differentially expressed genes associated with IL4, IL-7 and the unfolded protein response, suggesting alternative immunologic mechanisms may be active in these patients.

Conclusion

Antigen-driven immune responses may be a discriminatory pathologic feature in uveitis patients, particularly those with granulomatous features, while alternative mechanisms including unfolded protein responses may distinguish other uveitis subtypes.