Comprehensive analysis of a mouse model of spontaneous uveoretinitis using single-cell RNA sequencing

Autoimmune uveoretinitis is a significant cause of visual loss, and mouse models offer unique opportunities to study its disease mechanisms. Aire-/- mice fail to express self-antigens in the thymus, exhibit reduced central tolerance, and develop a spontaneous, chronic, and progressive uveoretinitis. Using single-cell RNA sequencing (scRNA-seq), we characterized wild type and Aire-/- retinas to define, in a comprehensive and unbiased manner, the cell populations and gene expression patterns associated with disease. Based on scRNA-seq, immunostaining, and in situ hybridization, we infer that (i) the dominant effector response in Aire-/- retinas is Th1-driven, (ii) a subset of monocytes convert to either a macrophage/microglia state or a dendritic cell state, (iii) the development of tertiary lymphoid structures constitutes part of the Aire-/- retinal phenotype, (iv) all major resident retinal cell types respond to Interferon gamma by changing their patterns of gene expression, and (v) Muller glia up-regulate specific genes in response to Interferon gamma and may act as antigen presenting cells. Single-cell RNAseq of AireKO and age- and sex-matched WT retinas. For AireKO retinas, two replicates for Grade 2 disease and two replicates for Grade 3 disease were used.