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

Jacob S. Heng, Sean F. Hackett, Genevieve L. Stein-O'Brien, Briana L. Winer, John Williams, Loyal A. Goff, Jeremy Nathans

Research output: Contribution to journalArticle

Abstract

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 1) the dominant effector response in Aire-/- retinas is Th1-driven, 2) a subset of monocytes convert to either a macrophage/microglia state or a dendritic cell state, 3) the development of tertiary lymphoid structures constitutes part of the Aire-/- retinal phenotype, 4) all major resident retinal cell types respond to interferon gamma (IFNG) by changing their patterns of gene expression, and 5) Muller glia up-regulate specific genes in response to IFN gamma and may act as antigen-presenting cells.

Original languageEnglish (US)
Pages (from-to)26734-26744
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number52
DOIs
StatePublished - Dec 26 2019

Keywords

  • Aire knockout
  • Autoimmune uveitis
  • Mouse model
  • Ocular immunology
  • Single-cell RNAseq

ASJC Scopus subject areas

  • General

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