Comprehensive Analysis of a Mouse Model of Spontaneous Uveoretinitis Using Single-Cell RNA Sequencing

Jacob S Heng 1,2, Sean F Hackett 3, Genevieve L Stein-O'Brien 2,4, Briana L Winer2,4, John Williams1,5, Loyal A Goff 2,4, Jeremy Nathans6,2,3,5

  1. Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
  2. The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
  3. Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
  4. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
  5. Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
  6. Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205; jnathans@jhmi.edu.

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.

Presented by Jacob Heng

Immunology & MicrobiologyNicholas Liao2019-12 (Dec)