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Proc Natl Acad Sci U S A. 2019 Dec 16. pii: 201915571. doi: 10.1073/pnas.1915571116. [Epub ahead of print]

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

Author information

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.

KEYWORDS:

Aire knockout; autoimmune uveitis; mouse model; ocular immunology; single-cell RNAseq

PMID:
31843893
PMCID:
PMC6936593
[Available on 2020-06-16]
DOI:
10.1073/pnas.1915571116

Conflict of interest statement

The authors declare no competing interest.

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