TY - JOUR
T1 - Comprehensive analysis of a mouse model of spontaneous uveoretinitis using single-cell RNA sequencing
AU - Heng, Jacob S.
AU - Hackett, Sean F.
AU - Stein-O'Brien, Genevieve L.
AU - Winer, Briana L.
AU - Williams, John
AU - Goff, Loyal A.
AU - Nathans, Jeremy
N1 - Funding Information:
helpful comments on the manuscript. This work was supported by the Jerome L. Greene Foundation (J.S.H and J.N.); the Thomas J. Kelly and Mary L. Kelly Young Scholar Award (to J.S.H); the Howard Hughes Medical Institute (J.W. and J.N.); the Johns Hopkins University Catalyst and Synergy Awards (L.A.G.); and the Chan-Zuckerberg Initiative Donor Advised Fund Grant 2018-183445 (to G.L.S.-O. and L.A.G.).
Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
PY - 2019/12/26
Y1 - 2019/12/26
N2 - 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.
AB - 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.
KW - Aire knockout
KW - Autoimmune uveitis
KW - Mouse model
KW - Ocular immunology
KW - Single-cell RNAseq
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U2 - 10.1073/pnas.1915571116
DO - 10.1073/pnas.1915571116
M3 - Article
C2 - 31843893
AN - SCOPUS:85077285492
SN - 0027-8424
VL - 116
SP - 26734
EP - 26744
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 52
ER -