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Deciphering Molecular and Phenotypic Changes Associated with Early Autoimmune Disease in the Aire-Deficient Mouse Model of Sjögren’s Syndrome

Sjögren’s syndrome (SS) is characterized by extensive lymphocytic infiltration of the salivary and lacrimal gland (LG), resulting in acinar cell destruction and organ dysfunction. The underlying pathogenesis of SS remains largely unknown, and studies historically focus on defining late-stage disease...

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Autores principales: Chen, Feeling YuTing, Gaylord, Eliza, McNamara, Nancy, Knox, Sarah
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274681/
https://www.ncbi.nlm.nih.gov/pubmed/30453645
http://dx.doi.org/10.3390/ijms19113628
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author Chen, Feeling YuTing
Gaylord, Eliza
McNamara, Nancy
Knox, Sarah
author_facet Chen, Feeling YuTing
Gaylord, Eliza
McNamara, Nancy
Knox, Sarah
author_sort Chen, Feeling YuTing
collection PubMed
description Sjögren’s syndrome (SS) is characterized by extensive lymphocytic infiltration of the salivary and lacrimal gland (LG), resulting in acinar cell destruction and organ dysfunction. The underlying pathogenesis of SS remains largely unknown, and studies historically focus on defining late-stage disease. Here, we identify tissue programs associated with disease onset using transcriptomic and immunohistological analysis of LGs from 5- and 7-week-old mice deficient in autoimmune response element (Aire). At 5 weeks of age (wk), Aire-/- mice show minimal tissue dysfunction and destruction compared to 7 wk Aire-/-, which exhibit severe dry eye, poor tear secretion, extensive lymphocytic infiltration, reduced functional innervation, and increased vascularization. Despite this mild phenotype, 5 wk Aire-/- LGs were highly enriched for signaling pathways previously associated with SS, including interferon gamma (IFNγ), interleukin 1 beta (IL1β), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), toll-like receptor (TLR) signaling, and interleukin-6/signal transducer and activator of transcription 3 (IL6/STAT3) signaling. Novel signaling pathways such as the semaphorin–plexin pathway were also noted. Intriguingly, we found an expansion of the ductal network with increasing disease. Activated STAT3, a blocker of apoptosis, was restricted to the ductal system and also increased with damage, highlighting its potential as a promoter of ductal cell survival. These data demonstrate the early activation of signaling pathways regulating inflammation, innervation, and cell survival before the onset of clinical disease indicators, suggesting their potential value as diagnostic biomarkers.
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spelling pubmed-62746812018-12-15 Deciphering Molecular and Phenotypic Changes Associated with Early Autoimmune Disease in the Aire-Deficient Mouse Model of Sjögren’s Syndrome Chen, Feeling YuTing Gaylord, Eliza McNamara, Nancy Knox, Sarah Int J Mol Sci Article Sjögren’s syndrome (SS) is characterized by extensive lymphocytic infiltration of the salivary and lacrimal gland (LG), resulting in acinar cell destruction and organ dysfunction. The underlying pathogenesis of SS remains largely unknown, and studies historically focus on defining late-stage disease. Here, we identify tissue programs associated with disease onset using transcriptomic and immunohistological analysis of LGs from 5- and 7-week-old mice deficient in autoimmune response element (Aire). At 5 weeks of age (wk), Aire-/- mice show minimal tissue dysfunction and destruction compared to 7 wk Aire-/-, which exhibit severe dry eye, poor tear secretion, extensive lymphocytic infiltration, reduced functional innervation, and increased vascularization. Despite this mild phenotype, 5 wk Aire-/- LGs were highly enriched for signaling pathways previously associated with SS, including interferon gamma (IFNγ), interleukin 1 beta (IL1β), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), toll-like receptor (TLR) signaling, and interleukin-6/signal transducer and activator of transcription 3 (IL6/STAT3) signaling. Novel signaling pathways such as the semaphorin–plexin pathway were also noted. Intriguingly, we found an expansion of the ductal network with increasing disease. Activated STAT3, a blocker of apoptosis, was restricted to the ductal system and also increased with damage, highlighting its potential as a promoter of ductal cell survival. These data demonstrate the early activation of signaling pathways regulating inflammation, innervation, and cell survival before the onset of clinical disease indicators, suggesting their potential value as diagnostic biomarkers. MDPI 2018-11-17 /pmc/articles/PMC6274681/ /pubmed/30453645 http://dx.doi.org/10.3390/ijms19113628 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chen, Feeling YuTing
Gaylord, Eliza
McNamara, Nancy
Knox, Sarah
Deciphering Molecular and Phenotypic Changes Associated with Early Autoimmune Disease in the Aire-Deficient Mouse Model of Sjögren’s Syndrome
title Deciphering Molecular and Phenotypic Changes Associated with Early Autoimmune Disease in the Aire-Deficient Mouse Model of Sjögren’s Syndrome
title_full Deciphering Molecular and Phenotypic Changes Associated with Early Autoimmune Disease in the Aire-Deficient Mouse Model of Sjögren’s Syndrome
title_fullStr Deciphering Molecular and Phenotypic Changes Associated with Early Autoimmune Disease in the Aire-Deficient Mouse Model of Sjögren’s Syndrome
title_full_unstemmed Deciphering Molecular and Phenotypic Changes Associated with Early Autoimmune Disease in the Aire-Deficient Mouse Model of Sjögren’s Syndrome
title_short Deciphering Molecular and Phenotypic Changes Associated with Early Autoimmune Disease in the Aire-Deficient Mouse Model of Sjögren’s Syndrome
title_sort deciphering molecular and phenotypic changes associated with early autoimmune disease in the aire-deficient mouse model of sjögren’s syndrome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274681/
https://www.ncbi.nlm.nih.gov/pubmed/30453645
http://dx.doi.org/10.3390/ijms19113628
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