Deciphering Molecular and Phenotypic Changes Associated with Early Autoimmune Disease in the Aire-Deficient Mouse Model of Sjögren's Syndrome.
Deciphering Molecular and Phenotypic Changes Associated with Early Autoimmune Disease in the Aire-Deficient Mouse Model of Sjögren's Syndrome.
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DOI：
10.3390/ijms19113628
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发表时间：
2018-11-17
影响因子：
5.6
通讯作者：
Knox S
中科院分区：
文献类型：
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作者：
Chen FY;Gaylord E;McNamara N;Knox S
Sjögren综合征（SS）的特点是广泛的淋巴细胞浸润涎腺和泪腺（LG），导致腺泡细胞破坏和器官功能障碍。SS的潜在发病机制在很大程度上仍然未知，历史上的研究主要集中在定义晚期疾病。在这里，我们通过对自身免疫反应元件（Aire）缺乏的5周龄和7周龄小鼠的LGs进行转录组学和免疫组织学分析，确定了与疾病发病相关的组织程序。在5周龄时，Aire-/-小鼠与7周龄的Aire-/-小鼠相比，表现出最小的组织功能障碍和破坏，Aire-/-小鼠表现出严重的干眼、泪液分泌差、广泛的淋巴细胞浸润、功能神经支配减少和血管化增加。尽管这种轻微的表型，5周的Aire-/- LGs在先前与SS相关的信号通路中高度富集，包括干扰素γ (IFNγ)、白细胞介素1β (IL1β)、活化B细胞的核因子kappa轻链增强子（NF-κB）、toll样受体（TLR）信号传导和白细胞介素6/信号传导和转录激活子3 （IL6/STAT3）信号传导。新的信号通路如信号丛通路也被注意到。有趣的是，我们发现导管网络随着疾病的增加而扩张。激活的STAT3是一种凋亡阻滞剂，仅限于导管系统，并且随着损伤而增加，这突出了其作为导管细胞存活促进剂的潜力。这些数据表明，在临床疾病指标出现之前，调节炎症、神经支配和细胞存活的信号通路的早期激活，表明它们作为诊断生物标志物的潜在价值。
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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DOI：
10.4049/jimmunol.1200493
发表时间：
2012-05-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
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作者：
Su MA;Davini D;Cheng P;Giang K;Fan U;DeVoss JJ;Johannes KP;Taylor L;Shum AK;Valenzise M;Meloni A;Bour-Jordan H;Anderson MS
通讯作者：
Anderson MS
影响因子：
15.9
作者：
Stott, DI;Hiepe, F;Berek, C
通讯作者：
Berek, C
影响因子：
4.6
作者：
Nguyen, DH;Toshida, H;Beuerman, RW
通讯作者：
Beuerman, RW
影响因子：
2.8
作者：
Stirling C;Andrews S;Croft T;Vickers J;Turner P;Robinson A
通讯作者：
Robinson A
DOI：
10.1038/labinvest.2011.189
发表时间：
2012-04
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
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作者：
通讯作者：
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