Department of Cell & Tissue Biology, University of California San Francisco, San Francisco, CA 94143, USA.
School of Optometry and Vision Science Graduate Program, University of California, Berkeley, CA 94720, USA.
Int J Mol Sci. 2018 Nov 17;19(11):3628. doi: 10.3390/ijms19113628.
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.
干燥综合征（SS）的特征是唾液腺和泪腺（LG）广泛的淋巴细胞浸润，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尚不清楚，既往研究主要集中在定义疾病晚期。在这里，我们使用自身免疫反应元件（Aire）缺失的 5 周和 7 周龄小鼠的 LG 的转录组和免疫组织化学分析，鉴定与疾病起始相关的组织程序。在 5 周龄（wk）时，与 7 wk Aire-/相比，Aire-/-小鼠的组织功能障碍和破坏极小，后者表现出严重的干眼、泪液分泌不良、广泛的淋巴细胞浸润、功能神经支配减少和血管化增加。尽管表现出轻度表型，但 5 wk Aire-/-LGs 高度富集了先前与 SS 相关的信号通路，包括干扰素 γ（IFNγ）、白细胞介素 1β（IL1β）、核因子 kappa-轻链增强子的激活 B 细胞（NF-κB）、Toll 样受体（TLR）信号和白细胞介素 6/信号转导和转录激活因子 3（IL6/STAT3）信号。还注意到了一些新的信号通路，如 semaphorin-plexin 通路。有趣的是，我们发现随着疾病的发展，导管网络扩张。激活的 STAT3 是细胞凋亡的抑制剂，局限于导管系统，并且随着损伤的增加而增加，突出了其作为促进导管细胞存活的潜在作用。这些数据表明，在出现临床疾病指标之前，调节炎症、神经支配和细胞存活的信号通路就已经被早期激活，提示它们作为诊断生物标志物的潜在价值。
