A MZB Cell Activation Profile Present in the Lacrimal Glands of Sjögren's Syndrome-Susceptible C57BL/6.NOD-Aec1Aec2 Mice Defined by Global RNA Transcriptomic Analyses.
A MZB Cell Activation Profile Present in the Lacrimal Glands of Sjögren's Syndrome-Susceptible C57BL/6.NOD-Aec1Aec2 Mice Defined by Global RNA Transcriptomic Analyses.
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DOI：
10.3390/ijms23116106
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发表时间：
2022-05-29
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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对C57 BL/6. NOD-Aec 1Aec 2小鼠进行了广泛研究，以确定干燥综合征（SS）发生和发展的潜在细胞和分子基础，干燥综合征是一种人类全身性自身免疫疾病，临床特征为正常泪腺和唾液腺功能丧失，分别导致干眼症和口干症。虽然在人类和啮齿动物模型中的绝大多数SS研究长期以来主要集中在病理生理学事件和T淋巴细胞在这些事件中的潜在作用，但最近在我们的小鼠模型中的研究表明，边缘区B（MZ B）淋巴细胞对SS疾病的发展和发作至关重要。虽然MZB细胞的迁移和功能很难在体内和体外研究，我们已经进行了离体调查，使用时间的全球RNA转录组学分析，以跟踪早期的细胞和分子事件，在这些外分泌腺的C57 BL/6. NOD-Aec 1Aec 2小鼠。在本报告中，泪腺的全基因组转录组分析表明，在疾病早期发作期间暂时上调的基因和基因组定义了Notch 2/NF-kβ14和1型干扰素信号转导途径，并鉴定了免疫细胞向泪腺的细胞迁移中的趋化因子，特别是Cxcl 13和Rho-GTP酶，包括DOCK分子。我们讨论了如何比较目前的结果与我们最近发表的唾液腺数据进行了类似的研究，在我们的C57 BL/6. NOD-Aec 1Aec 2小鼠，指出两个腺体内的自身免疫反应的病因的相似性和差异。总体而言，本研究使用转录组学分析的力量来确定SS疾病临床前隐性致病阶段激活的时间分子生物过程，以及这些发现如何影响未来的干预治疗，因为两个外分泌腺内的疾病可能不相同。
The C57BL/6.NOD-Aec1Aec2 mouse has been extensively studied to define the underlying cellular and molecular basis for the onset and development of Sjögren’s syndrome (SS), a human systemic autoimmune disease characterized clinically as the loss of normal lacrimal and salivary gland functions leading respectively to dry eye and dry mouth pathologies. While an overwhelming majority of SS studies in both humans and rodent models have long focused primarily on pathophysiological events and the potential role of T lymphocytes in these events, recent studies in our murine models have indicated that marginal zone B (MZB) lymphocytes are critical for both development and onset of SS disease. Although migration and function of MZB cells are difficult to study in vivo and in vitro, we have carried out ex vivo investigations that use temporal global RNA transcriptomic analyses to track early cellular and molecular events in these exocrine glands of C57BL/6.NOD-Aec1Aec2 mice. In the present report, genome-wide transcriptome analyses of lacrimal glands indicate that genes and gene-sets temporally upregulated during early onset of disease define the Notch2/NF-kβ14 and Type1 interferon signal transduction pathways, as well as identify chemokines, especially Cxcl13, and Rho-GTPases, including DOCK molecules, in the cellular migration of immune cells to the lacrimal glands. We discuss how the current results compare with our recently published salivary gland data obtained from similar studies carried out in our C57BL/6.NOD-Aec1Aec2 mice, pointing out both similarities and differences in the etiopathogeneses underlying the autoimmune response within the two glands. Overall, this study uses the power of transcriptomic analyses to identify temporal molecular bioprocesses activated during the preclinical covert pathogenic stage(s) of SS disease and how these findings may impact future intervention therapies as the disease within the two exocrine glands may not be identical.
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