Transcriptional landscapes of emerging autoimmunity: transient aberrations in the targeted tissue's extracellular milieu precede immune responses in Sjogren's syndrome
Transcriptional landscapes of emerging autoimmunity: transient aberrations in the targeted tissue's extracellular milieu precede immune responses in Sjogren's syndrome
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DOI：
10.1186/ar4362
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发表时间：
2013-01-01
影响因子：
4.9
通讯作者：
Peck, Ammon B.
中科院分区：
文献类型：
--
作者：
Delaleu, Nicolas;Cuong Q Nguyen;Peck, Ammon B.
导言：我们对自身免疫的理解相当偏向于显性疾病和慢性炎症的晚期。然而，确定靶器官在自身免疫性疾病出现过程中的作用是至关重要的，以确定其病因、早期和隐蔽的疾病阶段并描绘其分子基础。方法：以干燥综合征(SS)为典型的风湿性自身免疫性疾病和时间全球基因表达谱，我们系统地绘制了涉及唾液腺细胞外环境的生物主题之间的转录图景和时间相互关系。在一个定义明确的自发性SS模型C57BL/6.NOD-Aec1Aec2株中，研究的时间跨度从前期到亚临床，最终到显性疾病的发病。为了满足这一极具普遍性的目标，我们开发了一种基于生物信息学的新方法，该方法在交互网络中集成了全面的数据分析和可视化。后者是通过将数据集作为一个整体投影到先验定义的基于共识的知识上来计算的。结果：应用这些方法发现唾液腺内稳态和完整性在相当长的时间内出现了广泛的易感性、位置相关的异常和完整性。这些变化与主要依赖于SS易感基因Aec1和Aec2之外的基因的先天免疫反应不谋而合。经过一段时间的转录稳定后，除了自然杀伤细胞、T细胞和B细胞特异的基因模式外，绘制显性SS发病的网络还显示了焦点黏附、细胞连接和神经递质受体相关的改变的显著逆转，这些改变具有从预临床疾病到亚临床疾病的先前特征。结论：这种数据驱动的方法促进了对全球数据集的公正评估，允许对生物状态的复杂变化进行全面解释。它的应用描绘了在实验性SS的出现过程中靶器官的主要参与。
Introduction: Our understanding of autoimmunity is skewed considerably towards the late stages of overt disease and chronic inflammation. Defining the targeted organ's role during emergence of autoimmune diseases is, however, critical in order to define their etiology, early and covert disease phases and delineate their molecular basis.Methods: Using Sjogren's syndrome (SS) as an exemplary rheumatic autoimmune disease and temporal global gene-expression profiling, we systematically mapped the transcriptional landscapes and chronological interrelationships between biological themes involving the salivary glands' extracellular milieu. The time period studied spans from pre-to subclinical and ultimately to onset of overt disease in a well-defined model of spontaneous SS, the C57BL/6. NOD-Aec1Aec2 strain. In order to answer this aim of great generality, we developed a novel bioinformatics-based approach, which integrates comprehensive data analysis and visualization within interactive networks. The latter are computed by projecting the datasets as a whole on a priori-defined consensus-based knowledge.Results: Applying these methodologies revealed extensive susceptibility loci-dependent aberrations in salivary gland homeostasis and integrity preceding onset of overt disease by a considerable amount of time. These alterations coincided with innate immune responses depending predominantly on genes located outside of the SS-predisposing loci Aec1 and Aec2. Following a period of transcriptional stability, networks mapping the onset of overt SS displayed, in addition to natural killer, T-and B-cell-specific gene patterns, significant reversals of focal adhesion, cell-cell junctions and neurotransmitter receptor-associated alterations that had prior characterized progression from pre-to subclinical disease.Conclusions: This data-driven methodology advances unbiased assessment of global datasets an allowed comprehensive interpretation of complex alterations in biological states. Its application delineated a major involvement of the targeted organ during the emergence of experimental SS.