ICBM, Universidad de Chile, Santiago, Chile.
J Autoimmun. 2013 May;42:7-18. doi: 10.1016/j.jaut.2013.02.001. Epub 2013 Mar 13.
The most difficult component in our understanding of human autoimmunity remains a rigorous dissection of etiological events. Indeed, the vast literature on autoimmune diseases focuses on the inflammatory response, with the hope of developing drugs that reduce inflammation. However, there is increasing recognition that understanding the immunobiology of target tissues will also have direct relevance to disease natural history, including breach of tolerance. Sjögren's syndrome is essentially an epitheliitis and there are major changes to normal architectural salivary organization. We propose that loss of homeostasis is the initial event that precipitates inflammation and that such inflammatory response includes not only the adaptive response, but also an intense innate immune/bystander response. To understand these events this review focuses on the architecture, phenotype, function and epithelial cell organization. We further submit that there are several critical issues that must be defined to fully understand epithelial cell immunobiology in Sjögren's syndrome, including defining epithelial cell polarity, cell-cell and cell to extracellular matrix interactions and a variety of chemical and mechanical signals. We also argue that disruption of tight junctions induces disorganization of the apical pole of salivary acinar cells in Sjögren's syndrome. In addition, there will be a critical role of inflammatory cytokines in the apico-basal relocation of tight junction proteins. Further, the altered disorganization and relocation of proteins that participate in secretory granule formation are also dysregulated in Sjögren's syndrome and will contribute to abnormalities of mucins within the extracellular matrix. Our ability to understand Sjögren's syndrome and develop viable therapeutic options will depend on defining these events of epithelial cell biology.
在我们对人类自身免疫的理解中，最困难的部分仍然是对病因事件的严格剖析。事实上，大量关于自身免疫性疾病的文献都集中在炎症反应上，希望能开发出减少炎症的药物。然而，人们越来越认识到，了解靶组织的免疫生物学也将与疾病的自然史直接相关，包括对耐受性的破坏。干燥综合征本质上是一种上皮炎，正常唾液组织结构有重大改变。我们提出，失去体内平衡是引发炎症的最初事件，这种炎症反应不仅包括适应性反应，还包括强烈的固有免疫/旁观者反应。为了理解这些事件，本综述重点关注了结构、表型、功能和上皮细胞组织。我们进一步提出，要充分理解干燥综合征中的上皮细胞免疫生物学，有几个关键问题必须明确，包括确定上皮细胞极性、细胞-细胞和细胞-细胞外基质相互作用以及各种化学和机械信号。我们还认为，紧密连接的破坏会导致干燥综合征中唾液腺细胞顶极的紊乱。此外，炎症细胞因子在紧密连接蛋白的顶端到基底的重新定位中也将发挥关键作用。此外，参与分泌颗粒形成的蛋白质的异常组织和重新定位在干燥综合征中也失调，这将导致细胞外基质中粘蛋白的异常。我们理解干燥综合征并开发可行的治疗方法的能力将取决于对这些上皮细胞生物学事件的定义。
