Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA.
Clin Exp Immunol. 2019 Dec;198(3):326-340. doi: 10.1111/cei.13349. Epub 2019 Aug 14.
Recent studies in Type 1 Diabetes (T1D) support an emerging model of disease pathogenesis that involves intrinsic β-cell fragility combined with defects in both innate and adaptive immune cell regulation. This combination of defects induces systematic changes leading to organ-level atrophy and dysfunction of both the endocrine and exocrine portions of the pancreas, ultimately culminating in insulin deficiency and β-cell destruction. In this review, we discuss the animal model data and human tissue studies that have informed our current understanding of the cross-talk that occurs between β-cells, the resident stroma, and immune cells that potentiate T1D. Specifically, we will review the cellular and molecular signatures emerging from studies on tissues derived from organ procurement programs, focusing on in situ defects occurring within the T1D islet microenvironment, many of which are not yet detectable by standard peripheral blood biomarkers. In addition to improved access to organ donor tissues, various methodological advances, including immune receptor repertoire sequencing and single-cell molecular profiling, are poised to improve our understanding of antigen-specific autoimmunity during disease development. Collectively, the knowledge gains from these studies at the islet-immune interface are enhancing our understanding of T1D heterogeneity, likely to be an essential component for instructing future efforts to develop targeted interventions to restore immune tolerance and preserve β-cell mass and function.
最近关于 1 型糖尿病（T1D）的研究支持一种新的疾病发病机制模型，该模型涉及固有β细胞脆弱性，以及固有和适应性免疫细胞调节缺陷的结合。这种缺陷的组合诱导系统变化，导致胰腺内分泌和外分泌部分的器官水平萎缩和功能障碍，最终导致胰岛素缺乏和β细胞破坏。在这篇综述中，我们讨论了动物模型数据和人类组织研究，这些研究为我们目前对β细胞、固有基质和增强 T1D 的免疫细胞之间发生的串扰的理解提供了信息。具体来说，我们将回顾从器官获取计划衍生的组织研究中出现的细胞和分子特征，重点关注 T1D 胰岛微环境中发生的原位缺陷，其中许多缺陷尚未通过标准外周血生物标志物检测到。除了更好地获得器官供体组织外，各种方法学进展，包括免疫受体库测序和单细胞分子分析，有望提高我们对疾病发展过程中抗原特异性自身免疫的理解。总的来说，这些在胰岛-免疫界面的研究中的知识进展增强了我们对 T1D 异质性的理解，这可能是指导未来努力开发靶向干预措施以恢复免疫耐受和保护β细胞数量和功能的重要组成部分。
