Autoimmune Diabetes: Macrophage Responses

摘要 组织特异性自身免疫的发展是一个慢性的过程，在这个过程中，精细编程的自身免疫 反应在靶器官进行并达到顶峰。尽管组织环境最终被主宰 通过侵入性反应，起到对抗这种致病活动的调节作用的元件仍然存在 未得到充分研究。在1型糖尿病(T1D)中，产生胰岛素的β细胞是自我反应性T细胞的靶点 渗入胰岛。不太了解的是，在第一批T细胞进入之前，胰岛 环境已经建立了一种内在的机制来抑制自身免疫的继续攻击。是这样的 调节是由特定的胰岛驻留巨噬细胞亚群介导的，这些巨噬细胞专门清除 β细胞的凋亡，这一过程称为胞吐作用。泡腾吞噬程序诱导抗炎 反应和增强时，施加强大的免疫抑制功能，导致深刻保护 自身免疫性糖尿病。我们推测，胞吐程序可能作为原始的控制机制。 安装在正常的胰岛环境中，而不考虑自身免疫倾向。这种与生俱来的机制 在老鼠和人类中很常见，并且可能与其他免疫调节元件有很大的不同(即， 调节性T细胞(Tregs)，它们是随着适应性免疫入侵而引入的。因此，审查 胰岛的泡泡吞噬作用将为发生在胰岛的生物和自身免疫事件提供概念上的进展 这个重要的器官。此外，通过分析与巨噬细胞相关的免疫抑制成分 该项目将提供与人类T1D相关的翻译和治疗方面的见解。在这 建议，我们试图彻底检查泡出细胞性胰岛巨噬细胞，并确定它们在调节 复杂的自身免疫过程。

ABSTRACT The development of tissue-specific autoimmunity is a chronic process in which finely programmed autoimmune responses progress and culminate in the target organ. Although the tissue environment is eventually dominated by the invasive responses, regulatory elements that function to oppose such pathogenic activities remain understudied. In type 1 diabetes (T1D), the insulin-producing β cells are targeted by self-reactive T cells infiltrating into the pancreatic islets. Less appreciated is that before the entry of the first T cells, the islet environment has established an intrinsic mechanism that restrains the onward autoimmune attack. Such regulation is mediated by a specific subset of the islet resident macrophages specialized in the clearance of apoptotic β cells, a process referred to as efferocytosis. The efferocytosis program induces anti-inflammatory responses and when enhanced, imposes strong immunoinhibitory functions, leading to profound protection from autoimmune diabetes. We hypothesize that the efferocytosis program may act as an original control mechanism installed in the normal islet environment regardless of autoimmune propensity. This innate mechanism is common in mice and humans and may considerably differ from other immunomodulatory elements (i.e., regulatory T cells (Tregs)), which are introduced along with the adaptive immune invasion. Therefore, examining efferocytosis in islets will provide conceptual advances to the biological and autoimmune events taking place in this important organ. Moreover, by analyzing the immunoinhibitory components associated with macrophage efferocytosis, this project will provide translational and therapeutical insights relevant to human T1D. In this proposal, we seek to thoroughly examine the efferocytic islet macrophages and define their role in regulating a complex autoimmune process.