Examining the role of CVB in the generation of beta cell neoantigens and targeted approaches at therapeutic intervention

1型糖尿病(T1D)是一种自身免疫性疾病，其原因是靶向和破坏 胰岛β细胞由自身反应性免疫细胞，包括CD4+T细胞。细胞过程中的 对遗传易感于自身免疫的个体打破免疫耐受的了解甚少。在……里面 特别是，人们对胰岛免疫界面上发生的导致自动-免疫的事件知之甚少。 β细胞的免疫靶向。虽然识别β细胞自身抗原非常重要，但阐明β是如何 细胞蛋白的免疫原性至关重要。许多环境和生理因素与 T1D，包括柯萨奇病毒B(CVB)感染，可导致内质网(ER)应激/功能障碍 增加内质网功能障碍和异常处理和翻译后修饰(PTM)的可能性 蛋白质的含量。通过抗原呈现这些异常修饰的蛋白质(新抗原) 在许多疾病中，向T细胞提呈细胞(APC)会破坏免疫耐受性并加剧病理。 包括T1D。在对自身免疫和外周耐受失败的遗传易感性的背景下， 抗原提呈细胞(APC)向T细胞递送异常修饰的蛋白质启动 在许多疾病中的病理学。因此，在β内，例如由柯萨奇病毒感染诱导的内质网应激 细胞可能会产生异常修饰的蛋白质，作为自身免疫反应的新抗原 T1D。事实上，我们的工作表明，b细胞中的内质网(Er)应激会增加胞浆。 钙离子和组织转谷氨酰胺酶2(TTG2)的活性，导致脱酰胺生成PTM 形成新的表位，增加T细胞的识别。此外，我们已经证明，患有T1D的受试者 识别去酰胺化新表位的T细胞频率增加，具有这些表位的T细胞 在患有T1D的器官捐献者的胰腺淋巴结中可以发现特异性。因此，这似乎是合理的。 识别CVB脱胺表位的T细胞触发内质网应激诱导的钙离子流 而tTG2酶的激活在进展到发展型的受试者中变得激活和扩大 糖尿病1例。此外，最近的研究表明，肠道病毒家族成员表现出很强的 人类T1D患者和相当大比例的1型糖尿病患者与胰岛自身免疫的相关性 患者有长期/持续的肠道病毒感染与肠粘膜炎症相关。至 评估CVB感染在T1D进展中的作用我们将确定CVB感染的机制 影响β细胞蛋白内质网应激介导的PTM，促进人胰岛β细胞的免疫原性 并进一步确定CVB感染导致耐受性打破和 活体内加速疾病。我们还将评估阻碍这些酶的治疗策略。 影响T1D进展的机制。

Type 1 diabetes (T1D) is an autoimmune disease that results from the targeting and destruction of pancreatic islet β cells by autoreactive immune cells, including CD4+ T cells. The cellular processes that break immune tolerance in individuals genetically predisposed to autoimmunity are poorly understood. In particular, very little is known about the events that occur at the islet-immune interface that cause auto- immune targeting of β cells. While identifying β cell autoantigens is of great importance, elucidating how β cell proteins become immunogenic is crucial. Many environmental and physiologic factors associated with T1D, including Coxsackie virus B (CVB) infection, can induce endoplasmic reticulum (ER) stress/dysfunction increasing ER dysfunction and the potential for abnormal handling and post-translational modification (PTM) of proteins. The subsequent presentation of these abnormally modified proteins (neo-antigens), by antigen presenting cells (APC) to T cells breaks immune tolerance and exacerbates pathology in many diseases, including T1D. In the context of genetic susceptibility to autoimmunity and failure of peripheral tolerance, the presentation of abnormally modified proteins by antigen presenting cells (APC) to T cells initiates pathology in a number of diseases. Therefore, ER stress induced for example, by CVB infection, within β cells may generate abnormally modified proteins that act as neo-antigens for the autoimmune response in T1D. Indeed, our work demonstrates that endoplasmic reticulum (ER) stress in b cells increases cytosolic calcium Ca2+ and the activity of tissue transglutaminase 2 (tTG2), leading to PTM generation by deamidation forming neo-epitopes and increasing T cell recognition. Furthermore, we have shown that subjects with T1D have elevated frequencies of T cells that recognize deamidated neo-epitopes and that T cells with these specificities can be found in the pancreatic lymph nodes of organ donors with T1D. Hence, it is plausible that T cells that recognize deamidated epitopes, resulting from CVB triggered ER stress induced Ca2+ flux and activation of tTG2 enzymes become activated and expanded in subjects who progress to develop type 1 diabetes. Furthermore, recent work demonstrates that enterovirus family members show a strong association with islet autoimmunity in human T1D patients and a sizeable percentage of type 1 diabetic patients have prolonged/persistent enterovirus infection associated with gut mucosa inflammation. To assess the role of CVB infection in T1D progression we will define the mechanisms by which CVB infection affects ER stress-mediated PTM of β cell proteins, contributing to β cell immunogenicity in human islets in vitro, and further determine the mechanism by which CVB infection causes a break in tolerance and accelerated disease in vivo. We will also assess therapeutic strategies that impede these enzymatic mechanisms to affect T1D progression.