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

1型糖尿病（T1 D）是一种自身免疫性疾病，其起因于靶向和破坏糖尿病细胞。 胰岛β细胞通过自身反应性免疫细胞，包括CD 4 + T细胞。的细胞过程 人们对打破遗传上易患自身免疫的个体的免疫耐受性知之甚少。在 特别是，对发生在胰岛免疫界面的事件知之甚少，这些事件导致自体免疫， β细胞的免疫靶向。虽然鉴定β细胞自身抗原是非常重要的，但阐明β 细胞蛋白的免疫原性是至关重要的。许多环境和生理因素与 包括科萨基病毒B（CVB）感染在内的T1 D可诱导内质网（ER）应激/功能障碍 增加ER功能障碍和异常处理和翻译后修饰（PTM）的可能性 蛋白质。这些异常修饰的蛋白质（新抗原）的随后呈递，通过抗原 呈递细胞（APC）对T细胞的作用破坏了免疫耐受并加剧了许多疾病的病理， 包括T1 D。在自身免疫遗传易感性和外周耐受失败的背景下， 抗原呈递细胞（APC）向T细胞呈递异常修饰的蛋白质 病理学在许多疾病中。因此，例如由CVB感染诱导的ER应激，在β 细胞可以产生异常修饰的蛋白质，这些蛋白质作为自身免疫应答的新抗原， T1D事实上，我们的工作表明，在B细胞中内质网（ER）应激增加了细胞质中 钙Ca 2+和组织转氨酶2（tTG 2）的活性，导致通过脱酰胺产生PTM 形成新表位并增加T细胞识别。此外，我们已经表明，T1 D受试者 识别脱酰胺新表位的T细胞频率升高， 在患有T1 D的器官供体的胰腺淋巴结中可以发现特异性。因此， 识别CVB引起的脱酰胺表位的T细胞触发ER应激诱导Ca 2+通量 并且tTG 2酶的活化在发展为型糖尿病的受试者中变得活化和扩大。 1例糖尿病。此外，最近的研究表明，肠道病毒家族成员表现出强烈的免疫反应。 与人类T1 D患者和相当大比例的1型糖尿病患者的胰岛自身免疫相关 患者具有与肠粘膜炎症相关的延长/持续的肠病毒感染。到 评估CVB感染在T1 D进展中的作用，我们将确定CVB感染的机制， 影响ER应激介导的β细胞蛋白的PTM，促进人胰岛中的β细胞免疫原性， 体外，并进一步确定CVB感染引起耐受性破坏的机制， 加速体内疾病。我们还将评估阻碍这些酶的治疗策略， 影响T1 D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.