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

检查 CVB 在 β 细胞新抗原生成中的作用以及治疗干预的靶向方法

基本信息

批准号：
10601083
负责人：
Jon D Piganelli
金额：
$ 50.58万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-05 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10601083
关键词：
Acceleration Affect Antigen-Presenting Cells Antigens Autoantigens Autoimmune Autoimmune Diseases Autoimmune Responses Autoimmunity B-Lymphocytes Beta Cell Binding Biological Process CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Calcium Cell physiology Cells Coxsackie B Viruses Data Diabetes Mellitus Disease Endoplasmic Reticulum Enterovirus Enterovirus Infections Environmental Risk Factor Enzymes Epitopes Etiology Event Failure Family member Frequencies Functional disorder Generations Genetic Predisposition to Disease Gut Mucosa Human Immune Immune Tolerance In Vitro Inbred NOD Mice Individual Infection Insulin-Dependent Diabetes Mellitus Islets of Langerhans Mediating Methodology Modification Mucositis Mus Onset of illness Organ Donor Pancreas Pathogenesis Pathology Patients Peptides Physiological Post-Translational Protein Processing Process Proteins Publishing Role Self Tolerance Specificity T-Cell Receptor T-Lymphocyte Testing Therapeutic Therapeutic Intervention Viral Virus Diseases Visualization Work amidation autoreactive T cell autoreactivity cell mediated immune response deamidation design diabetes pathogenesis diabetic patient endocrine pancreas development endoplasmic reticulum stress immunogenic immunogenicity in vivo inhibitor innovation islet islet autoimmunity lymph nodes neoantigens novel peripheral tolerance prevent therapeutic target transglutaminase 2 type I diabetic

项目摘要

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.

1型糖尿病（T1D）是一种自身免疫性疾病，是由于靶向和破坏而导致的胰腺胰岛β细胞由自动反应性免疫细胞，包括CD4+ T细胞。细胞过程对自身免疫性易受偏见的个体中的免疫耐受性的理解很少。在特别，对于在引起自动的胰岛免疫接口上发生的事件知之甚少 β细胞的免疫靶向。同时识别β细胞自身抗原非常重要，阐明了β 细胞蛋白成为免疫原性至关重要。许多与之相关的环境和生理因素 T1D，包括Coxsackie病毒B（CVB）感染，可以诱导内质网（ER）应力/功能障碍 ER功能障碍增加以及转换后修饰异常的潜力（PTM）蛋白质。随后通过抗原对这些绝对修饰的蛋白质（新抗原）的呈现向T细胞呈现细胞（APC）会破坏免疫耐受性并加剧许多疾病的病理学，包括T1D。在遗传易感性自身免疫性和外围耐受性失败的背景下，通过抗原呈递细胞（APC）向T细胞呈现绝对修饰的蛋白质的呈现多种疾病中的病理学。因此，例如，通过CVB感染引起的ER应力细胞可能会产生绝对修饰的蛋白质，该蛋白充当新抗原的自身免疫反应 T1D。实际上，我们的工作表明，B细胞中内质网（ER）应激会增加胞质 CA2+钙和组织转谷氨酰胺酶2（TTG2）的活性，导致PTM通过死亡的生成形成新的ePitopes并增加T细胞识别。此外，我们已经证明了具有T1D的受试者具有识别脱膜的新ePitopes的T细胞的频率升高，并且T细胞与这些细胞特异性可以在具有T1D的器官供体的胰腺淋巴结中找到。因此，这是合理的 CVB引起的ER应力诱导的Ca2+通量，识别脱膜表位的T细胞 TTG2酶的激活被激活并扩展到发展为发展类型的受试者 1个糖尿病。此外，最近的工作表明，肠病毒家庭成员表现出强大与人类T1D患者的胰岛自身免疫相关，1型糖尿病的比例很大患者长期/持续性肠内病毒感染与肠粘膜感染有关。到评估CVB感染在T1D进展中的作用，我们将定义CVB感染的机制影响ER应力介导的β细胞蛋白的PTM，有助于人类胰岛中的β细胞免疫原性体外，并进一步确定CVB感染导致耐受性破裂的机制和体内加速疾病。我们还将评估阻碍这些酶促的治疗策略影响T1D进展的机制。