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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，其病因是细胞的靶向性和破坏