The role of beta-cell crinophagy in generating diabetogenic neoepitopes

β细胞吞噬在产生糖尿病新表位中的作用

基本信息

批准号：
10733153
负责人：
Xiaoxiao Wan
金额：
$ 61.17万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-18 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733153
关键词：
Address Affect Alleles Amino Acids Animal Model Animal Testing Antigen Presentation Antigens Autoimmune Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity Beta Cell Binding Biological Assay CD4 Positive T Lymphocytes Cells Cellular Stress Cellular biology Cysteine Deterioration Development Diabetes Mellitus Elements Endocrine Epitopes Family Generations Genetic HLA-DQ8 antigen Homeostasis Human Immunology Incidence Inflammation Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Knowledge Laboratories Link Lysosomes Modeling Mus Nature Outcome Pathogenicity Pathway interactions Patients Peptides Peripheral Blood Mononuclear Cell Persons Phenotype Positioning Attribute Post-Translational Protein Processing Postdoctoral Fellow Prevalence Process Reagent Research Research Personnel Risk Role Secretory Vesicles Serine Shapes Siblings Source Structure of beta Cell of islet System T cell response T-Lymphocyte Testing Therapeutic Tissues Transgenic Model United States Vesicle Work autoimmune pathogenesis autoreactive T cell autoreactivity diabetes pathogenesis diabetic diabetogenic immunogenic in vivo insight insulin dependent diabetes mellitus onset insulin granule islet neoantigens novel pharmacologic professor programs repository response secretory protein tenure track translational applications

项目摘要

ABSTRACT Autoimmune diseases affect more than 20 million people in the United States, and the worldwide prevalence is rising. Patients usually suffer from a lifetime of deteriorating illness because no cures are available for most autoimmune diseases, including type 1 diabetes. Addressing this formidable challenge requires a better understanding of the pathogenic elements eliciting autoreactive responses. Although extensive studies have examined the role of native antigens, whether neoantigens/neoepitopes function to drive the autoimmune process remains poorly understood. The identity of neoantigens, especially post-translational modifications (PTMs) responsible for generating immunogenic neoepitopes, requires a critical examination. Endocrine tissues are commonly targeted by autoimmunity. Diverse endocrine cells use the crinophagic pathway to dispose of excessive amounts of secretory proteins to maintain cellular homeostasis. In this process, the regular secretory granules are directly fused to lysosomes. The resulting vesicle, crinophagic bodies, or crinosomes, are enriched with catabolized peptide segments. In type 1 diabetes, a deteriorating autoimmune disease targeting the insulin-producing β cells in pancreatic islets, crinosomes function as an antigen source providing native peptides for recognition by pathogenic CD4 T cells. Our recent examination by immunopeptidomics uncovered diverse PTMs in crinosome-derived peptides, indicating that crinosomes are a specialized repository of potential neoantigens and neoepitopes related to type 1 diabetes. A novel neoepitope family, C19S (cysteine-to-serine conversion in the insulin B-chain), became progressively prominent along with the development of the diabetic autoimmune process. Most importantly, we identified highly compatible sequences of C19S in mice and humans with T1D. In mice, C19S can be recognized by previously unidentified CD4 T cells distinct from those reactive to the native epitope. It is therefore necessary to determine the pathogenicity of the autoreactive T cells targeting C19S. Furthermore, as a representative neoepitope family, C19S provides a setpoint for delineating how β-cell crinophagy functions as a novel pathogenic component in T1D. C19S may initiate a "feed-forward" loop in T1D pathogenesis by linking β-cell stress with autoimmunity. We also propose to assess translational applications of C19S in human crinophagy and T cell pathobiology. These analyses may lead to a broad identification of neoepitopes generated by human crinophagy, which may serve as valuable targets for T1D pathogenesis and therapeutics. Analysis of potential C19S-reactive T cells in human PBMCs may extend our knowledge of autoimmune pathogenesis beyond the current paradigm defined by native antigens.

抽象的自身免疫性疾病在美国影响着超过 2000 万人，并且在全球范围内患病率很高患者通常会终生遭受病情恶化的困扰，因为大多数人都无法治愈。自身免疫性疾病，包括 1 型糖尿病，应对这一艰巨的挑战需要更好的方法。尽管广泛的研究已经对引起自身反应的致病因素进行了了解。检查天然抗原的作用，新抗原/新表位是否具有驱动自身免疫的功能新抗原的身份，特别是翻译后修饰仍然知之甚少。（PTM）负责产生免疫原性新表位，需要严格检查。内分泌组织通常是自身免疫的目标。不同的内分泌细胞使用乳腺吞噬细胞。处理过量分泌蛋白以维持细胞稳态的途径。常规分泌颗粒直接与溶酶体融合，产生囊泡、噬菌体或。 crinosomes 富含 1 型糖尿病（一种恶化的自身免疫性疾病）中分解代谢的肽片段。针对胰岛中产生胰岛素的 β 细胞的疾病，crinosomes 作为抗原源提供天然肽供致病性 CD4 T 细胞识别。免疫肽组学在 crinosome 衍生肽中发现了多种 PTM，表明 crinosome 是一种与 1 型糖尿病相关的潜在新抗原和新表位的专门储存库。一个新的新表位家族 C19S（胰岛素 B 链中的半胱氨酸到丝氨酸的转化）逐渐成为最重要的是，我们高度认识到随着糖尿病自身免疫过程的发展。患有 T1D 的小鼠和人类中 C19S 的兼容序列在小鼠中，C19S 可以被先前识别。未鉴定的 CD4 T 细胞与那些对天然表位有反应的细胞不同，因此有必要确定。靶向 C19S 的自身反应性 T 细胞的致病性此外，作为代表性的新表位家族， C19S 提供了一个设定点来描述 β 细胞自噬如何作为一种新的致病成分发挥作用。 T1D。C19S 可能通过将 β 细胞应激与自身免疫联系起来，启动 T1D 发病机制中的“前馈”循环。我们还建议评估 C19S 在人类食肉和 T 细胞病理学中的转化应用。这些分析可能导致对人类食肉产生的新表位的广泛鉴定，这可能作为 T1D 发病机制和治疗中潜在 C19S 反应性 T 细胞分析的有价值的靶标。人类 PBMC 可能会扩展我们对自身免疫发病机制的了解，超越当前定义的范式通过天然抗原。