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:
  • 金额:
    $ 50.58万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
An orally available cancer drug AZD6738 prevents type 1 diabetes.
  • DOI:
    10.3389/fimmu.2023.1290058
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    7.3
  • 作者:
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Jon D Piganelli其他文献

Jon D Piganelli的其他文献

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{{ truncateString('Jon D Piganelli', 18)}}的其他基金

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
  • 批准号:
    10436562
  • 财政年份:
    2022
  • 资助金额:
    $ 50.58万
  • 项目类别:
REG. OF T CELL AUTOREACTIVITY IN IDDM BY CTLA-4/CD152
注册。
  • 批准号:
    6288017
  • 财政年份:
    2000
  • 资助金额:
    $ 50.58万
  • 项目类别:
REG. OF T CELL AUTOREACTIVITY IN IDDM BY CTLA-4/CD152
注册。
  • 批准号:
    6381951
  • 财政年份:
    2000
  • 资助金额:
    $ 50.58万
  • 项目类别:

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