Viral impact on autoimmune T cells

病毒对自身免疫 T 细胞的影响

• 批准号: 10317311
• 负责人: John F Alcorn
• 金额: $ 19.42万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-18 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10317311
• 关键词: Acute; Address; Antigens; Apoptosis; Appearance; Autoimmune; Autoimmune Diseases; Autoimmunity; Bacteria; Bacterial Infections; CNS autoimmune disease; Cell Survival; Cells; Central Nervous System Diseases; Cessation of life; Clinical; Data; Disease; Drug or chemical Tissue Distribution; Equilibrium; Exhibits; Experimental Autoimmune Encephalomyelitis; Flare; Generations; Immune response; Immunologics; Incidence; Infection; Inflammation; Influenza; Interferon-beta; Interferons; Interleukin-17; Kinetics; Lung; Lymphocyte; Lymphocytic choriomeningitis virus; Lymphoid Tissue; Memory; Modeling; Multiple Sclerosis; Myelin; Onset of illness; Pathogenesis; Pattern; Periodicity; Phenotype; Predisposition; Psoriasis; Relapse; Resolution; Risk; Role; Secondary to; Serum; Severity of illness; Stimulus; System; T-Lymphocyte; Testing; Time; Viral; Virus; Virus Diseases; autoreactive T cell; autoreactivity; disability; effective therapy; functional outcomes; lymph nodes; peripheral blood; response; side effect

IL-17 producing T cells have been implicated in the pathogenesis of numerous autoimmune diseases including multiple sclerosis. Autoimmune diseases frequently exhibit a cyclical pattern, with periods of quiescent disease followed by exacerbations or flares. The unpredictable onset of disease flares makes it difficult to balance the risk of more effective therapies (which come with significant side-effects) versus the risk of long-term disability that comes with each disease exacerbation. Hence, understanding the mechanisms that trigger flares is a critical unmet need. Recent viral infection is one of the most common clinically associated triggers for autoimmune disease flare. However, this presents a conundrum: viral infection drives a strong interferon response that is known to suppress the induction of a type-17 response. In fact, IFNb is one of the oldest and most widely-use therapies for MS, and successful therapy correlates with reduced Th17 cells in peripheral blood. Similarly, suppression of type-17 responses is thought to contribute to susceptibility of recently influenza-infected lungs to secondary bacterial infections. However, there is a paucity of data on how viral infection directly impacts existing type-17 cells: either innate- type gdT17 that provide immediate defense against bacteria amplify inflammation, or autoimmune memory Th17 cells that can trigger relapse. Our surprising new data prompts our hypothesis that viral infection causes transient loss of bystander type-17 cells, and that subsequent rebound of self-reactive Th17 cells contributes to autoimmune flare. If correct, this explains one mechanism underlying the perplexing connections between viral infection, acute susceptibility to secondary bacterial infection and later post-viral susceptibility to autoimmune disease flare. This hypothesis will be tested in the following specific aims: Aim 1: Determine fate of autoreactive Th17 and bystander resident IL-17+ cells during viral infection Aim 2: Define role of autoimmune Th17 cell reactivation by viral infection in EAE relapse susceptibility. These data will define for the first time the impact and consequences of viral infection on existing IL-17 producing T cells and autoimmune disease flare.

产生IL-17的T细胞与许多自身免疫性疾病的发病机制有关。 包括多发性硬化症在内的疾病。自身免疫性疾病经常表现出周期性模式， 伴随静止期疾病随后恶化或发作。无法预测的 疾病爆发使得难以平衡更有效的治疗方法的风险（伴随着 显著的副作用）与每种疾病带来的长期残疾风险 加重因此，了解触发耀斑的机制是一个关键的未满足的需求。 最近的病毒感染是最常见的临床相关的自身免疫性触发因素之一 疾病爆发然而，这提出了一个难题：病毒感染驱动强干扰素 已知抑制17型反应诱导的反应。事实上，IFNb是 最古老和最广泛使用的MS疗法，成功的治疗与减少 外周血Th 17细胞。类似地，17型反应的抑制被认为有助于 最近感染流感的肺部对继发性细菌感染的易感性。然而，在这方面， 关于病毒感染如何直接影响现有的17型细胞的数据很少：先天的- gdT 17型提供对细菌的直接防御，放大炎症，或自身免疫 Th 17记忆细胞可能引发复发。令人惊讶的新数据促使我们假设， 病毒感染引起旁观者17型细胞的短暂损失，随后的反弹， 自身反应性Th 17细胞有助于自身免疫爆发。如果是正确的，这就解释了一种机制 潜在的病毒感染，急性易感性，继发性 细菌感染和病毒感染后对自身免疫性疾病爆发的易感性。这一假设 目的1：确定自身反应性Th 17的命运， 病毒感染过程中旁观者驻留的IL-17+细胞目的2：确定自身免疫性Th 17细胞的作用 EAE复发易感性的病毒感染再激活。这些数据将首次定义 病毒感染对现有产生IL-17的T细胞的影响和后果， 自身免疫性疾病发作。