Viral impact on autoimmune T cells

产生IL-17的T细胞与许多自身免疫的发病机制有关 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一种周期性的模式， 伴随着疾病的静止期，紧随其后的是病情加重或症状发作。变幻莫测的爆发 疾病爆发使人们很难平衡更有效治疗的风险(伴随着 重大副作用)与每种疾病带来的长期残疾风险 病情恶化。因此，了解引发耀斑的机制是一个关键的未得到满足的需要。 最近的病毒感染是临床上最常见的自身免疫的诱因之一。 疾病爆发。然而，这提出了一个难题：病毒感染驱动了一种强大的干扰素 已知的抑制17类反应诱导的反应。事实上，IFNb是 最古老和最广泛使用的治疗多发性硬化症的方法，成功的治疗与减少 外周血中的Th17细胞。同样，抑制17型反应也被认为起到了作用 这与最近感染流感的肺部对继发性细菌感染的敏感性有关。然而， 关于病毒感染如何直接影响现有的17型细胞的数据很少：要么是天生的- GdT17型，提供即时防御细菌放大炎症或自身免疫 记忆可能引发复发的Th17细胞。我们令人惊讶的新数据促使我们假设 病毒感染会导致旁观者17类细胞的一过性损失，随后又会反弹 自身反应性Th17细胞参与了自身免疫性红斑狼疮。如果正确，这解释了一种机制 在病毒感染、急性易感性和继发性肺炎之间令人困惑的联系之下 细菌感染和病毒感染后对自身免疫性疾病的易感性暴发。这一假设 将在以下具体目标中进行测试：目标1：确定自身反应Th17和 病毒感染期间旁观者驻留的IL-17细胞目标2：确定自身免疫Th17细胞的作用 病毒感染在EAE复发易感性中的重新激活。这些数据将首次定义 病毒感染对现有产生IL-17的T细胞和 自身免疫性疾病爆发。

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.