Molecular mechanisms of Salmonella mediated autoimmunity

总结 慢性自身免疫性疾病发生时，免疫系统识别自我， 抗原是外来的，导致炎症和特定组织的破坏， 机关尽管许多慢性自身免疫性疾病的病因通常是 未知，有许多疾病的例子，其中细菌感染开始 或加重自身免疫反应一种常见的自身免疫性 反应性关节炎（ReA）是对感染作出反应而产生的疾病， 被称为感染后关节炎或强直性脊柱炎。以下 肠道病原体如沙门氏菌、志贺氏菌或 耶尔森氏菌，5-10%的患者发展ReA，一种疼痛的炎性关节炎。通过 以鼠伤寒沙门氏菌（STm）为模式生物， 发现STm淀粉样蛋白表面结构参与生物膜的形成，卷曲， 原纤维与DNA形成稳定的复合物，卷曲/DNA复合物是 自身免疫的强效刺激剂全身接触这些复合物会触发 一种以产生I型干扰素为特征的自身免疫反应 （IFN）和抗双链DNA（抗dsDNA）自身抗体。 本申请的主要目的是通过以下方式研究机制： 哪些卷曲/DNA复合物被免疫系统识别并触发 胃肠道感染后的自身免疫。我们假设 侵袭性STm在肠道中产生卷曲导致自身免疫后遗症 通过触发上皮损伤和激活TLR 2和TLR 9，这反过来又导致 I型干扰素和17型免疫的上调。在目标1中， 确定表达curli的细菌和curli/DNA复合物在 自身免疫的发展。在目标2中，我们将确定免疫途径， 有助于STm感染诱导的自身免疫。在目标3中，我们 确定自身免疫的遗传易感性是否能增强免疫功能， 通过卷曲/DNA复合物激活。

Summary Chronic autoimmune diseases occur when the immune system recognizes self- antigens as foreign, leading to inflammation and destruction of specific tissues and organs. Although the etiology of many chronic autoimmune diseases is generally unknown, there are many examples of diseases in which bacterial infections initiate or exacerbate autoimmune responses. One of the well-described autoimmune conditions that develop in response to an infection is reactive arthritis (ReA), also known as post-infectious arthritis or ankylosing spondylitis. Following gastrointestinal infections with enteric pathogens such as Salmonella, Shigella, or Yersinia, 5-10% of patients develop ReA, a painful form of inflammatory arthritis. By using Salmonella enterica serovar Typhimurium (STm) as a model organism, we discovered that a STm amyloid surface structure involved in biofilm formation, curli fibrils, form stable complexes with DNA, and that the curli/DNA complexes are potent stimulators of autoimmunity. Systemic exposure to these complexes triggers an autoimmune response characterized by the production of type I interferons (IFNs) and anti-double stranded DNA (anti-dsDNA) autoantibodies. The primary objective of this application is to investigate the mechanisms by which curli/DNA complexes are recognized by the immune system and trigger autoimmunity following gastrointestinal infection. Here, we hypothesize that that the production of curli in the gut by the invasive STm leads to autoimmune sequelae by triggering epithelial damage and activating TLR2 and TLR9, which in turn results in the upregulation of type-I IFN and of type-17 immunity. In aim 1, we will determine the role of curli-expressing bacteria and of curli/DNA complexes in the development of autoimmunity. In aim 2, we will identify the immune pathways that contribute to the autoimmunity induced by STm infection. In aim 3, we will determine whether genetic susceptibility to autoimmunity enhances the immune activation by curli/DNA complexes.