GRAM NEGATIVE ENTERIC PATHOGENS AND AUTOIMMUNITY

肠道革兰氏阴性病原体感染与自身免疫性疾病的后续发展有关。利用小鼠模型，我们发现沙门氏菌感染后引起的CD8+ ctl的很大一部分利用了一种具有有限多态性的新型i类抗原呈递结构。这些CD8+ ctl识别一种保守的沙门氏菌- groel衍生肽，该肽由鼠类类分子Qa-1呈递，鼠类类分子HLA-E的同源物。此外，这些ctl交叉识别来自哺乳动物GroEL分子的类似肽以及应激巨噬细胞。因此，沙门氏菌感染后引起的CD8+ ctl具有自身反应性。我们提出这些ctl可能在自身免疫性疾病的后续发展中发挥作用。我们提出了一系列研究细菌反应性T细胞在人类关节炎疾病中的潜在作用。在目标1中，我们将使用暴露于沙门氏菌的人类受试者来研究正常宿主T细胞对沙门氏菌感染的免疫反应。唤起的T细胞反应将以功能状态、识别的表位和利用的抗原呈递结构为特征。利用这些信息，我们将在目标2中生成表位特异性T细胞跟踪试剂，并利用它们在暴露于革兰氏阴性病原体的个体中表征这种反应，并解决在诊断为关节炎相关疾病的个体中是否存在细菌反应性T细胞。该患者人群来自我院风湿病科的大型患者队列，包括反应性关节炎、瑞特氏病和强直性脊柱炎患者。在这些研究中，将尝试将细菌特异性和/或自身反应性T细胞的存在与疾病状态联系起来。我们相信这些研究将为革兰氏阴性感染和自身免疫性疾病之间的病因学联系提供见解，并为扩大自身反应性T细胞的发展及其在疾病中的作用的研究提供概念基础。

Infection with Enteric Gram-Negative pathogens has been associated with the subsequent development of autoimmune disease. Utilizing a murine model, we have found that a significant fraction of the CD8+ CTLs evoked following Salmonella infection utilize a novel class I-like antigen presentation structure with limited polymorphism. These CD8+ CTLs recognize a conserved Salmonella-GroEL derived peptide presented by the murine class I- like molecule Qa-1, the murine orthologue of the human class I molecule HLA-E. In addition, these CTLs cross recognize an analogous peptide derived from the mammalian GroEL molecule as well as stressed macrophages. Thus CD8+ CTLs evoked following infection with Salmonella are autoreactive. We have proposed that these CTLs may play a role in the subsequent development of autoimmune disease. We propose a series of studies investigating the potential role for bacterial-reactive T cells in human arthritis disease. In aim number 1 we will use human subjects exposed to Salmonella to investigate the normal host T cell immune response to Salmonella infection. The T cell responses evoked will be characterized with regard to functional status, epitopes recognized and antigen presentation structures utilized. Using this information we will generate, in Aim number 2, epitope-specific T cell tracking reagents and utilize them in the characterization of this response in individuals exposed to gram-negative pathogens and address whether bacterial-reactive T cells are present in individuals that have diagnosed arthritis-related disease. This patient population is derived from the large patient cohort seen by the Division of Rheumatology at our institution and includes individuals with Reactive Arthritis, Reiter's Disease and Ankylosing Spondylitis. In these studies an attempt will be made to co-related the presence of bacterial-specific and/or autoreactive T cells and disease state. We believe these studies will yield insights into the etiological link between gram- negative infection and autoimmune diseases and provide the conceptual basis for expanded studies in development of autoreactive T cells and their role in disease.