Mechanisms of Continued Tolerance Breakdown in Autoimmunity

描述(申请人提供)：在慢性炎症中，淋巴细胞并不局限于淋巴组织，而是经常渗透和聚集在受影响的组织中。这些存在于各种受影响的非淋巴组织中的淋巴细胞可以通过一种称为淋巴新生或异位淋巴器官发生的过程形成三级淋巴结构。这些三级淋巴结构存在于许多自身免疫性疾病中，包括类风湿性关节炎、桥本甲状腺炎、干燥综合征和重症肌无力。此外，在慢性感染中，如幽门螺杆菌胃炎、丙型肝炎和伯氏疏螺旋体引起的莱姆病，异位淋巴结构也经常出现在受影响的组织中。已有研究表明，在自身免疫性疾病中，淋巴新生从无组织浸润物到GC反应的过程与疾病严重程度的增加和自我耐受性的加速崩溃有关。我们假设异位淋巴微结构中的淋巴细胞与自身抗原发生反应或交叉反应。这些特殊的三级淋巴结构的局部环境可以捕获和丰富最初不参与疾病过程的抗原，并提供支持反应/对抗自身抗原的基础设施。因此，炎症部位的这些淋巴结构前哨不仅在丧失自我耐受性方面发挥重要作用，而且在疾病进展中也是至关重要的。我们还将检验假设，由于局部微环境的独特性质，炎症组织中异位淋巴结构中的淋巴细胞可能会改变其对凋亡诱导的敏感性，并逃脱自我反应淋巴细胞的审查。因此，我们提出以下具体目标：目的1.评价局部炎症组织中淋巴细胞浸润诱导细胞凋亡的特性。目的2.确定局部自身反应是否通过对起始抗原的反应性来维持。目的3.确定B细胞浸润性杂交瘤的抗原反应性和传播疾病的能力。

DESCRIPTION (provided by applicant): In chronic inflammation, lymphocytes are not restricted to lymphoid tissues but often infiltrate and accumulate in affected tissues. These lymphocytic infiltrates present in various affected nonlymphoid tissues can form tertiary lymphoid structures by a process called lymphoid neogenesis or ectopic lymphoid organogenesis. These tertiary lymphoid structures are found in many autoimmune diseases including rheumatoid arthritis, Hashimoto's thyroiditis, Sj"gren's syndrome, and Myasthenia gravis. In addition, in chronic infections such as Helicobacter pylori gastritis, hepatitis C, and Borrelia burgdorferi caused Lyme disease, ectopic lymphoid structures can also be frequently found in affected tissues. It has been suggested that the process of lymphoid neogenesis from non-organized infiltrates to GC reaction in autoimmune diseases is associated with increased disease severity and accelerated breakdown in self-tolerance. We hypothesize that lymphocytes in ectopic lymphoid microstructures are reactive or cross-reactive with auto-antigens. The local environment of these specialized tertiary lymphoid structures may trap and enrich antigens that are not initially involved in the disease process and provide an infrastructure to support responses/against self-antigens. Thus, these outposts of lymphoid structures at the inflammatory sites not only play an important role in the loss of self-tolerance, but also are critical in disease progression. We will also test the hypothesis that, due to the unique property of local microenvironment, lymphocytes in ectopic lymphoid structures in inflamed tissues may alter their sensitivity to apoptosis induction and escape the censorship of self-reactive lymphocytes. Therefore, we propose the following specific aims: Aim 1. To evaluate the properties of apoptosis induction in lymphocyte infiltrates in local inflamed tissues. Aim 2. To determine if the local autoreactive response is maintained by reactivity to the initiating antigen. Aim 3. To define the antigen reactivity and ability to transfer disease of hybridomas generated from infiltrating B cells.