Mechanisms of Continued Tolerance Breakdown in Autoimmunity

描述（由申请人提供）：在慢性炎症中，淋巴细胞不仅局限于淋巴组织，而且经常浸润和积聚在受影响的组织中。这些淋巴细胞浸润存在于各种受影响的非淋巴组织中，可通过称为淋巴样新生或异位淋巴样器官发生的过程形成三级淋巴样结构。这些三级淋巴样结构见于许多自身免疫性疾病，包括类风湿关节炎、桥本甲状腺炎、格林综合征和重症肌无力。此外，在幽门螺杆菌胃炎、丙型肝炎和伯氏疏螺旋体引起的莱姆病等慢性感染中，也可在受累组织中经常发现异位淋巴样结构。有研究表明，自身免疫性疾病的淋巴样细胞新生从无组织浸润到GC反应的过程与疾病严重程度的增加和自身耐受性的加速破坏有关。我们假设异位淋巴微结构中的淋巴细胞与自身抗原具有反应性或交叉反应性。这些特化的三级淋巴结构的局部环境可能会捕获和丰富最初不参与疾病过程的抗原，并提供支持应答/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自我耐受性丧失中起重要作用，而且在疾病进展中也起关键作用。我们还将验证一个假设，即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改变其对细胞凋亡诱导的敏感性，从而逃避自身反应性淋巴细胞的审查。为此，我们提出以下具体目标：目标1。探讨局部炎症组织淋巴细胞浸润诱导细胞凋亡的特性。目标2。通过对初始抗原的反应性来确定局部自身反应性反应是否得以维持。目标3。目的：探讨B细胞浸润性杂交瘤的抗原反应性和疾病转移能力。

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.