Mechanisms of Continued Tolerance Breakdown in Autoimmunity

描述（由申请方提供）：在慢性炎症中，淋巴细胞不限于淋巴组织，但经常浸润并积聚在受影响的组织中。这些存在于各种受影响的非淋巴组织中的淋巴细胞浸润可以通过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、丙型肝炎和莱姆病引起的伯氏疏螺旋体，异位淋巴结构也经常出现在受影响的组织中。已经表明，在自身免疫性疾病中，从非组织化浸润到GC反应的淋巴新生过程与疾病严重程度的增加和自身耐受的加速破坏有关。我们假设异位淋巴微结构中的淋巴细胞与自身抗原反应或交叉反应。这些特化的三级淋巴结构的局部环境可以捕获和富集最初不参与疾病过程的抗原，并提供支持应答/针对自身抗原的基础结构。因此，这些炎症部位的淋巴结构前哨不仅在自身耐受性丧失中起重要作用，而且在疾病进展中也至关重要。我们还将测试的假设，由于局部微环境的独特属性，淋巴细胞在异位淋巴结构在发炎组织可能会改变其敏感性诱导凋亡和逃避审查的自我反应性淋巴细胞。因此，我们提出以下具体目标：目标1。探讨局部炎症组织中淋巴细胞浸润诱导细胞凋亡的特性。目标2.确定局部自身反应性应答是否通过对起始抗原的反应性维持。目标3。确定浸润性B细胞产生的杂交瘤的抗原反应性和转移疾病的能力。

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.