Mechanisms of Continued Tolerance Breakdown in Autoimmunity

自身免疫耐受持续崩溃的机制

• 批准号: 7456501
• 负责人: Biao Zheng
• 金额: $ 18.82万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7456501
• 关键词: Affect; Affinity; Antigens; Atypical lymphocyte; Autoantigens; Autoimmune Diseases; Autoimmunity; B cell differentiation; B-Lymphocytes; Borrelia burgdorferi; Cells; Chronic; Collagen Arthritis; Collagen Type II; Disease; Disease Progression; Environment; Gastritis; Generations; Hashimoto Disease; Helicobacter pylori; Hepatitis C; Hybridomas; Induction of Apoptosis; Infection; Inflammation; Inflammatory; Lyme Disease; Lymphocyte; Lymphocytic Infiltrate; Lymphoid; Lymphoid Follicle; Lymphoid Tissue; Memory B-Lymphocyte; Mus; Myasthenia Gravis; Organogenesis; Pathogenesis; Patients; Play; Process; Property; Reaction; Research Infrastructure; Rheumatoid Arthritis; Role; Self Tolerance; Severity of illness; Site; Sjogren' s Syndrome; Structure; Structure of germinal center of lymph node; Syndrome; Testing; Tissues; immunogenicity; response

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.

描述（由申请人提供）：在慢性炎症中，淋巴细胞不限于淋巴组织，而是通常浸润并在受影响的组织中积累。这些淋巴细胞浸润物存在于各种受影响的非淋巴组织中，可以通过称为淋巴新生殖或异位淋巴管风机发生的过程形成三级淋巴结构。 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在受影响的组织中也经常发现结构这些专业的三级淋巴结构的环境可能会捕获并富集最初参与疾病过程的抗原，并提供支持反应/对自我抗原的反应的基础设施，因此，这些在炎症部位的淋巴结结构的前哨不仅在自我体育疾病中起重要作用，而且在疾病中也起着重要作用。我们还将检验以下假设：由于局部微环境的独特特性，发炎组织中异位淋巴样结构中的淋巴细胞可能会改变其对凋亡诱导的敏感性并避免自反应性淋巴细胞的审查。因此，我们提出以下特定目的：目标1。评估局部发炎组织中淋巴细胞浸润中凋亡诱导的特性。目标2。确定是否通过对启动抗原的反应性来维持局部自动反应。目的3。定义抗原反应性和转移由浸润B细胞产生的杂交瘤疾病的能力。