Beta cell antigen presentation in models of Beta cell a*

Beta 细胞 a* 模型中的 Beta 细胞抗原呈递

• 批准号: 7038622
• 负责人: MICHIKO SHIMODA
• 金额: $ 7.31万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7038622
• 关键词: antigen presentation; memory; model

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a chronic, multisystem human autoimmue disease characterized by the differentiation of short- and long-lived plasma cells (PCs) that secrete autoantibodies. Although the exact cause of SLE is unclear, environmental factors such as polyclonal B cell activation by bacterial and/or viral infection seem to play a significant role in the emergence of disease. In this case, it is anticipated that activated autoreactive B cells may participate in germinal center reaction and remain as memory cells long after infection, which may give rise to long-lived PCs secreting autoantibodies. We propose a hypothesis that memory B cells can differentiate into PCs only when receiving CD40/CD40L signals by antigen presentation to T cells. However, immunomodulatory factors such as CpG DNA may bypass this pathway, which potentially results in generation of autoreactive long-lived PC. We recently generated IA-B mice that lack MHC-II on about 95% of all B cells due to B-cell-restricted deletion of a loxP-flanked iab-neo allele by the cd19cre (Cre recombinase) transgene. Upon immunization with a T cell dependent antigen, a small number of antigen-specific MHC-II+ B cells in IA-B mice dramatically expand to differentiate into GC B cells and make normal levels of B220+ CD38+ memory B cells. However, these memory B cells lose MHC-II expression later because of ongoing deletion of MHC-II by the cd19cre transgene. In association with loss of MHC-II on memory B cells, IA-B mice showed impaired affinity maturation in long-lived PCs. With use of IAB mice, the specific aims to test our hypothesis are: 1) determination of the role of CD40/CD40L signal on memory B cell differentiation to long-lived PC by using IA-B mice carrying B cell specific CD40L transgene, and 2) determination of the effect of immunomodulatory factors that can bypass the requirement of MHC-II dependent antigen-presentation to T cells in long-lived PC differentiation. The outcome will provide a great help for understanding the development of autoreactive long-lived PCs and create new avenues for exploring therapy for SLE patients.

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种慢性、多系统人类自身免疫性疾病，其特征是分泌自身抗体的短寿命和长寿命浆细胞（PC）的分化。尽管 SLE 的确切病因尚不清楚，但细菌和/或病毒感染引起的多克隆 B 细胞激活等环境因素似乎在疾病的出现中发挥着重要作用。在这种情况下，预计激活的自身反应性 B 细胞可能参与生发中心反应，并在感染后很长时间内仍保留为记忆细胞，这可能会产生分泌自身抗体的长寿命 PC。我们提出一个假设，即记忆 B 细胞只有在通过抗原呈递给 T 细胞而接收 CD40/CD40L 信号时才能分化为 PC。然而，CpG DNA 等免疫调节因子可能会绕过该途径，从而可能导致自身反应性长寿命 PC 的产生。我们最近产生了约 95% 的 B 细胞缺乏 MHC-II 的 IA-B 小鼠，这是由于 cd19cre（Cre 重组酶）转基因对 loxP 侧翼的 iab-neo 等位基因的 B 细胞限制性删除。使用 T 细胞依赖性抗原进行免疫后，IA-B 小鼠中的少量抗原特异性 MHC-II+ B 细胞急剧扩增，分化为 GC B 细胞，并产生正常水平的 B220+ CD38+ 记忆 B 细胞。然而，由于 cd19cre 转基因持续删除 MHC-II，这些记忆 B 细胞后来失去了 MHC-II 表达。与记忆 B 细胞上 MHC-II 的缺失相关，IA-B 小鼠在长寿命 PC 中表现出亲和力成熟受损。使用 IAB 小鼠，检验我们的假设的具体目的是：1) 通过使用携带 B 细胞特异性 CD40L 转基因的 IA-B 小鼠，确定 CD40/CD40L 信号对记忆 B 细胞分化为长寿命 PC 的作用，以及2) 确定免疫调节因子的作用，这些因子可以绕过长寿命 PC 分化中 T 细胞 MHC-II 依赖性抗原呈递的要求。该结果将为了解自身反应性长寿命PC的发展提供很大帮助，并为探索SLE患者的治疗方法创造新途径。