Beta cell antigen presentation in models of Beta cell a*

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种慢性、多系统的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（PCs）分化。虽然SLE的确切病因尚不清楚，但环境因素，如细菌和/或病毒感染引起的多克隆B细胞活化，似乎在疾病的出现中起着重要作用。在这种情况下，预计活化的自身反应性B细胞可能参与生发中心反应，并在感染后很长一段时间内作为记忆细胞存在，这可能导致长寿命的pc分泌自身抗体。我们提出一个假设，记忆B细胞只有在接受CD40/CD40L信号时才能分化为PCs。然而，CpG DNA等免疫调节因子可能绕过这一途径，这可能导致自身反应性长寿命PC的产生。我们最近通过cd19cre （Cre重组酶）转基因在大约95%的B细胞上产生了缺乏MHC-II的IA-B小鼠，这是由于B细胞限制性地缺失了一个loxp侧的iab-neo等位基因。免疫T细胞依赖性抗原后，IA-B小鼠体内少量抗原特异性MHC-II+ B细胞显著扩增分化为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细胞随后失去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。在IAB小鼠中，验证我们假设的具体目的是：1)通过携带B细胞特异性CD40L转基因的IA-B小鼠，确定CD40/CD40L信号在记忆B细胞向长寿PC分化过程中的作用；2)确定免疫调节因子在长寿PC分化过程中可以绕过MHC-II依赖性抗原呈递T细胞的要求。该结果将为了解自身反应性长寿命pc的发展提供很大的帮助，并为探索SLE患者的治疗方法创造新的途径。

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.