B cell antigen presentation in models of B cell a*

B 细胞 a* 模型中的 B 细胞抗原呈递

• 批准号: 7387451
• 负责人: MICHIKO SHIMODA
• 金额: $ 6.99万
• 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 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7387451
• 关键词: 4-hydroxy-5-nitrophenyl acetic acid; Affinity; Alleles; Amino Acids; Antibodies; Antibody Affinity; Antigen Presentation; Antigens; Apoptosis; Architecture; Autoantibodies; Autoimmune Diseases; B cell differentiation; B-Cell Activation; B-Lymphocytes; Bone Marrow; Bypass; Cells; Chronic; DNA; Development; Disease; Environmental Risk Factor; Follicular Dendritic Cells; Frequencies; Generations; Genes; Genetically Engineered Mouse; Haptens; Human; Immune response; Immunization; Immunoglobulin-Secreting Cells; Infection; Lead; Life; Lupus Erythematosus; Measures; Memory; Memory B-Lymphocyte; Modeling; Mus; Mutate; Mutation; Nitrophenol; Numbers; Outcome; PTPRC gene; Pathway interactions; Patients; Plasma Cells; Play; Positioning Attribute; Process; Production; Proliferating; Reaction; Receptors, Antigen, B-Cell; Role; Serum; Signal Transduction; Somatic Mutation; Spleen; Structure of germinal center of lymph node; System; Systemic Lupus Erythematosus; Systemic Therapy; T-Lymphocyte; TNFSF5 gene; Testing; Transgenes; Transgenic Organisms; Virus Diseases; Week; autoreactive B cell; cell type; differentiated B cell; genetic analysis; knowledge base; mouse model; plasma cell differentiation; prevent; recombinase

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（PC）的分化。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发生中起重要作用。在这种情况下，预期活化的自身反应性B细胞可能参与生发中心反应，并在感染后长时间保持为记忆细胞，这可能产生分泌自身抗体的长寿命PC。我们提出了一个假设，即记忆B细胞只有在接受CD 40/CD 40 L信号时才能分化为PC。然而，免疫调节因子如CpG DNA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。我们最近产生了IA-B小鼠，由于cd 19 cre（Cre重组酶）转基因对loxP侧翼的iab-neo等位基因的B细胞限制性缺失，约95%的所有B细胞上缺乏MHC-II。在用T细胞依赖性抗原免疫后，IA-B小鼠中的少量抗原特异性MHC-II+ B细胞显著扩增以分化成GC B细胞并产生正常水平的B220+ CD 38+记忆B细胞。然而，这些记忆B细胞由于通过cd 19 cre转基因持续缺失MHC-II而在以后失去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。使用IA B小鼠，检验我们假设的具体目的是：1）通过使用携带B细胞特异性CD 40 L转基因的IA-B小鼠，确定CD 40/CD 40 L信号在记忆B细胞分化为长寿PC中的作用，和2）确定可以绕过在长寿PC分化中对T细胞的MHC-II依赖性抗原呈递的需要的免疫调节因子的作用。这一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患者的治疗开辟新的途径。