Regulation of antibody production by innate immune cells

先天免疫细胞调节抗体产生

• 批准号: 6928075
• 负责人: ANDREA CERUTTI
• 金额: $ 42万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6928075
• 关键词: B lymphocyte; CD40 molecule; antibody formation; antigen receptors; bacterial antigens; bacterial polysaccharides; bioterrorism /chemical warfare; carbohydrate sequence; cell differentiation; cellular immunity; cytokine receptors; gene mutation; genetic recombination; immune response; leukocyte activation /transformation; lipopolysaccharides; membrane proteins; receptor binding; receptor expression; tissue /cell culture; toll like receptor; tumor necrosis factor alpha; vaccine development; virus antigen; virus protein

DESCRIPTION (provided by applicant): The emerging threat of bioterrorism calls for the development of new or improved vaccine strategies against infectious agents. Vaccines require innate immune cell activation by adjuvants in order to effectively elicit protective immune responses, including B cell production of neutralizing antibodies. The long-term goal of this proposal is to analyze the mechanisms by which innate stimuli regulate antibody production in human B cells. Antibody production includes two intriguing processes known as Ig heavy chain class switch DMA recombination (CSR), which diversifies the antibody effector functions, and Ig V(D)J gene somatic hypermutation (SHM), which increases the antibody affinity for antigen. Complex antigens, such as microbial proteins, elicit CSR, SHM and antibody production through a mechanism involving engagement of CD40 on B cells by CD40 ligand on CD4+ T cells. Although inducing protective high-affinity antibodies and long-lasting immune memory, T cell-dependent B cell responses do not provide immune protection for the initial five to seven days, which is too much of a delay to neutralize quickly replicating pathogens such as viruses and encapsulated bacteria. To compensate for this limitation, B cells rapidly undergo T cell-independent antibody production in response to antigens with repetitive structure, also known as pathogen-associated molecular patterns (PAMPs). These antigens include viral envelope glycoproteins, bacterial capsule polysaccharides and bacterial wall lipopolysaccharides. In this proposal we argue that T cell-independent antibody responses require the activation of innate immune cells by PAMPs. Engagement of Toll-like receptors (TLRs) by PAMPs would induce innate immune cells to release BAFF and APRIL, two CD40 ligand-like molecules that activate B cells through TACI, BCMA and BAFF-R receptors. PAMPs would further enhance T cell-independent antibody production by stimulating B cells through the B cell antigen receptor and innate antigen receptors, including TLRs and complement receptors. Three specific aims are proposed. Aim 1 is to elucidate how TLR-binding microbial products and small antiviral compounds, including guanine nucleoside analogues and imidazoquinolines, stimulate innate immune cells to up-regulate BAFF and APRIL. Aim 2 is to dissect the relative contribution of TACI, BCMA and BAFF-R to the induction of CSR, SHM, and antibody production in B cells. Aim 3 is to determine the role of B cell-bound TLRs in the initiation of CSR, SHM, and antibody production. Findings resulting from these studies may support the use of recombinant BAFF and synthetic TLR-binding compounds as B cell-stimulating adjuvants for vaccines against bioterrorism agents. In addition to facilitating the development of new vaccine strategies, the proposed studies should lead to a better understanding of the fascinating interplay between the innate and adaptive immune systems.

描述（由申请人提供）：生物恐怖主义的新兴威胁要求开发针对感染者的新疫苗策略。疫苗需要佐剂先天免疫细胞激活，以有效地引起保护性免疫反应，包括中和抗体的B细胞产生。该提案的长期目标是分析先天刺激调节人B细胞抗体产生的机制。抗体的产生包括两个有趣的过程，称为IG重链类开关DMA重组（CSR），它们使抗体效应子功能多样化，Ig V（d）J Gene Somatic Somatic HyperMoart（SHM），增加了抗原的抗体亲和力。复杂的抗原，例如微生物蛋白，通过CD40配体在CD4+ T细胞上涉及CD40在B细胞上的CD40的机制引起CSR，SHM和抗体的产生。尽管诱导保护性的高亲和力抗体和持久的免疫记忆，但T细胞依赖性B细胞反应在最初的五到七天中并不能提供免疫保护，这太大了，无法延迟快速复制病原体，例如病毒和封装的细菌。为了弥补这一限制，B细胞迅速对具有重复结构的抗原（也称为病原体相关的分子模式（PAMP））迅速接受T细胞独立的抗体产生。这些抗原包括病毒包膜糖蛋白，细菌胶囊多糖和细菌壁脂多糖。在此提案中，我们认为T细胞独立的抗体反应需要PAMP激活先天免疫细胞。 PAMPS对TOLL样受体（TLR）的参与将诱导先天免疫细胞释放BAFF和4月，两个CD40配体样分子通过TACI，BCMA和BAFF-R受体激活B细胞。通过B细胞抗原受体和先天抗原受体（包括TLR和补体受体）刺激B细胞，PAMP将进一步增强T细胞独立的抗体产生。提出了三个具体目标。目的1是阐明TLR结合微生物产物和小型抗病毒化合物，包括鸟嘌呤核苷类似物和咪唑喹啉，刺激先天的免疫细胞上调BAFF和4月。 AIM 2是剖析Taci，BCMA和BAFF-R对B细胞中CSR，SHM和抗体产生的诱导的相对贡献。 AIM 3是确定B细胞结合的TLR在CSR，SHM和抗体产生的启动中的作用。这些研究产生的发现可能支持使用重组BAFF和合成TLR结合化合物作为B细胞刺激性佐剂的疫苗对生物恐怖剂的佐剂。除了促进新的疫苗策略的发展外，拟议的研究还应更好地理解先天和适应性免疫系统之间引人入胜的相互作用。