Regulation of antibody production by innate immune cells

描述（由申请人提供）：生物恐怖主义的新威胁要求开发新的或改进的针对传染性病原体的疫苗策略。疫苗需要通过佐剂激活先天免疫细胞以有效地引发保护性免疫应答，包括中和抗体的B细胞产生。这项提案的长期目标是分析先天刺激调节人类B细胞抗体产生的机制。抗体产生包括两个有趣的过程，称为IG重链类别转换DNA重组（CSR），其使抗体效应子功能多样化，和IG V（D）J基因体细胞超突变（SHM），其增加抗体对抗原的亲和力。复合抗原，如微生物蛋白，通过涉及B细胞上的CD 40与CD 4 + T细胞上的CD 40配体结合的机制引发CSR、SHM和抗体产生。虽然诱导保护性高亲和力抗体和持久的免疫记忆，但T细胞依赖性B细胞应答在最初的5至7天内不提供免疫保护，这对于中和快速复制的病原体如病毒和包囊细菌来说延迟太多。为了弥补这一限制，B细胞响应于具有重复结构的抗原（也称为病原体相关分子模式（PAMP））而快速经历T细胞非依赖性抗体产生。这些抗原包括病毒包膜糖蛋白、细菌荚膜多糖和细菌壁脂多糖。在这个提议中，我们认为T细胞非依赖性抗体反应需要PAMP激活先天免疫细胞。PAMP与Toll样受体（TLR）的结合将诱导先天性免疫细胞释放BAFF和APRIL，这两种CD 40配体样分子通过TACI、BCMA和BAFF-R受体激活B细胞。PAMP将通过经由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细胞来进一步增强T细胞非依赖性抗体产生。提出了三个具体目标。目的1是阐明TLR结合的微生物产物和小的抗病毒化合物，包括鸟嘌呤核苷类似物和咪唑喹啉，如何刺激先天免疫细胞上调BAFF和APRIL。目的2是分析TACI、BCMA和BAFF-R对诱导B细胞中CSR、SHM和抗体产生的相对贡献。目的3是确定B细胞结合的TLR在启动CSR、SHM和抗体产生中的作用。这些研究的结果可能支持使用重组BAFF和合成TLR结合化合物作为生物恐怖分子疫苗的B细胞刺激佐剂。除了促进新疫苗策略的开发外，拟议中的研究还应有助于更好地理解先天免疫系统和适应性免疫系统之间迷人的相互作用。

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.