Regulation of antibody production by innate immune cells

描述(由申请人提供)：新出现的生物恐怖主义威胁要求开发新的或改进的疫苗战略来对抗感染性病原体。疫苗需要佐剂激活天然免疫细胞，以有效地诱导保护性免疫反应，包括B细胞产生中和抗体。这项建议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。抗体的产生包括两个有趣的过程，即Ig重链类开关DMA重组(CSR)和Ig V(D)J基因体细胞高度突变(SHM)，前者使抗体效应器功能多样化，后者增加抗体对抗原的亲和力。复合抗原，如微生物蛋白，通过CD4T细胞上的CD40配体与B细胞上的CD40结合，诱导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，但依赖T细胞的B细胞反应在最初的五到七天内不能提供免疫保护，这对于中和快速复制的病原体，如病毒和被包裹的细菌来说，太迟了。为了弥补这一局限性，B细胞对具有重复结构的抗原，也称为病原体相关分子模式(PAMPs)，迅速产生T细胞无关的抗体。这些抗原包括病毒包膜糖蛋白、细菌被膜多糖和细菌壁脂多糖。在这项建议中，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(TLRs)的结合可诱导天然免疫细胞释放BAFF和APRIL，这两个CD40配体样分子通过TACI、BCMA和BAFF-R受体激活B细胞。PAMPS将通过B细胞抗原受体和天然抗原受体(包括TLRs和补体受体)刺激B细胞，进一步提高T细胞非依赖性抗体的产生。提出了三个具体目标。目的1是阐明结合TLR的微生物产品和小分子抗病毒化合物，包括鸟嘌呤核苷类似物和咪唑喹啉类化合物，是如何刺激天然免疫细胞上调BAFF和APRIL的。目的2分析TACI、BCMA和BAFF-R在诱导CSR、SHM和B细胞产生抗体中的相对作用。目的3是确定B细胞结合的TLRs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和合成的TLR结合化合物作为B细胞刺激佐剂用于对抗生物恐怖主义制剂的疫苗。除了促进新疫苗策略的开发外，拟议的研究还应有助于更好地理解先天免疫系统和获得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.