The role of IgE in human schistosomiasis

 描述(由申请人提供)：有效的疫苗将减轻血吸虫病流行地区的影响，尽管实施了化疗，这些地区的发病率和传播率仍然很高。然而，疫苗开发的一个主要问题是缺乏对人类对血吸虫病免疫的了解。与耐药性一致的相关性是寄生虫特异性IgE升高，但IgE在中介保护中的功能意义尚不明确。我们已经发现，IgE和CD23协同作用，提高了B细胞对血吸虫的反应性。我们发表的工作表明，CD23结合的IgE促进B细胞从循环到脾的滤泡区的动员，在那里CD23也介导了抗原呈递给广泛的T细胞克隆。我们的新数据表明，CD23激活的B细胞促进CCR3T细胞的特定亚群，这可能在产生保护性Th2免疫反应中起重要作用。因此，我们的中心假设是，血吸虫特异性IgE介导了循环中CD23B细胞的运输和T细胞的激活途径，这些途径对产生耐药性至关重要。我们的关键创新是定义了IgE和CD23在人类蠕虫病和免疫中的替代作用，这是以前从未研究过的。在具体目标1中，我们通过与肯尼亚医学研究所的合作，确定了CD23结合的IgE在B细胞贩运中的作用。我们将前瞻性地表征在儿童队列中年龄获得性耐药发展过程中CD23 B细胞特定克隆上CXCR5的表达。我们将通过模拟实验来确定与该领域耐药相关的B细胞表型和功能，以确定CD23结合的IgE在抗原和细胞体外运输中的作用。在特定的目标2中，我们将确定B细胞CD23结合的IgE在Th2细胞激活中的作用，这对于通过诱导CCR3T细胞增强保护性Th2反应至关重要。我们将前瞻性和机械性地确定CD23结合的多克隆IgE对产生抵抗和Th2免疫的抑制作用，以解释慢性易感性。血吸虫裂解CD23并释放具有免疫抑制功能的独特的可溶性(S)CD23片段的证据将为特定的目标3研究提供信息，其中我们将详细说明该片段如何抑制IgE的产生和粒细胞介导的杀灭血吸虫。总之，我们的提案将定义新的和有益的免疫球蛋白E的功能和潜在的策略，以预防血吸虫病。我们的结果将填补我们目前在人类免疫学知识方面的巨大空白，具有重要的临床意义。

 DESCRIPTION (provided by applicant): Effective vaccines would mitigate the impact of schistosomiasis in endemic regions that continue to experience high morbidity and transmission despite implementation of chemotherapy. However, a major problem with vaccine development is the lack of understanding of human immunity to schistosomiasis. A consistent correlate of resistance is elevated parasite-specific IgE, but the functional significance of IgE in mediating protection is undefined. We have found that IgE and CD23 work in concert to increase B cell responsiveness to schistosomes. Our published work suggests that CD23-bound IgE promotes mobilization of B cells from the circulation to the follicular regions of the spleen where CD23 also mediates antigen presentation to a broad repertoire of T cell clones. Our new data indicates that CD23-activated B cells promote specific subsets of CCR3+ T cells that may be important in generating protective Th2-immune responses. Thus, our central hypothesis is that schistosome-specific IgE mediates circulating CD23+ B cell trafficking and T cell activation pathways critical for developing resistance. Our key innovation is defining alternate, previously unexamined for roles for IgE and CD23 in human helminthiasis and immunity. In Specific Aim 1, we define the role of CD23-bound IgE in B cell trafficking through a collaboration with the Kenyan Medical Research Institute We will prospectively characterize the expression of CXCR5 on specific clones of CD23+ B cells during the development of age-acquired resistance in a pediatric cohort. We will determine the role of CD23-bound IgE in antigen and cellular trafficking in vitro through modeling experiments to define the B cell phenotypes and function associated with resistance in the field. In Specific Aim 2, we will define the role of B cell CD23-bound IgE o Th2 cell activation critical for augmenting protective Th2 responses through induction of CCR3+ T cells. We will prospectively and mechanistically determine the suppressive effects of CD23-bound polyclonal IgE on the ability to generate resistance and Th2 immunity towards explaining chronic susceptibility. Evidence that schistosomes cleave CD23 and release a unique soluble (s) CD23 fragment with immuno-suppressive functions will inform Specific Aim 3 studies where we will detail how this fragment suppresses IgE production and granulocyte-mediated killing of schistosomes. Altogether, our proposal will define novel and beneficial functions of IgE and potential strategies to vaccinate against schistosomiasis. Our results will fill current large gapsin our knowledge of human immunology with important clinical significance.