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在流行地区的影响，这些地区尽管实施了化疗，但仍存在高发病率和传播。然而，疫苗开发的一个主要问题是缺乏对血吸虫病人体免疫力的了解。抗性的一致相关性是寄生虫特异性IgE升高，但IgE在介导保护中的功能意义尚不明确。我们已经发现IgE和CD 23协同工作以增加B细胞对溶酶体的反应性。我们发表的工作表明，CD 23结合的IgE促进B细胞从循环到脾脏滤泡区的动员，在那里CD 23还介导抗原呈递到广泛的T细胞克隆库。我们的新数据表明，CD 23激活的B细胞促进特定的CCR3+ T细胞亚群，这可能是重要的，在产生保护性Th2免疫应答。因此，我们的中心假设是，IgE介导的循环CD 23 + B细胞运输和T细胞活化途径的发展耐药的关键。我们的关键创新是定义替代的，以前未检查的IgE和CD23在人类蠕虫病和免疫中的作用。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CD 23结合IgE在B细胞运输中的作用。我们将前瞻性地描述儿童队列中年龄获得性耐药发展过程中CD 23 + B细胞特定克隆上CXCR 5的表达。我们将通过模拟实验确定CD 23结合IgE在体外抗原和细胞运输中的作用，以确定B细胞表型和与田间耐药相关的功能。在具体目标2中，我们将确定B细胞CD 23结合IgE对Th2细胞活化的作用，该活化对于通过诱导CCR 3 + T细胞来增强保护性Th2应答至关重要。我们将前瞻性地和机械地确定CD23结合的多克隆IgE对产生耐药性和Th2免疫的能力的抑制作用，以解释慢性易感性。证据表明，CD23切割和释放一个独特的可溶性（S）CD23片段具有免疫抑制功能，将通知特定目标3研究，我们将详细说明该片段如何抑制IgE的生产和粒细胞介导的杀伤的CD23。总之，我们的建议将确定新的和有益的功能IgE和潜在的战略，以预防血吸虫病疫苗。我们的研究结果将填补目前人类免疫学知识的巨大空白，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.