The role of IgE in human schistosomiasis

IgE 在人类血吸虫病中的作用

• 批准号: 9012016
• 负责人: LISA M GANLEY-LEAL
• 金额: $ 56.99万
• 依托单位: STC BIOLOGICS, INC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-10 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9012016
• 关键词: Affect; Age; Antigen Presentation; Antigens; Asthma; B-Lymphocytes; BLR1 gene; Binding; Blood Circulation; Cell surface; Cells; Child; Childhood; Chronic; Cleaved cell; Collaborations; Complex; Critical Pathways; Data; Development; Disease; Health; Helminthiasis; Human; Hypersensitivity; IgE; IgE Receptors; Immune; Immune response; Immunity; Immunology; In Vitro; Individual; Infection; Knowledge; Lymphoid Follicle; Mediating; Medical Research; Modeling; Morbidity - disease rate; Parasites; Parasitic Diseases; Phenotype; Platyhelminths; Predisposition; Production; Publishing; Regulation; Research Institute; Resistance; Resistance development; Role; Sampling; Schistosoma; Schistosomiasis; Site; Spleen; Surface; T-Cell Activation Pathway; T-Lymphocyte; Testing; Th2 Cells; Vaccinated; Vaccination; Vaccines; Work; chemokine receptor; chemotherapy; clinically significant; cohort; crosslink; design; experience; granulocyte; high risk; human subject; in vitro Model; innovation; insight; killings; novel; novel marker; prevent; receptor; research study; response; trafficking; transmission process; vaccination strategy; vaccine development

 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.

 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，但这些地区的发病率和传播率仍然很高。然而，疫苗研发的一个主要问题是缺乏对人体对血吸虫病免疫的了解。耐药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清楚。我们发现 IgE 和 CD23 协同作用可增强 B 细胞对血吸虫的反应性。我们发表的研究表明，CD23 结合的 IgE 促进 B 细胞从循环系统动员到脾脏的滤泡区域，其中 CD23 还介导抗原呈递给广泛的 T 细胞克隆。我们的新数据表明，CD23 激活的 B 细胞会促进特定的 CCR3+ T 细胞亚群，这可能对产生保护性 Th2 免疫反应很重要。因此，我们的中心假设是血吸虫特异性 IgE 介导循环 CD23+ B 细胞运输和 T 细胞激活途径，这对产生耐药性至关重要。我们的关键创新是定义 IgE 和 CD23 在人类蠕虫病和免疫中的先前未经检验的替代作用。在具体目标 1 中，我们通过与肯尼亚医学研究所合作，定义了 CD23 结合 IgE 在 B 细胞运输中的作用。我们将前瞻性地描述儿科队列中年龄获得性耐药性发展过程中 CD23+ B 细胞特定克隆上 CXCR5 的表达。我们将通过建模实验来确定 CD23 结合的 IgE 在体外抗原和细胞运输中的作用，以定义与现场耐药性相关的 B 细胞表型和功能。在具体目标 2 中，我们将定义 B 细胞 CD23 结合 IgE 在 Th2 细胞激活中的作用，这对于通过诱导 CCR3+ T 细胞来增强保护性 Th2 反应至关重要。我们将前瞻性地、机制性地确定 CD23 结合的多克隆 IgE 对产生耐药性和 Th2 免疫能力的抑制作用，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可溶性 CD23 片段的证据将为 Specific Aim 3 研究提供信息，我们将详细介绍该片段如何抑制 IgE 产生和粒细胞介导的血吸虫杀伤。总而言之，我们的提案将定义 IgE 的新颖且有益的功能以及血吸虫病疫苗接种的潜在策略。我们的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。