The role of CD23+ B cells in human schistosomiasis

CD23 B 细胞在人血吸虫病中的作用

• 批准号: 7471857
• 负责人: LISA M GANLEY-LEAL
• 金额: $ 20.13万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7471857
• 关键词: Adult; Affect; Antibodies; Antigen Presentation; Antigens; B cell differentiation; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Biology; Blood Vessels; CD19 gene; CXCL13 gene; Cell physiology; Chemotaxis; Cohort Studies; Complex; Data; Developed Countries; Developing Countries; Development; Disease; Flow Cytometry; Future; Generations; Glycoproteins; HIV-1; Helminths; Human; IgE; IgE Receptors; Immune; Immune system; Immunity; Immunologics; In Vitro; Individual; Infection; Inflammatory; Invasive; Knowledge; Lead; Low affinity IgE receptor; Maintenance; Mediating; Morbidity - disease rate; Parasites; Pathway interactions; Phenotype; Platyhelminths; Play; Population; Population Heterogeneity; Population Study; Predisposition; Protein Isoforms; Public Health; Recording of previous events; Regulation; Resistance; Role; Sampling; Schistosoma; Schistosoma mansoni; Schistosomiasis; Serum; Staging; Structure of germinal center of lymph node; Technology; Tissues; Vaccines; atopy; base; chemotherapy; clinically significant; cohort; crosslink; cytokine; killings; men' s group; monocyte; pathogen; protective effect; research study; vaccine development

DESCRIPTION (provided by applicant): Human schistosomiasis, caused by three main species of tissue invasive parasitic trematodes, currently affects over 207 million individuals and remains a significant cause of morbidity in developing countries. Vaccine development for this disease has been hampered by a poor understanding of the mechanisms involved in protective immunity in humans. Many field-based studies have defined a correlation between high serum concentrations of parasite-specific IgE and resistance to reinfection following curative chemotherapy. The protective effect(s) of IgE remain elusive and may include roles as diverse as direct killing of worms or in regulating immunity. Our preliminary data shows that expression of CD23, the low affinity IgE receptor (Fc5RII), on CD19+ B cells is strongly associated with a history of resistance against S. mansoni in a well- defined cohort of occupationally hyper-exposed Kenyan laborers. We propose to define the role of CD23+ B cells in schistosomiasis by characterizing the specific subsets of B cells that express CD23 and the immunological predictors of CD23 expression. These analyses will be done on circulating B cells and serum samples derived from our well-defined study group of Kenyan laborers using flow cytometry and bead technology. CD23-bound IgE must be cross-linked by antigen to induce B cell activation. Most compelling, there are several antigens synthesized by pathogens which cross-link IgE in a non-antigen specific manner, likely via the Fc region of the antibody, including IPSE/alpha-1, produced by schistosomes. Our preliminary analysis demonstrates that the mechanism by which IgE is cross-linked influences that pathway of B cell differentiation. Whereas antigen-specific CD23-bound IgE cross-linking appears to lead B cells along a pathway of differentiation, non-specific cross-linking reduces activation levels. We hypothesize that IgE has an immunoregulatory role in human schistosomiasis through CD23 expressed on B cells in the development and maintenance of immunity to schistosomes. We plan to determine the effect of differential cross-linking of CD23-bound IgE by schistosome antigens on B cell differentiation and activation using IgE derived from our study population and naove B cells from uninfected donors. We predict that these studies will broaden our knowledge of the potential roles of IgE in protective immunity to schistosomiasis and pave the way for future studies. PUBLIC HEALTH RELEVENCE: Schistosomiasis is a disease that affects 207 million people worldwide and is caused by parasitic flatworms that reside in blood vessels. There is no vaccine because we do not understand how the human immune system is able to kill worms. These studies will delve into the mechanisms involved in human host protection to promote the development of an effective vaccine.

描述（由申请人提供）：人类血吸虫病由三种主要的组织侵入性寄生吸虫引起，目前影响超过 2.07 亿人，并且仍然是发展中国家发病的重要原因。由于对人类保护性免疫机制了解甚少，该疾病的疫苗开发受到阻碍。许多实地研究已经确定了高血清浓度的寄生虫特异性 IgE 与治疗性化疗后对再感染的抵抗力之间的相关性。 IgE 的保护作用仍然难以捉摸，可能包括直接杀死蠕虫或调节免疫等多种作用。我们的初步数据表明，CD19+ B 细胞上 CD23（低亲和力 IgE 受体 (Fc5RII)）的表达与一组明确的职业过度暴露的肯尼亚劳工中对曼氏沙门氏菌的耐药史密切相关。我们建议通过表征表达 CD23 的特定 B 细胞亚群和 CD23 表达的免疫学预测因子来定义 CD23+ B 细胞在血吸虫病中的作用。这些分析将使用流式细胞术和微珠技术对来自我们明确的肯尼亚劳工研究小组的循环 B 细胞和血清样本进行。 CD23 结合的 IgE 必须通过抗原交联才能诱导 B 细胞活化。最引人注目的是，病原体合成了多种抗原，它们可能通过抗体的 Fc 区以非抗原特异性方式交联 IgE，其中包括由血吸虫产生的 IPSE/alpha-1。我们的初步分析表明，IgE 交联的机制影响 B 细胞分化的途径。抗原特异性 CD23 结合 IgE 交联似乎会导致 B 细胞沿着分化途径发展，而非特异性交联会降低激活水平。我们假设 IgE 通过 B 细胞上表达的 CD23 在血吸虫免疫的发展和维持中发挥免疫调节作用。我们计划使用来自我们研究群体的 IgE 和来自未感染供体的幼稚 B 细胞，确定血吸虫抗原对 CD23 结合 IgE 的差异交联对 B 细胞分化和激活的影响。我们预测这些研究将拓宽我们对 IgE 在血吸虫病保护性免疫中潜在作用的认识，并为未来的研究铺平道路。公共卫生相关性：血吸虫病是一种影响全球 2.07 亿人的疾病，由寄生在血管中的扁形虫引起。没有疫苗是因为我们不了解人体免疫系统如何杀死蠕虫。这些研究将深入研究人类宿主保护所涉及的机制，以促进有效疫苗的开发。