The role of CD23+ B cells in human schistosomiasis

描述(申请人提供)：人类血吸虫病由三种主要的组织侵袭性寄生吸虫引起，目前影响2.07亿人，仍然是发展中国家发病的一个重要原因。由于对人类保护性免疫涉及的机制了解不深，这种疾病的疫苗开发一直受到阻碍。许多基于现场的研究已经确定了高血清寄生虫特异性IgE浓度与根治性化疗后再感染的抵抗力之间的相关性。免疫球蛋白E的保护作用(S)仍然难以捉摸，可能包括直接杀灭蠕虫或调节免疫等多种作用。我们的初步数据显示，CD19 B细胞上低亲和力IgE受体(Fc5RII)CD23的表达与明确的职业过度暴露的肯尼亚劳动者中对曼氏葡萄球菌的抵抗史密切相关。我们建议通过鉴定表达CD23的B细胞亚群和表达CD23的免疫学预测因子来确定CD23 B细胞在血吸虫病中的作用。这些分析将使用流式细胞仪和珠子技术对来自我们明确界定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，有几种抗原是由病原体合成的，它们以非抗原特异性的方式将IgE交联，可能是通过抗体的Fc区，包括血吸虫产生的IPSE/α-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。虽然抗原特异性CD23结合的IgE交联物似乎引导B细胞沿着分化途径，但非特异性交联物降低了激活水平。我们推测，IgE通过表达于B细胞上的CD23在血吸虫免疫的形成和维持中发挥免疫调节作用。我们计划使用来自我们研究人群的IgE和来自未感染供者的NAOVE B细胞来确定血吸虫抗原与CD23结合的IgE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的潜在作用的认识，并为未来的研究铺平道路。公共卫生报道：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虫引起。没有疫苗是因为我们不知道人类免疫系统是如何杀死蠕虫的。这些研究将深入探讨人类宿主保护的机制，以促进有效疫苗的开发。

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.