The role of CD23+ B cells in human schistosomiasis

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，仍然是发展中国家发病率的重要原因。由于对人类保护性免疫的机制了解不足，这种疾病的疫苗开发受到了阻碍。许多基于实地的研究已经确定了高血清寄生虫特异性IgE浓度与治疗性化疗后再感染耐药性之间的相关性。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。我们的初步数据显示，CD19+ B细胞上CD23（低亲和力IgE受体（Fc5RII））的表达与职业高暴露的肯尼亚劳工对曼氏链球菌的耐药性密切相关。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确定CD23+ B细胞在血吸虫病中的作用。这些分析将在循环B细胞和血清样本上进行，这些样本来自我们定义明确的肯尼亚劳工研究小组，使用流式细胞术和头部技术。cd23结合的IgE必须通过抗原交联才能诱导B细胞活化。最令人信服的是，有几种由病原体合成的抗原可能通过抗体的Fc区以非抗原特异性方式交联IgE，包括血吸虫产生的IPSE/ α -1。我们的初步分析表明，IgE交联的机制影响了B细胞分化途径。而抗原特异性cd23结合的IgE交联似乎引导B细胞沿着分化途径，非特异性交联降低激活水平。我们假设IgE通过在B细胞上表达的CD23在人血吸虫病中对血吸虫免疫的发展和维持具有免疫调节作用。我们计划利用来自本研究人群的IgE和来自未感染供体的原始B细胞的IgE，确定血吸虫抗原与cd23结合的IgE的差异交联对B细胞分化和激活的影响。我们预计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，并为今后的研究铺平道路。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。目前还没有疫苗，因为我们不知道人类免疫系统是如何杀死蠕虫的。这些研究将深入研究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.