Role of basophils in the immune response to filariae

描述（由申请人提供）：丝虫是节肢动物传播的组织栖息蠕虫，是世界范围内主要的疾病负担。它们通常会引起2型免疫反应，其特征是嗜酸性粒细胞增多，血清中ag特异性和多克隆IgE水平升高，t细胞产生IL-4、IL-5和IL-13增加。这种2型反应可能有助于控制蠕虫感染。虽然很明显，IL-4在驱动2型免疫反应中起着核心作用，但在丝虫病感染中触发和维持长时间2型免疫反应的确切因素仍不清楚。我们在知识上的这些空白是有问题的，因为它们损害了我们开发蠕虫特异性疫苗的能力，这种疫苗产生具有高滴度ag特异性IgE的长期2型免疫反应。因为嗜碱性粒细胞是最不常见的外周白细胞，而且很难处理，所以它们在对传染病的免疫反应中所起的作用在很大程度上尚未得到研究。然而，最近的证据表明，嗜碱性粒细胞是丝虫病感染者IL-4库的主要贡献者，这表明它们可能在对丝虫病感染的免疫反应中发挥重要作用。本应用的目的是表征嗜碱性粒细胞在丝虫病感染中启动和维持2型反应中的作用。正在验证的中心假设是：B细胞持续产生丝虫特异性IgE，使嗜碱性细胞能够在丝虫暴露后通过释放大量IL-4和驱动幼稚t细胞向2型表型发展来协调快速的2型记忆反应。这一假设将通过追求以下目标来解决。特异性目的1：确定嗜碱性细胞是否能被丝虫抗原激活而非特异性释放IL-4。特异性目的2：确定在治疗丝虫病感染的情况下，ag特异性IgE产生和ag特异性IgE介导的嗜碱性粒细胞激活是否持续存在。特异性目的3：确定嗜碱性细胞在驱动幼稚T细胞向2型表型中所起的作用。

DESCRIPTION (provided by applicant): Filariae are arthropod-borne tissue-dwelling helminths that are a major worldwide burden of disease. They typically cause a type 2 immune response characterized by eosinophilia, elevated serum levels of Ag-specific and polyclonal IgE, and increases in T-cell production of IL-4, IL-5, and IL-13. This type 2 response is likely helpful in controlling helminth infections. While it is clear that IL-4 plays a central role in driving type 2 responses, the exact factors responsible for triggering and maintaining prolonged type 2 immune responses in filarial infections remain unknown. These gaps in our knowledge are problematic because they impair our ability to develop helminth-specific vaccines that produce long-standing type 2 immune responses with high titers of Ag-specific IgE. Because they are the least common peripheral leukocyte and because they are difficult to work with, the role basophils play in the immune response to infectious diseases has largely gone unstudied. However, recent evidence demonstrates that basophils are major contributors to the IL-4 pool in filaria-infected humans, suggesting they may play an important role in the immune response to filarial infections. The objective of this application is to characterize the role basophils play in initiating and maintaining type 2 responses in filarial infections. The central hypothesis being tested is: sustained production of filarial-specific IgE by B cells enables basophils to coordinate a rapid Type 2 memory response following filarial exposure by releasing large quantities of IL-4 and by driving naive T-cells toward a type 2 phenotype. This hypothesis will be addressed by pursuing the following aims. Specific Aim 1: To determine whether basophils can be activated by filarial antigen to release IL-4 non-specifically. Specific Aim 2: To determine whether Ag-specific IgE production and Ag-specific IgE-mediated basophil activation persists in the context of treated filarial infections. Specific Aim 3: To determine the role basophils play in driving naive T cells toward a type 2 phenotype.