Role of basophils in the immune response to filariae

描述（由申请方提供）：丝虫是节肢动物传播的组织寄生蠕虫，是全球主要的疾病负担。它们通常引起以嗜酸性粒细胞增多、Ag特异性和多克隆IgE的血清水平升高以及IL-4、IL-5和IL-13的T细胞产生增加为特征的2型免疫应答。这种2型反应可能有助于控制蠕虫感染。虽然IL-4在驱动2型免疫应答中起着重要作用，但在丝虫感染中触发和维持长期2型免疫应答的确切因素仍然未知。我们知识中的这些差距是有问题的，因为它们削弱了我们开发蠕虫特异性疫苗的能力，这些疫苗产生长期存在的具有高滴度Ag特异性IgE的2型免疫应答。由于嗜碱性粒细胞是最不常见的外周血白细胞，并且难以处理，因此嗜碱性粒细胞在对感染性疾病的免疫应答中所起的作用在很大程度上未被研究。然而，最近的证据表明，嗜碱性粒细胞是丝虫感染人群中IL-4库的主要贡献者，这表明它们可能在丝虫感染的免疫应答中发挥重要作用。本申请的目的是描述嗜碱性粒细胞在丝虫感染中启动和维持2型反应中的作用。正在测试的中心假设是：由B细胞持续产生丝虫特异性IgE，使嗜碱性粒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。具体目的1：探讨丝虫抗原是否能激活嗜碱性粒细胞非特异性地释放IL-4。具体目标二：确定在治疗的丝虫感染背景下，Ag特异性IgE产生和Ag特异性IgE介导的嗜碱性粒细胞活化是否持续存在。具体目标3：确定嗜碱性粒细胞在驱动幼稚T细胞向2型表型发展中的作用。

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.