Role of basophils in the immune response to filariae

丝虫是一种寄生于节肢动物组织的蠕虫，是世界范围内的主要疾病负担。他们 通常会引起以嗜酸性粒细胞增多为特征的2型免疫反应，血清Ag- 特异性和多克隆IgE，以及IL-4、IL-5和IL-13的T细胞产生增加。2型反应 可能有助于控制蠕虫感染。虽然很明显IL-4在驱动类型中起着核心作用， 2反应，负责触发和维持延长的2型免疫的确切因素 对丝虫感染的反应仍然未知。我们知识中的这些空白是有问题的，因为它们 削弱了我们开发蠕虫特异性疫苗的能力， 有高滴度的抗原特异性IgE因为它们是最不常见的外周血白细胞， 嗜碱性粒细胞在对传染病的免疫反应中所起的作用， 大部分都没有被研究过然而，最近的证据表明，嗜碱性粒细胞是主要的贡献者， IL-4库在感染ftlaria的人，这表明他们可能在免疫反应中发挥重要作用， 丝虫感染本申请的目的是描述嗜碱性粒细胞在启动和维持细胞凋亡中的作用。 维持丝虫感染的2型反应。正在检验的中心假设是： 由B细胞产生丝虫特异性IgE使嗜碱性粒细胞能够协调快速的2型记忆反应 通过释放大量的IL-4和驱动幼稚T细胞向2型细胞分化， 表型这一假设将通过追求以下目标来解决。具体目标1：确定 嗜碱性粒细胞是否能被丝虫抗原激活而非特异性地释放IL-4。具体目标2： 确定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于 治疗丝虫感染的背景。具体目标3：确定嗜碱性粒细胞在驱动幼稚细胞中的作用 T细胞向2型表型转化。

Filariae are arthropod-bornetissue-dwelling helminths that are a majorworldwide burden of disease. They typically cause a type 2 immune responsecharacterizedby 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 becausethey impair our ability to develop helminth-specific vaccinesthat produce long-standing type 2 immune responses with high titers of Ag-specific IgE. Because they are the least common peripheral leukocyte andbecause they are difficult to work with, the role basophils play in the immune response to infectious diseases has largely gone unstudied. However,recent evidence demonstratesthat basophils are major contributorsto the IL-4 pool in ftlaria-infected humans, suggesting they may play an important role in the immune response to filarial infections. The objective of this appliation 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 memoryresponse 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.