Role of basophils and IgE in the immune response to Litomosoides

丝虫病是一种由昆虫传播的居住在组织中的蛔虫，是世界范围内疾病的主要原因。它们引起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lgE水平升高，t细胞中IL-4、IL-5和il - 3的产生增加。然而，随着时间的推移，慢性感染患者会出现免疫反应性低下的状态，对丝虫病抗原的T细胞增殖和细胞因子产生减少。长期目标是最终下调2型免疫反应。要验证的中心假设是，一旦存在ag特异性IgE，嗜碱性粒细胞最初会增强和重建针对丝虫病的2型免疫应答。中心假设的验证将通过解决两个特定目标来实现：1)IgE介导的嗜碱性粒细胞激活是否会增强针对丝虫病感染的2型免疫应答；2)先前存在的ag特异性IgE是否能在再次感染丝虫病时迅速重建2型免疫应答。目的1将通过评估在存在和不存在IgE阻断、FcER1缺乏和嗜碱性粒细胞耗竭的情况下丝虫病感染诱导的2型反应来完成。目的2将通过评估用丝虫病特异性IgE致敏或通过事先接种疫苗或感染诱导产生丝虫病特异性IgE的小鼠对丝虫病感染的2型反应发展的速度来解决。这些研究将使用象形石线虫的丝虫病模型，因为它是唯一一种感染小鼠的丝虫病模型，在这种模型中，受感染的幼虫发育成成熟的、有性繁殖的成虫。从这些研究中获得的信息有可能导致以下方面的进展：1)蠕虫疫苗的开发，2)诱导免疫调节的机制，以及3)过敏和哮喘的预防和治疗。的

Filariae are insect-borne tissue-dwelling roundworms that are a major worldwide cause of disease. They cause a type 2 immune response characterized by eosinophilia, elevated serum levels of Ag-specific and polyclonal lgE, and increases in T-cell production of IL-4, IL-5, and IL-I 3. Over time, though, chronically infected patients develop a state of immune hyporesponsiveness, with decreased T - cell proliferation and cytokine production in response to filarial antigen. The long range goal of this ultimately downregulate type 2 immune responses. The central hypothesis to be tested is that basophils initially serve to amplify and reestablish type 2 immune responses towards filariae once Ag-specific IgE is present Testing of the central hypothesis will be performed by addressing two specific aims: I) whether IgE-mediated activation of basophils amplifies ongoing type 2 immure responses towards filarial infections, and 2) whether preexisting Ag-specific IgE can rapidly reestablish a type 2 immune response upon reinfection with filariae. Aim I will be accomplished by evaluating type 2 responses induced by filarial infection in the presence and absence of IgE blockade, FcER1 -deficiency, and basophil depletion. Aim 2 will be addressed by assessing the rapidity with which type 2 rosponses develop in response to filarial infection in mice sensitized with filaria-specific IgE or induced to produce filaria-specific lgE by either prior vaccination or infection. The filarial model of Litomosoides sigmodontis will be used in these studies because it is the only model of filarial infection in mice in which infective larvae develop into mature, sexually reproducing adults. Information gained from these studies has the potential to lead to advances in I) helminth vaccine development, 2) mechanisms of inducing immune modulation, and 3) prevention and treatment of allergy and asthma. of