Role of basophils and IgE in the immune response to Litomosoides

丝虫是一种以昆虫为媒介的组织寄居蛔虫，是世界范围内的主要致病原因。它们引起以嗜酸性粒细胞增多为特征的2型免疫反应，血清中抗原特异性和多克隆的IgE水平升高，T细胞产生IL-4、IL-5和IL-I3增加。然而，随着时间的推移，慢性感染患者会发展成免疫低反应状态，T细胞增殖和细胞因子产生减少，以应对丝虫抗原。这项研究的长期目标最终是下调2型免疫反应。需要测试的中心假设是，一旦存在Ag特异性IgE，嗜碱性粒细胞最初用于放大和重建针对丝虫的2型免疫反应。中心假设的检验将通过解决两个特定目标来进行：i)IgE介导的嗜碱性粒细胞的激活是否放大正在进行的针对丝虫感染的2型免疫反应，以及2)先前存在的Ag特异性IgE是否能够在再次感染丝虫时迅速重建2型免疫反应。目的通过评估丝虫感染在存在和不存在IgE阻断、FcER1缺乏和嗜碱性粒细胞耗竭的情况下诱导的2型反应来完成I。目的2将通过评估用丝虫特异性IgE致敏的小鼠或通过先前接种或感染诱导产生丝虫特异性LGE的小鼠中2型玫瑰花环对丝虫感染的快速反应来解决。Sitomosoids sigmodontis的丝虫模型将用于这些研究，因为这是小鼠感染丝虫的唯一模型，在该模型中，感染幼虫发育成成熟的、可进行有性繁殖的成虫。从这些研究中获得的信息有可能在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方面取得进展。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