IMMEDIATE HYPERSENSITIVITY RESPONSES--CONTROL IN PARASITIC HELMINTH INFECTIONS

使用虫药治疗诱导的嗜酸性粒细胞（淋巴丝虫病和盘尾丝虫病）作为生理激活和嗜酸性粒细胞募集的模型，我们已经明确地建立了循环RANTES水平和嗜酸性粒细胞从血液迁移到炎症部位的能力之间的反比关系。利用伊维菌素治疗后盘尾丝虫病患者皮肤活检的免疫组织化学染色，我们已经表明，一旦募集，嗜酸性粒细胞脱粒并刺激eotaxin的产生，从而允许进一步的嗜酸性粒细胞积累。在印度的一项独立研究中，流式细胞仪是可用的，我们已经检查了嗜酸性粒细胞激活的动力学后，明确的抗丝虫病治疗。数据显示，在头24小时内，整合素（VLA-4、CD44和alpha4beta7）和CD23的表达明显上调。此后不久，IL-5水平达到峰值，早于治疗后发生的普遍嗜酸性粒细胞增多。另一种理解嗜酸性粒细胞激活和调节的主要方法是遗传学方法，我们已经确定了一个家族性嗜酸性粒细胞过多的大亲属。这种综合征是常染色体显性的，并允许相关基因与靠近标记D5S1505的5号染色体的物理连锁。该区域有许多基因，包括白介素5的基因，但随后对IL-5、IL-3和GM-CSF基因及其促进子的完整测序尚未确定候选基因或突变。在过去的一年里，通过研究近17名亲属，研究人员采取了一种综合方法来治疗这种疾病。从他们的细胞和嗜酸性粒细胞收集的数据表明，他们的嗜酸性粒细胞没有主要的活化表型（基于细胞表面标记表达，电子显微镜，嗜酸性粒细胞存活测定）。另外两个候选基因已经确定，但正在等待全面测序。使用正常和活化的嗜酸性粒细胞的差异代表性分析接近65活化特异性基因产物已被确定。每个都在各种体外系统中进行差异表达检查。由于寄生虫感染时IgE和IgG4水平升高，因此研究了这些升高的机制，最初使用寄生虫抗原驱动的体外抗体生产模型。已经确定了能够诱导同型转换为IgG4/IgE的重组抗原，这些抗原在没有T细胞的情况下驱动B细胞的能力被证明是存在的，提供了抗cd40和适当的细胞因子环境。此外，这些相同的抗原已被证明能够以这样一种方式从原始宿主中启动T细胞，它们（在这些重组抗原的存在下）诱导B细胞分化为能够产生抗原特异性IgE和IgG4的B细胞。此外，在急性寄生虫感染中，IgE和IgG4的种系表达现已得到证实，并提示了寄生虫抗原特异性诱导转换为这些重要同型的机制。-嗜酸性粒细胞增多症，过敏，即时过敏，蠕虫，丝虫病感染，细胞因子，IgE -人类受试者

Using anthelminthic treatment-induced eosinophilia (in both lymphatic filariasis and onchocerciasis) as a model for physiological activation and recruitment of eosinophils, we have clearly established that there is an inverse relationship between circulating levels of RANTES and the ability of eosinophils to migrate from the blood to the sites of inflammation. Using immunohistochemical staining of skin biopsies taken from patients with onchocerciasis after ivermectin therapy, we have shown that, once recruited, the eosinophils degranulate and stimulate eotaxin production thereby allowing further eosinophil accumulation. In a separate study in India where a flow cytometer is available, we have examined the kinetics of eosinophil activation following definitive antifilarial therapy. The data show that there is marked upregulation of the integrins (VLA-4, CD44 and alpha4beta7) as well as CD23 within the first 24 hours. IL-5 levels peaked soon thereafter and predated the universal eosinophilia that occurred following therapy.One other major approach taken to understand eosinophil activation and regulation is a genetic approach in which we have identified a large kindred with familial hypereosinophilia. This syndrome is autosomal dominant and has allowed physical linkage of the responsible gene to chromosome 5 near to marker D5S1505. There are a number of genes in the area, including that for interleukin 5, but subsequent complete sequencing of the IL-5, IL-3 and GM-CSF gene and their promotes has not identified the candidate gene or mutation. Over the past year an integrated approach to this disorder has been taken by studying close to 17 members of the kindred. Data collected on their cells and eosinophils have suggested that their eosinophils are without major activation phenotypes (based on cell surface marker expression, electron microscopy, eosinophil survival assays). Two other candidate genes have been identified but await full sequencing. Using differential representational analysis of normal and activated eosinophils close to 65 activation-specific gene products have been identified. Each is being examined for differential expression in a variety of in vitro systems.Because IgE and IgG4 levels are increased in helminth infection, the mechanisms underlying these increases have been examined, initially using a model of parasite antigen-driven in vitro production of antibody. Having identified recombinant antigens capable of inducing isotype switching to IgG4/IgE, the ability of these antigens to drive B cells in the absence of T cells was shown to occur, providing anti-CD40 and the appropriate cytokine milieu was provided. Further, these same antigens have been shown capable of priming T cells from naive hosts in such a way that they (in presence of these recombinant antigens) induce B cells to differentiate into B cells capable of producing antigen-specific IgE and IgG4. Moreover, germline expression of IgE and IgG4 in acute helminth infections has now been shown and suggests a mechanism by which parasite antigen specifically induce switching to these important isotypes. - Hypereosinophilia, allergy, immediate hypersensitivity, helminth, filarial infections, cytokines, IgE - Human Subjects