IMMEDIATE HYPERSENSITIVITY RESPONSES--CONTROL IN PARASITIC HELMINTH INFECTIONS

立即超敏反应——控制寄生虫感染

• 批准号: 6099120
• 负责人: Thomas B Nutman
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6099120
• 关键词: cytokine; enzyme linked immunosorbent assay; eosinophil; flow cytometry; helminthiasis; helminthic antigen; host organism interaction; human tissue; immediate hypersensitivity; immunoglobulin E; immunoglobulin G; immunoregulation; inflammation

The surface molecule expression from helminth-infected and idiopathic eosinophilia patients has been compared to normal individuals. We have found CD69, CD66, and CD81 to be significantly more expressed on eosinophils from patients than from normal individuals. Further, we have found CD23 expression to be significantly lower on patients than normal individuals. Treatment of these helminth-infected patients resulted in a decrease in CD66 and CD69 suggesting that the helminth infection indeed is responsible for the activation seen. 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 intergrins (VLA-4, CD44 and a4b7) 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 promoter has not identified the candidate gene or mutation. 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.

表面分子表达从 寄生虫感染和特发性嗜酸性粒细胞增多症患者已被 与正常人相比。我们发现了CD 69、CD 66和 CD 81在嗜酸性粒细胞上的表达显著增加， 患者比正常人。此外，我们还发现 患者的CD 23表达明显低于正常人 个体对这些蠕虫感染患者的治疗导致 CD 66和CD 69的减少表明蠕虫 感染确实是导致所见激活的原因。使用 驱虫剂治疗诱导的嗜酸性粒细胞增多症（淋巴和 丝虫病和盘尾丝虫病）作为生理激活的模型 和嗜酸性粒细胞的募集，我们已经清楚地确定， 循环水平之间存在反比关系， RANTES和嗜酸性粒细胞从血液中迁移的能力 到达炎症部位。使用免疫组织化学染色 盘尾丝虫病患者的皮肤活检， 伊维菌素治疗，我们已经表明，一旦招募， 嗜酸性粒细胞减少并刺激嗜酸性粒细胞活化趋化因子的产生 允许进一步的嗜酸性粒细胞积聚。在另一项研究中， 在印度，流式细胞仪可用，我们检查了 确定性抗丝虫治疗后嗜酸性粒细胞活化的动力学 疗法数据显示，在小鼠中， 整合素（VLA-4，CD 44和a4 b7）以及CD 23在 头24小时IL-5水平在此后不久达到峰值， 治疗后发生的普遍性嗜酸性粒细胞增多症。一个其他 了解嗜酸性粒细胞活化的主要方法， 调控是一种遗传方法，我们已经确定了一个大的 有家族性嗜酸性粒细胞增多症的亲属这种综合征是常染色体的 显性，并允许负责基因的物理连锁 位于第5染色体标记D5 S1505附近。有许多 基因在该地区，包括白细胞介素5，但随后 IL-5、IL-3和GM-CSF基因的完整测序， 启动子未识别候选基因或突变。 因为IgE和IgG 4水平在蠕虫感染中增加， 已经研究了这些增加背后的机制， 最初使用寄生虫抗原驱动的体外生产模型 抗体。已经鉴定出能够 诱导同种型转换为IgG 4/IgE，这些抗原 在T细胞不存在的情况下驱动B细胞， 提供抗CD 40和适当的细胞因子环境， 提供了此外，这些相同的抗原已经显示能够 以这样的方式从幼稚宿主中引发T细胞， 这些重组抗原的存在）诱导B细胞 分化为能够产生抗原特异性IgE的B细胞 IgG4