Immunosuppression in human filarial disease involves regulatory T cells. We hypothesized that natural or worm antigen-induced FOXP3 regulatory T cells could be involved locally, suppressing effector cells via granzymes. Natural and treatment-induced death of worms implies enhanced exposure to worm antigens. Therefore, we examined FOXP3+T cells and granzyme expression in onchocercomas harbouring adult Onchocerca volvulus worms, with respect to worm viability, productivity, the patient's immune status and filaricidal treatment. The immunohistological analysis revealed that dead adult worms were strongly associated with FOXP3+T cells in generalized hyporeactive onchocerciasis. FOXP3+ cells hardly expressed granzymes, but cell contacts with granzyme A+ or B+ cells were frequent. While suramin directly kills most adult worms within 6 months, the Wolbachia depleting antibiotic doxycycline indirectly causes adult worm degeneration within 18 months. Contrary to suramin, depletion of Th1-driving endobacteria most strongly promoted FOXP3+T cells and granzyme-expressing cells. In hyperreactive patients, FOXP3+ cells were less frequent. This is the first demonstration of local FOXP3+Treg cells in human filariasis and their induction by natural worm death and anti-parasitic treatment. We newly report granzyme responses to helminths and their association with immunosuppression. FOXP3+Treg and granzyme+ cells might locally suppress defence against newly acquired worms.

译文

人丝虫病的免疫抑制涉及调节性T细胞。我们假设天然或蠕虫抗原诱导的FOXP3调节性T细胞可能局部参与,通过颗粒酶抑制效应细胞。自然和由治疗引起的蠕虫死亡意味着增加了对蠕虫抗原的暴露。因此,我们就蠕虫的生存能力,生产力,患者的免疫状况和杀螨治疗方面,研究了携带成年Onchocerca volvulus蠕虫的Onchocercomas中的FOXP3 T细胞和颗粒酶的表达。免疫组织学分析表明,死于成虫的蠕虫在广泛的低反应性盘尾丝虫病中与FOXP3 T细胞密切相关。 FOXP3细胞几乎不表达颗粒酶,但是细胞经常与颗粒酶A或B细胞接触。苏拉明可在6个月内直接杀死大多数成虫,而消耗沃尔多巴氏菌的抗生素多西环素会在18个月内间接导致成虫的退化。与苏拉明相反,驱动Th1的内细菌的耗竭最能促进FOXP3 T细胞和表达颗粒酶的细胞。在高反应性患者中,FOXP3细胞的频率较低。这是人类丝虫病中局部FOXP3 Treg细胞的首次展示,并通过自然蠕虫死亡和抗寄生虫治疗诱导它们。我们新近报道了粒酶对蠕虫的反应以及它们与免疫抑制的关系。 FOXP3 Treg和粒酶细胞可能会局部抑制对新获得的蠕虫的防御。

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