Excretory/secretory-products of Echinococcus multilocularis larvae induce apoptosis and tolerogenic properties in dendritic cells in vitro.
Excretory/secretory-products of Echinococcus multilocularis larvae induce apoptosis and tolerogenic properties in dendritic cells in vitro.
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DOI：
10.1371/journal.pntd.0001516
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发表时间：
2012
影响因子：
3.8
通讯作者：
Brehm K
中科院分区：
文献类型：
--
作者：
Nono JK;Pletinckx K;Lutz MB;Brehm K
泡状棘球蚴病是由多房棘球蚴幼虫引起的一种慢性疾病，与宿主免疫反应的显著调节有关。树突状细胞（DC）是塑造免疫反应的关键效应子，也是寄生虫在感染期间遇到的第一批细胞。虽然假设多房棘球绦虫通过排泄/分泌（E/S）产物特异性地影响DC以偏离免疫应答，但关于相应E/S产物的分子性质及其作用模式的信息很少。我们建立了培养系统暴露DC活材料从早期（六钩蚴），慢性（后绦虫）和晚期（原头节）感染阶段。当与棘球蚴原代细胞（代表入侵的六钩蚴或后囊蚴囊泡）共孵育时，显著比例的DC发生凋亡，存活的DC未能成熟。与此相反，DC暴露于protoplastices上调成熟标志物，并没有经历凋亡。与原代细胞和后囊泡预孵育后，DC显示出被TLR配体LPS激活的能力强烈受损，这在用原头节E/S-产物预处理的DC中未观察到。虽然没有幼虫诱导促炎性IL-12 p70的分泌，但免疫抑制性IL-10的产生响应于原代细胞E/S产物而升高。最后，在与DC和幼稚T细胞孵育后，来自后绦虫囊泡的E/S产物导致Foxp 3 + T细胞在体外显著扩增。这是第一次报告的诱导细胞凋亡的DC绦虫E/S-产品。我们的数据表明，E.多房疟原虫是DC中耐受性的强诱导物，这对于在寄生虫非常容易受到宿主攻击的感染阶段产生免疫抑制环境是最重要的。通过后绦虫E/S产物诱导CD 4 + CD 25 + Foxp 3 + T细胞表明这些细胞在慢性包虫病期间寄生虫持续存在中发挥重要作用。寄生蠕虫是慢性疾病的诱导物，并且已经进化出抑制宿主免疫反应的机制。主要来自对蛔虫的研究，目前正在出现的一种情况是，蠕虫分泌直接作用于免疫系统的哨兵树突细胞的因子（E/S产物），以实现免疫抑制性调节性T细胞（T-reg）的扩增。寄生蠕虫目前也被深入研究作为治疗剂对自身免疫性疾病和过敏，这是直接联系到他们的免疫抑制活动。因此，寄生蠕虫的免疫调节产物对于理解感染期间的免疫病理学和用于治疗过敏症具有高度兴趣。本工作是以绦虫E.多房棘球蚴，像肿瘤一样生长到周围宿主组织中，从而引起致命的泡状棘球蚴病。作者发现，早期感染幼虫的E/S产物是体外致耐受性DC的强诱导物，并且表明慢性期幼虫的E/S产物导致Foxp 3 + T细胞的体外扩增，这表明这些T细胞的扩增和低反应性DC对于E.多房幼虫在宿主体内。
Alveolar echinococcosis, caused by Echinococcus multilocularis larvae, is a chronic disease associated with considerable modulation of the host immune response. Dendritic cells (DC) are key effectors in shaping the immune response and among the first cells encountered by the parasite during an infection. Although it is assumed that E.multilocularis, by excretory/secretory (E/S)-products, specifically affects DC to deviate immune responses, little information is available on the molecular nature of respective E/S-products and their mode of action. We established cultivation systems for exposing DC to live material from early (oncosphere), chronic (metacestode) and late (protoscolex) infectious stages. When co-incubated with Echinococcus primary cells, representing the invading oncosphere, or metacestode vesicles, a significant proportion of DC underwent apoptosis and the surviving DC failed to mature. In contrast, DC exposed to protoscoleces upregulated maturation markers and did not undergo apoptosis. After pre-incubation with primary cells and metacestode vesicles, DC showed a strongly impaired ability to be activated by the TLR ligand LPS, which was not observed in DC pre-treated with protoscolex E/S-products. While none of the larvae induced the secretion of pro-inflammatory IL-12p70, the production of immunosuppressive IL-10 was elevated in response to primary cell E/S-products. Finally, upon incubation with DC and naïve T-cells, E/S-products from metacestode vesicles led to a significant expansion of Foxp3+ T cells in vitro. This is the first report on the induction of apoptosis in DC by cestode E/S-products. Our data indicate that the early infective stage of E. multilocularis is a strong inducer of tolerance in DC, which is most probably important for generating an immunosuppressive environment at an infection phase in which the parasite is highly vulnerable to host attacks. The induction of CD4+CD25+Foxp3+ T cells through metacestode E/S-products suggests that these cells fulfill an important role for parasite persistence during chronic echinococcosis. Parasitic helminths are inducers of chronic diseases and have evolved mechanisms to suppress the host immune response. Mostly from studies on roundworms, a picture is currently emerging that helminths secrete factors (E/S-products) that directly act on sentinels of the immune system, dendritic cells, in order to achieve an expansion of immunosuppressive, regulatory T cells (T-reg). Parasitic helminths are currently also intensely studied as therapeutic agents against autoimmune diseases and allergies, which is directly linked to their immunosuppressive activities. The immunomodulatory products of parasitic helminths are therefore of high interest for understanding immunopathology during infections and for the treatment of allergies. The present work was conducted on larvae of the tapeworm E. multilocularis, which grow like a tumor into surrounding host tissue and thus cause the lethal disease alveolar echinococcosis. The authors found that E/S-products from early infective larvae are strong inducers of tolerogenic DC in vitro and show that E/S-products of larvae of the chronic stage lead to an in vitro expansion of Foxp3+ T cells, suggesting that both the expansion of these T cells and poorly responsive DC are important for the establishment and persistence of E. multilocularis larvae within the host.
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DOI：
10.1084/jem.20101074
发表时间：
2010-10-25
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Grainger JR;Smith KA;Hewitson JP;McSorley HJ;Harcus Y;Filbey KJ;Finney CA;Greenwood EJ;Knox DP;Wilson MS;Belkaid Y;Rudensky AY;Maizels RM
通讯作者：
Maizels RM
影响因子：
4
作者：
Konrad, C;Kroner, A;Brehm, K
通讯作者：
Brehm, K
影响因子：
2
作者：
Dvoroznakova, Emilia;Porubcova, Jarmila;Sevcikova, Zuzana
通讯作者：
Sevcikova, Zuzana
影响因子：
8.7
作者：
Grainger JR;Hall JA;Bouladoux N;Oldenhove G;Belkaid Y
通讯作者：
Belkaid Y
影响因子：
3.1
作者：
KIZAKI, T;ISHIGE, M;ONOE, K
通讯作者：
ONOE, K