Brugia malayi microfilariae induce a regulatory monocyte/macrophage phenotype that suppresses innate and adaptive immune responses.
Brugia malayi microfilariae induce a regulatory monocyte/macrophage phenotype that suppresses innate and adaptive immune responses.
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DOI：
10.1371/journal.pntd.0003206
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发表时间：
2014-10
影响因子：
3.8
通讯作者：
Hartmann S
中科院分区：
文献类型：
--
作者：
O'Regan NL;Steinfelder S;Venugopal G;Rao GB;Lucius R;Srikantam A;Hartmann S
单核细胞和巨噬细胞参与了丝虫病免疫反应的紊乱。在显性感染期间，单核细胞在血液中遇到微丝虫病，这一事件发生在免疫低反应的无症状感染丝虫病患者中。为了确定血液微丝虫是否直接作用于血液单核细胞和体外产生的巨噬细胞来诱导干扰先天和适应性反应的调节表型。用马来丝虫微丝虫(MF)裂解物体外刺激丝虫病非流行区正常献血员单核细胞和体外产生的巨噬细胞。我们可以证明，单核细胞在MF裂解物刺激下发展出明确的调节表型，其特征是免疫调节标记物IL-10和PD-L1的表达。值得注意的是，这种调节表型在无症状感染患者的单核细胞中重现，但在有病理或地方性正常的患者中没有。来自非地方病供者的单核细胞经MF裂解物刺激后，直接抑制CD_4+T细胞的增殖和细胞因子(干扰素-γ、IL-13和IL-10)的产生。通过中和IL-10或PD-1来恢复干扰素-γ应答。此外，用MF裂解液刺激的巨噬细胞表达高水平的IL-10，并抑制吞噬能力。最后，在巨噬细胞体外分化过程中应用MF裂解物，选择性地干扰巨噬细胞对随后的内毒素刺激的反应能力。综上所述，我们的研究表明，MF裂解液对健康供者单核细胞的体外刺激诱导了一种以PD-L1和IL-10表达为特征的调节性表型。这种表型直接反映在丝虫病患者无症状感染的单核细胞中，而不是病理或地方性正常人的单核细胞中。我们认为淋巴丝虫病中常见的T细胞功能抑制是由微丝虫调节的单核细胞以IL-10依赖的方式引起的。再加上对巨噬细胞固有反应的抑制，这可能有助于在无症状感染患者中观察到免疫反应的整体下调。淋巴丝虫病是一种影响全球100多万人的寄生虫病，在大多数感染者中导致慢性疾病。一定比例的人会出现无症状感染，从而使寄生虫持续存在，从而通过血液循环的微丝虫传播疾病。我们发现，单核细胞和巨噬细胞，先天的效应细胞，在血液中循环，迁移或居住在组织中，并与微丝虫接触，可以在体外被微丝虫(MF)裂解物刺激，通过表达PD-L1和IL-10来形成调节表型。值得注意的是，在没有外界刺激的情况下，这种调节性单核细胞表型直接反映在丝虫无症状感染患者的单核细胞中。MF裂解物调节的单核细胞抑制适应性免疫功能，其中一些功能可以通过中和IL-10来恢复。MF裂解物调节的巨噬细胞吞噬能力降低，而在MF裂解物存在下分化的巨噬细胞对内毒素刺激的先天反应显示出显著的抑制。这表明微丝虫通过作用于巨噬细胞分化和巨噬细胞本身来调节先天反应，并通过作用于单核细胞来调节适应性的CD4+T细胞反应。调节的单核细胞观察到的表型模式在活体感染中得到重现。这突显了以前不清楚的寄生虫免疫调节机制。
Monocytes and macrophages contribute to the dysfunction of immune responses in human filariasis. During patent infection monocytes encounter microfilariae in the blood, an event that occurs in asymptomatically infected filariasis patients that are immunologically hyporeactive. To determine whether blood microfilariae directly act on blood monocytes and in vitro generated macrophages to induce a regulatory phenotype that interferes with innate and adaptive responses. Monocytes and in vitro generated macrophages from filaria non-endemic normal donors were stimulated in vitro with Brugia malayi microfilarial (Mf) lysate. We could show that monocytes stimulated with Mf lysate develop a defined regulatory phenotype, characterised by expression of the immunoregulatory markers IL-10 and PD-L1. Significantly, this regulatory phenotype was recapitulated in monocytes from Wuchereria bancrofti asymptomatically infected patients but not patients with pathology or endemic normals. Monocytes from non-endemic donors stimulated with Mf lysate directly inhibited CD4+ T cell proliferation and cytokine production (IFN-γ, IL-13 and IL-10). IFN-γ responses were restored by neutralising IL-10 or PD-1. Furthermore, macrophages stimulated with Mf lysate expressed high levels of IL-10 and had suppressed phagocytic abilities. Finally Mf lysate applied during the differentiation of macrophages in vitro interfered with macrophage abilities to respond to subsequent LPS stimulation in a selective manner. Conclusively, our study demonstrates that Mf lysate stimulation of monocytes from healthy donors in vitro induces a regulatory phenotype, characterized by expression of PD-L1 and IL-10. This phenotype is directly reflected in monocytes from filarial patients with asymptomatic infection but not patients with pathology or endemic normals. We suggest that suppression of T cell functions typically seen in lymphatic filariasis is caused by microfilaria-modulated monocytes in an IL-10-dependent manner. Together with suppression of macrophage innate responses, this may contribute to the overall down-regulation of immune responses observed in asymptomatically infected patients. Lymphatic filariasis is a parasitic disease that affects over one million people worldwide, causing chronic morbidity in the majority of infected individuals. A certain proportion of individuals develop asymptomatic infection that allows persistence of the parasite and therefore transmission of disease through the blood-circulating microfilariae. We show that monocytes and macrophages, innate effector cells that circulate in the blood, migrate or reside in tissues and come into contact with microfilariae, can be stimulated by microfilarial (Mf) lysate in vitro to develop a regulatory phenotype via expression of PD-L1 and IL-10. Significantly, this regulatory monocyte phenotype was directly reflected in monocytes isolated from filaria asymptomatically infected patients in the absence of external stimuli. Mf lysate-modulated monocytes inhibited adaptive immune functions, some of which could be restored by neutralisation of IL-10. Mf lysate-modulated macrophages had reduced phagocytic capacity, while macrophages differentiated in the presence of Mf lysate displayed significantly inhibited innate responses to LPS stimulation. This suggests that microfilariae modulate the innate response by acting on macrophage differentiation and macrophages themselves, and modulate the adaptive CD4+ T cell response by acting on monocytes. The phenotypic pattern observed by modulated monocytes is recapitulated in vivo in active infection. This highlights a previously unclear mechanism of immune modulation by the parasite.
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影响因子：
6.7
作者：
Broadhurst MJ;Leung JM;Lim KC;Girgis NM;Gundra UM;Fallon PG;Premenko-Lanier M;McKerrow JH;McCune JM;Loke P
通讯作者：
Loke P
影响因子：
6.4
作者：
Babu, Subash;Kumaraswami, V.;Nutman, Thomas B.
通讯作者：
Nutman, Thomas B.
DOI：
10.4049/jimmunol.0902009
发表时间：
2010-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Herbert DR;Orekov T;Roloson A;Ilies M;Perkins C;O'Brien W;Cederbaum S;Christianson DW;Zimmermann N;Rothenberg ME;Finkelman FD
通讯作者：
Finkelman FD
影响因子：
6.7
作者：
Klotz C;Ziegler T;Figueiredo AS;Rausch S;Hepworth MR;Obsivac N;Sers C;Lang R;Hammerstein P;Lucius R;Hartmann S
通讯作者：
Hartmann S
影响因子：
4.8
作者：
Cao, Shanjin;Zhang, Xia;Mosser, David M.
通讯作者：
Mosser, David M.