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Patients with idiopathic recurrent miscarriage have abnormally high TGFß+ blood NK, NKT and T cells in the presence of abnormally low TGFß plasma levels
BMC Immunology ( IF 3 ) Pub Date : 2019-03-04 , DOI: 10.1186/s12865-019-0290-3
Li Zhu , Mostafa Aly , Ruben Jeremias Kuon , Bettina Toth , Haihao Wang , Hristos Karakizlis , Rolf Weimer , Christian Morath , Eman Ibrahim , Naruemol Ekpoom , Gerhard Opelz , Volker Daniel

Previously, we demonstrated up-regulated activated CD4+ and CD8+ T lymphocytes as well as up-regulated cytotoxic NK cells in the blood of patients with idiopathic recurrent miscarriage. In the present study, we tried to identify deficiencies in counter-regulating immune mechanisms of these patients. Cytokines were determined in NK cells and in plasma samples of 35 healthy controls, 33 patients with idiopathic recurrent miscarriage, 34 patients with end stage renal disease, 10 transplant patients early and 37 transplant patients late post-transplant using flow-cytometry and luminex. In addition, cytokines were studied in supernatants of cell cultures with peripheral blood mononuclear cells stimulated in-vitro with tumor cell line K562. Patients with idiopathic recurrent miscarriage exhibited the highest absolute cell counts of circulating TGFß1+ NK, NKT and T lymphocytes and the lowest TGFß1 plasma levels of all study groups (for all p < 0.050). In-vitro, peripheral blood mononuclear cells of patients with idiopathic recurrent miscarriage showed high spontaneous TGFß1 production that could not be further increased by stimulation with K562, indicating increased consumption of TGFß1 by activated cells in the cell culture. Moreover, patients with idiopathic recurrent miscarriage had abnormally high IL4+ as well as abnormally high IFNy+ NK cells (p < 0.010) but similar IL10+ NK cell numbers as female healthy controls and showed the lowest plasma levels of IL10, TGFß3, IL1RA, IL1ß, IL5, IL6, IL8, IL17, TNFα, GM-CSF, TPO and VEGF and the highest plasma levels of G-CSF, FGF-basic, CCL3 and CXCL5 as compared to female HC and female transplant recipients (for all p < 0.050). Patients with idiopathic recurrent miscarriage show an activated immune system that can hardly be stimulated further and cannot be efficiently down-regulated by up-regulated TGFß1+ and IL4+ NK, NKT and T lymphocytes which are present concomitantly in these patients. The strongly decreased TGFß and IL10 plasma levels indicate deficient down-regulation and reflect a dysbalance of the immune system in patients with idiopathic recurrent miscarriage. These findings may be relevant for explaining the pathogenesis of idiopathic recurrent miscarriage.

中文翻译:

特发性反复流产患者血浆中TGFβ含量异常低时,TGFβ+血NK,NKT和T细胞异常高

以前,我们证明了特发性反复流产患者血液中活化的CD4 +和CD8 + T淋巴细胞上调以及细胞毒性NK细胞上调。在本研究中,我们试图找出反调节这些患者免疫机制的缺陷。使用流式细胞仪和luminex在35位健康对照,33位特发性反复流产,34位晚期肾病患者,10位早期移植患者和37位移植晚期患者的NK细胞和血浆样本中测定了细胞因子。另外,在细胞培养物的上清液中研究了细胞因子,其中用肿瘤细胞系K562体外刺激了外周血单核细胞。特发性反复流产患者的循环中TGFβ1+ NK的绝对细胞数最高,在所有研究组中,NKT和T淋巴细胞以及最低的TGFβ1血浆水平(所有p <0.050)。特发性反复流产患者的体外外周血单核细胞显示出高自发性TGFβ1产生,而用K562刺激无法进一步增加,表明细胞培养物中活化细胞对TGFβ1的消耗增加。此外,特发性反复流产患者的IL4 +异常高,而IFNy + NK细胞异常高(p <0.010),但IL10 + NK细胞数量与女性健康对照组相似,并且血浆IL10,TGFβ3,IL1RA,IL1ß,IL5最低与雌性HC和雌性移植受者相比,IL6,IL8,IL17,TNFα,GM-CSF,TPO和VEGF以及G-CSF,FGF碱性,CCL3和CXCL5的血浆水平最高(所有p <0.050)。特发性反复流产的患者显示出激活的免疫系统,很难被进一步刺激,并且不能通过这些患者中同时存在的TGFβ1+和IL4 + NK,NKT和T淋巴细胞的上调来有效地下调。特发性反复流产患者中,TGFβ和IL10血浆水平的强烈降低表明其下调不足,反映了免疫系统的失衡。这些发现可能与解释特发性反复流产的发病机理有关。特发性反复流产患者中,TGFβ和IL10血浆水平的强烈降低表明其下调不足,反映了免疫系统的失衡。这些发现可能与解释特发性反复流产的发病机理有关。特发性反复流产患者中,TGFβ和IL10血浆水平的强烈降低表明其下调不足,反映了免疫系统的失衡。这些发现可能与解释特发性反复流产的发病机理有关。
更新日期:2019-03-04
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