eprintid: 26159 rev_number: 17 eprint_status: archive userid: 1589 dir: disk0/00/02/61/59 datestamp: 2019-05-10 16:35:33 lastmod: 2024-05-03 20:46:17 status_changed: 2019-05-10 16:35:33 type: article metadata_visibility: show creators_name: Zhu, Li creators_name: Aly, Mostafa creators_name: Kuon, Ruben Jeremias creators_name: Toth, Bettina creators_name: Wang, Haihao creators_name: Karakizlis, Hristos creators_name: Weimer, Rolf creators_name: Morath, Christian creators_name: Ibrahim, Eman creators_name: Ekpoom, Naruemol creators_name: Opelz, Gerhard creators_name: Daniel, Volker title: Patients with idiopathic recurrent miscarriage have abnormally high TGFß+ blood NK, NKT and T cells in the presence of abnormally low TGFß plasma levels subjects: ddc-610 divisions: i-910100 divisions: i-910400 divisions: i-911600 keywords: Idiopathic recurrent miscarriage, TGFß, IL4, IL10, TNFα, NK cells, Plasma cytokines, Cell cultures, K562, Supernatants, Patients, Transplantation abstract: Background: 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. Method: 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. Results: 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). Conclusions: 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. date: 2019 publisher: BioMed Central ; Springer id_scheme: DOI ppn_swb: 1666412651 own_urn: urn:nbn:de:bsz:16-heidok-261594 language: eng bibsort: ZHULIPATIENTSWI2019 full_text_status: public publication: BMC Immunology volume: 20 number: 10 place_of_pub: London ; Berlin, Heidelberg pagerange: 1-15 issn: 1471-2172 citation: Zhu, Li ; Aly, Mostafa ; Kuon, Ruben Jeremias ; Toth, Bettina ; Wang, Haihao ; Karakizlis, Hristos ; Weimer, Rolf ; Morath, Christian ; Ibrahim, Eman ; Ekpoom, Naruemol ; Opelz, Gerhard ; Daniel, Volker (2019) 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, 20 (10). pp. 1-15. ISSN 1471-2172 document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/26159/1/12865_2019_Article_290.pdf