|
1
|
Xu X, Chen H, Gao L, Sun C, Li X, Li Y, Wang W, Zheng Y. Maternal-offspring brain and tissue cross-talk in preeclampsia: insights from a rat model. Metab Brain Dis 2025; 40:173. [PMID: 40192930 PMCID: PMC11976809 DOI: 10.1007/s11011-025-01593-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 03/21/2025] [Indexed: 04/10/2025]
Abstract
This study aimed to investigate the differential metabolic profiles across maternal and offspring brains, serum, and placental tissues in preeclampsia (PE), with a particular focus on elucidating the maternal-offspring brain and tissue cross-talk that may contribute to the complex pathophysiology of PE. PE was induced in rats using the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) to simulate both early-onset PE (EOPE) and late-onset PE (LOPE). We utilized non-targeted proton nuclear magnetic resonance (NMR) metabolomics to characterize the metabolic profiles of serum, placental tissue extracts, and brain tissues from both mothers and offspring. Multivariate analysis, Spearman correlation, Density-Based Spatial Clustering of Applications with Noise algorithm, Data-Driven Statistical Predictive Correlation network analysis and Tissue heterogeneity analysis were employed to explore tissue-specific metabolic signatures and their interactions. Following L-NAME induction, both EOPE and LOPE presented significant metabolic differences and shared traits across tissues, with distinct tissue-specific responses characterizing the metabolic profile of PE. Serum from both PE groups showed a decrease in tryptophan, isobutyrate, and lactate, with an increase in betaine. Lactate was upregulated in placental tissues, highlighting its metabolic role. Extensive intra-tissue metabolic correlations and inter-tissue metabolite exchanges were detected among the maternal brain, serum, placenta, and offspring brain across all three experimental groups. EOPE and LOPE exhibited distinctly different metabolic characteristics and trajectories of differential metabolites, along with diverse interaction patterns between the maternal/offspring brain and the placenta. This study uncovers the multi-tissue metabolic remodeling in response to preeclampsia, implying that addressing pathophysiological stress is crucial and may have potential implications for neurological outcomes. The comprehensive analysis highlights the pivotal role of the brain-placenta axis in preeclampsia, advocating for a classified diagnostic and management approach.
Collapse
Affiliation(s)
- Xiaomin Xu
- Scientific Research Center, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People'S Hospital, Wenzhou, China
| | - Haiyin Chen
- Scientific Research Center, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People'S Hospital, Wenzhou, China
| | - Lidan Gao
- Scientific Research Center, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People'S Hospital, Wenzhou, China
| | - Congcong Sun
- Scientific Research Center, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People'S Hospital, Wenzhou, China
| | - Xiaoqing Li
- Scientific Research Center, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People'S Hospital, Wenzhou, China
| | - Yanjun Li
- Scientific Research Center, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People'S Hospital, Wenzhou, China
| | - Wenhuan Wang
- Scientific Research Center, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People'S Hospital, Wenzhou, China
| | - Yanyan Zheng
- Scientific Research Center, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People'S Hospital, Wenzhou, China.
- Neurology Department, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People'S Hospital, Wenzhou, China.
| |
Collapse
|
|
2
|
Marzioni D, Piani F, Di Simone N, Giannubilo SR, Ciavattini A, Tossetta G. Importance of STAT3 signaling in preeclampsia (Review). Int J Mol Med 2025; 55:58. [PMID: 39918020 PMCID: PMC11878484 DOI: 10.3892/ijmm.2025.5499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 01/20/2025] [Indexed: 03/06/2025] Open
Abstract
Placentation is a key process that is tightly regulated that ensures the normal placenta and fetal development. Preeclampsia (PE) is a hypertensive pregnancy‑associated disorder characterized by increased oxidative stress and inflammation. STAT3 signaling plays a key role in modulating important processes such as cell proliferation, differentiation, invasion and apoptosis. The present review aimed to analyse the role of STAT3 signaling in PE pregnancies, discuss the main natural and synthetic compounds involved in modulation of this signaling both in vivo and in vitro and summarize the main cellular modulators of this signaling to identify possible therapeutic targets and treatments to improve the outcome of PE pregnancies.
Collapse
Affiliation(s)
- Daniela Marzioni
- Department of Experimental and Clinical Medicine, Polytechnic University of Marche, I-60126 Ancona, Italy
| | - Federica Piani
- Hypertension and Cardiovascular Risk Research Center, Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, I-40126 Bologna, Italy
| | - Nicoletta Di Simone
- Department of Biomedical Sciences, Humanitas University, I-20072 Milan, Italy
- Scientific Institutes for Hospitalization and Care (IRCCS), Humanitas Research Hospital, I-20089 Rozzano, Italy
| | | | - Andrea Ciavattini
- Department of Clinical Sciences, Polytechnic University of Marche, I-60123 Ancona, Italy
| | - Giovanni Tossetta
- Department of Experimental and Clinical Medicine, Polytechnic University of Marche, I-60126 Ancona, Italy
| |
Collapse
|
|
3
|
Levenson D, Romero R, Miller D, Galaz J, Garcia-Flores V, Neshek B, Pique-Regi R, Gomez-Lopez N. The maternal-fetal interface at single-cell resolution: uncovering the cellular anatomy of the placenta and decidua. Am J Obstet Gynecol 2025; 232:S55-S79. [PMID: 40253083 DOI: 10.1016/j.ajog.2024.12.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 12/12/2024] [Accepted: 12/27/2024] [Indexed: 04/21/2025]
Abstract
The maternal-fetal interface represents a critical site of immunological interactions that can greatly influence pregnancy outcomes. The unique cellular composition and cell-cell interactions taking place within these tissues has spurred substantial research efforts focused on the maternal-fetal interface. With the recent advent of single-cell technologies, multiple investigators have applied such methods to gain an unprecedented level of insight into maternal-fetal communication. Here, we provide an overview of the dynamic cellular composition and cell-cell communications at the maternal-fetal interface as reported by single-cell investigations. By primarily focusing on data from pregnancies in the second and third trimesters, we aim to showcase how single-cell technologies have bolstered the foundational understanding of each cell's contribution to physiologic gestation. Indeed, single-cell technologies have enabled the examination of classical placental cells, such as the trophoblast, as well as uncovered new roles for structural cells now recognized as active participants in pregnancy and parturition, such as decidual and fetal stromal cells, which are reviewed herein. Furthermore, single-cell data investigating the ontogeny, function, differentiation, and interactions among immune cells present at the maternal-fetal interface, namely macrophages, T cells, dendritic cells, neutrophils, mast cells, innate lymphoid cells, natural killer cells, and B cells are discussed in this review. Moreover, a key output of single-cell investigations is the inference of cell-cell interactions, which has been leveraged to not only dissect the intercellular communications within specific tissues but also between compartments such as the decidua basalis and placental villi. Collectively, this review emphasizes the ways by which single-cell technologies have expanded the understanding of cell composition and cellular processes underlying pregnancy in mid-to-late gestation at the maternal-fetal interface, which can prompt their continued application to reveal new pathways and targets for the treatment of obstetrical disease.
Collapse
Affiliation(s)
- Dustyn Levenson
- Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO; Department of Physiology, Wayne State University School of Medicine, Detroit, MI
| | - Roberto Romero
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD; Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI; Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI
| | - Derek Miller
- Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO
| | - Jose Galaz
- Division of Obstetrics and Gynecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Valeria Garcia-Flores
- Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO
| | - Barbara Neshek
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI
| | - Roger Pique-Regi
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI
| | - Nardhy Gomez-Lopez
- Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
| |
Collapse
|
|
4
|
Wen B, Liao H, Lin W, Li Z, Ma X, Xu Q, Yu F. The Role of TGF-β during Pregnancy and Pregnancy Complications. Int J Mol Sci 2023; 24:16882. [PMID: 38069201 PMCID: PMC10706464 DOI: 10.3390/ijms242316882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/28/2023] [Accepted: 10/03/2023] [Indexed: 12/18/2023] Open
Abstract
Transforming growth factor beta (TGF-β), a multifunctional cytokine, is one of the most important inflammatory cytokines closely related to pregnancy. It plays significant roles in hormone secretion, placental development, and embryonic growth during pregnancy. TGF-β is implicated in embryo implantation and inhibits the invasion of extraepithelial trophoblast cells. It also moderates the mother-fetus interaction by adjusting the secretion pattern of immunomodulatory factors in the placenta, consequently influencing the mother's immune cells. The TGF-β family regulates the development of the nervous, respiratory, and cardiovascular systems by regulating gene expression. Furthermore, TGF-β has been associated with various pregnancy complications. An increase in TGF-β levels can induce the occurrences of pre-eclampsia and gestational diabetes mellitus, while a decrease can lead to recurrent miscarriage due to the interference of the immune tolerance environment. This review focuses on the role of TGF-β in embryo implantation and development, providing new insights for the clinical prevention and treatment of pregnancy complications.
Collapse
Affiliation(s)
- Baohong Wen
- Basic Medical Experiment Teaching Center, Shantou University Medical College, Shantou 515041, China; (B.W.); (H.L.); (W.L.); (Z.L.); (X.M.)
| | - Huixin Liao
- Basic Medical Experiment Teaching Center, Shantou University Medical College, Shantou 515041, China; (B.W.); (H.L.); (W.L.); (Z.L.); (X.M.)
| | - Weilin Lin
- Basic Medical Experiment Teaching Center, Shantou University Medical College, Shantou 515041, China; (B.W.); (H.L.); (W.L.); (Z.L.); (X.M.)
| | - Zhikai Li
- Basic Medical Experiment Teaching Center, Shantou University Medical College, Shantou 515041, China; (B.W.); (H.L.); (W.L.); (Z.L.); (X.M.)
| | - Xiaoqing Ma
- Basic Medical Experiment Teaching Center, Shantou University Medical College, Shantou 515041, China; (B.W.); (H.L.); (W.L.); (Z.L.); (X.M.)
| | - Qian Xu
- Laboratory of Molecular Pathology, Department of Pathology, Shantou University Medical College, Shantou 515041, China
| | - Feiyuan Yu
- Basic Medical Experiment Teaching Center, Shantou University Medical College, Shantou 515041, China; (B.W.); (H.L.); (W.L.); (Z.L.); (X.M.)
- Department of Cell Biology and Genetics, Shantou University Medical College, Shantou 515041, China
| |
Collapse
|
|
5
|
Ersoy Canillioglu Y, Senturk GE, Sahin H, Sahin S, Seval-Celik Y. The Distribution of Foxp3 and CD68 in Preeclamptic and Healthy Placentas: A Histomorphological Evaluation. J Histochem Cytochem 2023; 71:211-225. [PMID: 37070940 PMCID: PMC10149892 DOI: 10.1369/00221554231170662] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 03/27/2023] [Indexed: 04/19/2023] Open
Abstract
Preeclampsia is a complication of pregnancy that affects 3-5% of pregnancies and is one of the major causes of maternal/neonatal mortality and morbidities worldwide. We aimed to investigate the distribution of Foxp3+ regulatory T-cells and CD68+ Hofbauer cells in the placenta of preeclamptic and healthy pregnant women with a special focus on correlating these findings with placental histology. Decidua and chorionic villi of the placenta obtained from healthy and preeclamptic pregnancies were evaluated in full-thickness sections. Sections were stained with hematoxylin and eosin and Masson's trichrome and immunostained for Foxp3 and CD68 for histological analyses. The total histomorphological score for placentas was found to be higher in preeclamptic placentas than that in the controls. The CD68 immunoreactivity was higher in the chorionic villi of preeclamptic placentas than that in the controls. The immunoreactivity of Foxp3 was found widely distributed within the decidua in both the groups and did not differ significantly. Interestingly, Foxp3 immunoreactivity in the chorionic villi was found mainly in the villous core and, to a lesser extent, in the syncytiotrophoblasts. We found no significant relation between Foxp3 expressions and morphological changes observed in preeclamptic placentas. Although extensive research is being carried out regarding the pathophysiology of preeclampsia, the findings are still controversial.
Collapse
Affiliation(s)
| | - Gozde Erkanli Senturk
- Department of Histology and Embryology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Hakan Sahin
- Department of Histology and Embryology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Sadik Sahin
- Department of Obstetrics and Gynecology, Medeniyet University, Istanbul, Turkey
| | - Yasemin Seval-Celik
- Faculty of Medicine, Department of Histology and Embryology, Izmir University of Economics, Izmir, Turkey
| |
Collapse
|
|
6
|
Alteration in IFN-γ and CCL2 serum levels at first trimester of pregnancy contribute to development of preeclampsia and fetal growth restriction. Taiwan J Obstet Gynecol 2023; 62:71-76. [PMID: 36720555 DOI: 10.1016/j.tjog.2022.09.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/12/2022] [Indexed: 01/30/2023] Open
Abstract
OBJECTIVE Pregnancy is a unique challenge for the immune system. Any disturbance in the immune system in the first trimester could result in further pregnancy complications. In this regard, the current study aimed to investigate the association between serum levels of a group of cytokines in the first trimester of pregnancy with the onset of preeclampsia (PE) and fetal growth restriction (FGR). MATERIALS AND METHODS Serum samples were collected from 550 pregnant women at their 11th - 13th weeks of pregnancy and followed up to delivery. Out of all cases, 15 women complicated with preeclampsia and 15 ones diagnosed with FGR were included in the study. The serum levels of IFN-γ, CCL2, IL-10, IL-35 and IL-27 were checked in the collected sera of mentioned patients and compared to 60 women with normal pregnancy outcomes. RESULTS In the preeclampsia group, the mean level of IFN-γ was significantly higher (p < 0.001) while the CCL2 serum level was significantly lower (p < 0.003) as compared to control group. There was no significant difference between the preeclampsia group and controls regarding other cytokines. In the FGR group, the mean serum level of IFN-γ was significantly higher compared to the healthy pregnancy group (p < 0.001) but other cytokines showed no significant differences. In the FGR group, a significant positive correlation was found between IL-10 level and neonates' weight (p < 0.05). CONCLUSION Based on the results of the present study, an elevated level of IFN-γ and a reduced level of CCL2 at the first trimester of pregnancy could lead to complications such as PE and/or FGR.
Collapse
|
|
7
|
Manchorova D, Papadopoulou M, Alexandrova M, Dimitrova V, Djerov L, Zapryanova S, Dimitrova P, Vangelov I, Vermijlen D, Dimova T. Human decidual gamma/delta T cells possess unique effector and TCR repertoire profiles during pregnancy. Cell Immunol 2022; 382:104634. [PMID: 36308817 DOI: 10.1016/j.cellimm.2022.104634] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 08/21/2022] [Accepted: 10/19/2022] [Indexed: 01/13/2023]
Abstract
Human γδ T cells are enriched at the maternal-fetal interface (MFI, decidua basalis) showing a highly differentiated phenotype. However, their functional potential is not well-known and it is not clear whether this decidua-enrichment is associated with specific γδ T cell receptors (TCR) as is observed in mice. Here we addressed these open questions by investigating decidual γδ T cells during early and late gestation, in comparison with paired blood samples, with flow cytometry (cytotoxic mediators, cytokines) and TCR high-throughput sequencing. While decidual γδ T cells expressed less perforin than their counterparts in the blood, they expressed significant more granulysin during early pregnancy. Strikingly, this high granulysin expression was limited to early pregnancy, as it was reduced at term pregnancy. In contrast to this granulysin expression pattern, decidual γδ T cells produced reduced levels of IFNγ and TNFα (compared to paired blood) in early pregnancy that then increased by term pregnancy. TCR repertoire analysis indicated that human decidual γδ T cells are not generated early in life as in the mouse. Despite this, a specific enrichment of the Vγ2 chain in the decidua in early pregnancy was observed that disappeared later onwards, reflecting dynamic changes in the decidual γδ TCR repertoire during human gestation. In conclusion, our data indicate that decidual γδ T cells express a specific and dynamic pattern of cytotoxic mediators, Th1 cytokines and TCR repertoire suggesting an important role for these unconventional T cells in assuring a healthy pregnancy in human.
Collapse
Affiliation(s)
- D Manchorova
- Institute of Biology and Immunology of Reproduction "Acad. K. Bratanov", Bulgarian Academy of Sciences, Sofia 1113, 73 Tzarigradsko shosse blv, Bulgaria
| | - M Papadopoulou
- Department of Pharmacotherapy and Pharmaceutics, Universite Libre de Bruxelles (ULB), 1050 Brussels, Belgium
| | - M Alexandrova
- Institute of Biology and Immunology of Reproduction "Acad. K. Bratanov", Bulgarian Academy of Sciences, Sofia 1113, 73 Tzarigradsko shosse blv, Bulgaria
| | - V Dimitrova
- Medical University, University Obstetrics and Gynecology Hospital "Maichin Dom", Sofia 1463, 2 Zdrave Str., Bulgaria
| | - L Djerov
- Medical University, University Obstetrics and Gynecology Hospital "Maichin Dom", Sofia 1463, 2 Zdrave Str., Bulgaria
| | - S Zapryanova
- Institute of Biology and Immunology of Reproduction "Acad. K. Bratanov", Bulgarian Academy of Sciences, Sofia 1113, 73 Tzarigradsko shosse blv, Bulgaria
| | - P Dimitrova
- Institute of Microbiology "Acad. St. Angelov", Bulgarian Academy of Sciences, Sofia 1113, 25 Acad. G. Bonchev str., Bulgaria
| | - I Vangelov
- Institute of Biology and Immunology of Reproduction "Acad. K. Bratanov", Bulgarian Academy of Sciences, Sofia 1113, 73 Tzarigradsko shosse blv, Bulgaria
| | - D Vermijlen
- Department of Pharmacotherapy and Pharmaceutics, Universite Libre de Bruxelles (ULB), 1050 Brussels, Belgium; Institute for Medical Immunology, Universitȇ Libre de Bruxelles (ULB), 6041 Gosselies, Belgium; ULB Center for Research in Immunology (U-CRI), Universite Libre de Bruxelles (ULB), Belgium; Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Wavre, Belgium
| | - T Dimova
- Institute of Biology and Immunology of Reproduction "Acad. K. Bratanov", Bulgarian Academy of Sciences, Sofia 1113, 73 Tzarigradsko shosse blv, Bulgaria.
| |
Collapse
|
|
8
|
Ribeiro VR, Romao-Veiga M, Nunes PR, de Oliveira LRC, Romagnoli GG, Peracoli JC, Peracoli MTS. Silibinin downregulates the expression of the Th1 and Th17 profiles by modulation of STATs and transcription factors in pregnant women with preeclampsia. Int Immunopharmacol 2022; 109:108807. [DOI: 10.1016/j.intimp.2022.108807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 04/18/2022] [Accepted: 04/24/2022] [Indexed: 11/29/2022]
|
|
9
|
Romao-Veiga M, Ribeiro VR, Matias ML, Nunes PR, Romagnoli GG, Peracoli JC, Peracoli MTS. DAMPs are able to skew CD4 + T cell subsets and increase the inflammatory profile in pregnant women with preeclampsia. J Reprod Immunol 2021; 149:103470. [PMID: 34972043 DOI: 10.1016/j.jri.2021.103470] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 12/17/2021] [Accepted: 12/23/2021] [Indexed: 12/24/2022]
Abstract
Preeclampsia (PE) is characterized by abnormal activation of the immune system. The intense systemic inflammatory reaction, could be related to the presence of molecules released after cell stress or death, that are capable of inducing inflammation and are known as damage-associated molecular patterns (DAMP). This study evaluated the profile of T cells through the analysis of transcription factors and the cytokines produced after culture with or without DAMPs: heat shock protein 70 (Hsp70), hyaluronan (HA) and monosodium urate (MSU). Twenty pregnant women with PE, 20 normotensive (NT) pregnant women and 20 non-pregnant (NP) women were studied. The results showed polarization toward Th1/Th17 and a decrease in Th2/Treg profiles in preeclamptic women associated with elevated levels of TNF, IFN-γ, and IL-17A and diminished levels of TGF-β1 and IL-10 when compared to the normotensive group. In addition, preeclamptic women had a higher percentage of cells co-expressing T-bet/GATA-3 and T-bet/RORγt and fewer T-bet/FoxP3 cells when compared to normotensive group. MSU induced an increase in IFN-γ and IL-22 in all studied groups. MSU, HA, and Hsp70 induced significant higher production of TNF in the PE and NP groups. The PE group showed elevated levels of TGF-β1 after incubation with MSU, HA, and Hsp70, whereas HA and Hsp70 decreased TGF-β1 production in NT group. The results suggest that these alarmins may play a role in the activation of innate and adaptive immune systems by skewing CD4 + T cells and increasing the release of inflammatory cytokines, thereby contributing to the pathogenesis of this important syndrome.
Collapse
Affiliation(s)
- Mariana Romao-Veiga
- Department of Chemistry and Biological Sciences, Institute of Biosciences, Sao Paulo State University - Unesp, Botucatu, Sao Paulo, Brazil.
| | - Vanessa Rocha Ribeiro
- Department de Gynecology and Obstetrics, Botucatu Medical School, Sao Paulo State University - Unesp, Botucatu, Sao Paulo, Brazil
| | - Mariana Leticia Matias
- Department de Gynecology and Obstetrics, Botucatu Medical School, Sao Paulo State University - Unesp, Botucatu, Sao Paulo, Brazil
| | - Priscila Rezeck Nunes
- Department de Gynecology and Obstetrics, Botucatu Medical School, Sao Paulo State University - Unesp, Botucatu, Sao Paulo, Brazil
| | | | - Jose Carlos Peracoli
- Department de Gynecology and Obstetrics, Botucatu Medical School, Sao Paulo State University - Unesp, Botucatu, Sao Paulo, Brazil
| | - Maria Terezinha Serrao Peracoli
- Department of Chemistry and Biological Sciences, Institute of Biosciences, Sao Paulo State University - Unesp, Botucatu, Sao Paulo, Brazil
| |
Collapse
|
|
10
|
Ribeiro VR, Romao-Veiga M, Nunes PR, Matias ML, Peracoli JC, Peracoli MTS. Vitamin D modulates the transcription factors of T cell subsets to anti-inflammatory and regulatory profiles in preeclampsia. Int Immunopharmacol 2021; 101:108366. [PMID: 34810124 DOI: 10.1016/j.intimp.2021.108366] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 10/27/2021] [Accepted: 11/09/2021] [Indexed: 12/24/2022]
Abstract
Vitamin D (VD) is a multifunctional prohormone and low VD status in pregnancy may contribute to the risk of adverse perinatal outcomes, such as preeclampsia (PE). This molecule may modulate the polarization of T cell subsets during gestation. This study evaluated the in vitro immunomodulatory effect of VD [1,25(OH)2D3] on the gene expression of transcription factors and on cytokine production by T cell subsets. Twenty pregnant women with PE and twenty normotensive (NT) pregnant women were studied. Plasma concentration of VD, [25(OH)D3], was evaluated by chemiluminescence. PBMCs from preeclamptic and NT pregnant women were cultured in the absence or presence of VD to determine gene expression of T-bet (Th1), GATA-3 (Th2), RORγt, and RUNX1 (Th17), FoxP3 (regulatory T cell- Treg), and the receptors of VD (VDR) and IL-23 (IL-23R) by quantitative PCR. The concentration of cytokines in the PBMC supernatant culture was determined by cytometric bead array and ELISA immunoassay. The results showed that plasmatic levels of VD were significantly lower in the PE group. The treatment of PBMCs from PE pregnant women with VD induced downregulation of genes related to inflammatory profiles (Th1 and Th17), as well as an increase of the Th2 and Treg profiles. Thus, VD treatment decreased the release of IFN-γ, TNF-α, IL-17, IL-6, and IL-23 while it increased the levels of IL-10 in the PE group. VD induces an immunomodulatory effect in T cell subsets from pregnant women with PE, polarizing these cells to an anti-inflammatory and regulatory profile.
Collapse
Affiliation(s)
- Vanessa Rocha Ribeiro
- Department of Gynecology and Obstetrics, Botucatu Medical School, Sao Paulo State University-UNESP, Botucatu, Sao Paulo, Brazil.
| | - Mariana Romao-Veiga
- Department of Gynecology and Obstetrics, Botucatu Medical School, Sao Paulo State University-UNESP, Botucatu, Sao Paulo, Brazil
| | - Priscila Rezeck Nunes
- Department of Gynecology and Obstetrics, Botucatu Medical School, Sao Paulo State University-UNESP, Botucatu, Sao Paulo, Brazil
| | - Mariana Leticia Matias
- Department of Gynecology and Obstetrics, Botucatu Medical School, Sao Paulo State University-UNESP, Botucatu, Sao Paulo, Brazil
| | - Jose Carlos Peracoli
- Department of Gynecology and Obstetrics, Botucatu Medical School, Sao Paulo State University-UNESP, Botucatu, Sao Paulo, Brazil
| | - Maria Terezinha Serrao Peracoli
- Department of Gynecology and Obstetrics, Botucatu Medical School, Sao Paulo State University-UNESP, Botucatu, Sao Paulo, Brazil; Department of Chemistry and Biological Sciences, Institute of Biosciences, Sao Paulo State University-UNESP, Botucatu, Sao Paulo, Brazil
| |
Collapse
|
|
11
|
Wu H, Huang Q, Zhang X, Yu Z, Zhong Z. Analysis of Genomic Copy Number Variation in Miscarriages During Early and Middle Pregnancy. Front Genet 2021; 12:732419. [PMID: 34603391 PMCID: PMC8484914 DOI: 10.3389/fgene.2021.732419] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 08/31/2021] [Indexed: 12/13/2022] Open
Abstract
The purpose of this study was to explore the copy number variations (CNVs) associated with miscarriage during early and middle pregnancy and provide useful genetic guidance for pregnancy and prenatal diagnosis. A total of 505 fetal specimens were collected and CNV sequencing (CNV-seq) analysis was performed to determine the types and clinical significance of CNVs, and relevant medical records were collected. The chromosomal abnormality rate was 54.3% (274/505), among which the numerical chromosomal abnormality rate was 40.0% (202/505) and structural chromosomal abnormality rate was 14.3% (72/505). Chromosomal monosomy mainly occurred on sex chromosomes, and chromosomal trisomy mainly occurred on chromosomes 16, 22, 21, 15, 13, and 9. The incidence of numerical chromosomal abnormalities in ≥35 year-old age pregnant women was significantly higher than <35 year-old age group. The highest incidence of pathogenic CNV (pCNV) was found in fetuses at ≤6 weeks of pregnancy (5.26%), and the incidence of variants of unknown significance (VOUS) CNVs decreased gradually with the increase of gestational age. The rate of chromosomal abnormalities of fetuses in early pregnancy (59.5%) was higher than that of fetuses in middle pregnancy (27.2%) (p < 0.001). There were 168 genes in VOUS + pCNV regions. 41 functions and 12 pathways (p < 0.05) were enriched of these genes by Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Some meaningful genetic etiology information such as genes and pathways has been obtained, it may provide useful genetic guidance for pregnancy and prenatal diagnosis.
Collapse
Affiliation(s)
- Heming Wu
- Center for Precision Medicine, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China.,Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China
| | - Qingyan Huang
- Center for Precision Medicine, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China.,Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China
| | - Xia Zhang
- Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China.,Center for Prenatal Diagnosis, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China
| | - Zhikang Yu
- Center for Precision Medicine, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China.,Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China
| | - Zhixiong Zhong
- Center for Precision Medicine, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China.,Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China
| |
Collapse
|
|
12
|
Yoo I, Kye YC, Han J, Kim M, Lee S, Jung W, Hong M, Park TS, Yun CH, Ka H. Uterine epithelial expression of the tumor necrosis factor superfamily: a strategy for immune privilege during pregnancy in a true epitheliochorial placentation species. Biol Reprod 2021; 102:828-842. [PMID: 31901087 DOI: 10.1093/biolre/ioz233] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 09/06/2020] [Accepted: 12/31/2019] [Indexed: 12/13/2022] Open
Abstract
The maternal immune system tolerates semi-allogeneic placental tissues during pregnancy. Fas ligand (FASLG) and tumor necrosis factor superfamily 10 (TNFSF10) are known to be components of maternal immune tolerance in humans and mice. However, the role of FASLG and TNFSF10 in the tolerance process has not been studied in pigs, which form a true epitheliochorial type placenta. Thus, the present study examined the expression and function of FASLG and TNFSF10 and their receptors at the maternal-conceptus interface in pigs. The endometrium and conceptus tissues expressed FASLG and TNFSF10 and their receptor mRNAs during pregnancy in a stage-specific manner. During pregnancy, FASLG and TNFSF10 proteins were localized predominantly to endometrial luminal epithelial cells with strong signals on Day 30 to term and on Day 15, respectively, and receptors for TNFSF10 were localized to some stromal cells. Interferon-γ (IFNG) increased the expression of TNFSF10 and FAS in endometrial tissues. Co-culture of porcine endometrial epithelial cells over-expressing TNFSF10 with peripheral blood mononuclear cells yielded increased apoptotic cell death of lymphocytes and myeloid cells. In addition, many apoptotic T cells were found in the endometrium on Day 15 of pregnancy. The present study demonstrated that FASLG and TNFSF10 were expressed at the maternal-conceptus interface and conceptus-derived IFNG increased endometrial epithelial TNFSF10, which, in turn, induced apoptotic cell death of immune cells. These results suggest that endometrial epithelial FASLG and TNFSF10 may be critical for the formation of micro-environmental immune privilege at the maternal-conceptus interface for the establishment and maintenance of pregnancy in pigs.
Collapse
Affiliation(s)
- Inkyu Yoo
- Division of Biological Science and Technology, Yonsei University, Wonju, 26493
| | - Yoon Chul Kye
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, 08826
| | - Jisoo Han
- Division of Biological Science and Technology, Yonsei University, Wonju, 26493
| | - Minjeong Kim
- Division of Biological Science and Technology, Yonsei University, Wonju, 26493
| | - Soohyung Lee
- Division of Biological Science and Technology, Yonsei University, Wonju, 26493
| | - Wonchul Jung
- Division of Biological Science and Technology, Yonsei University, Wonju, 26493
| | - Minsun Hong
- Division of Biological Science and Technology, Yonsei University, Wonju, 26493
| | - Tae Sub Park
- Graduate School of International Agricultural Technology and Institute of Green-Bio Science and Technology, Seoul National University, Pyeongchang, 25354, Republic of Korea
| | - Cheol-Heui Yun
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, 08826
| | - Hakhyun Ka
- Division of Biological Science and Technology, Yonsei University, Wonju, 26493
| |
Collapse
|
|
13
|
The function of adipsin and C9 protein in the complement system in HIV-associated preeclampsia. Arch Gynecol Obstet 2021; 304:1467-1473. [PMID: 33881585 DOI: 10.1007/s00404-021-06069-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 04/09/2021] [Indexed: 12/27/2022]
Abstract
OBJECTIVE In preeclampsia, there are excessive complement components expressed due to increased complement activation; therefore, this study investigated the concentration of adipsin and C9 in HIV-associated preeclampsia. METHOD The study population (n = 76) was stratified by pregnancy type (normotensive pregnant and preeclampsia) and by HIV status. Serum was assayed for the concentration of adipsin and C9 using a Bioplex immunoassay procedure. RESULTS Maternal weight did not differ (p = 0.1196) across the study groups. The concentration of adipsin was statistically different between the PE vs normotensive pregnant groups, irrespective of HIV status (p = 0.0439). There was no significant difference in adipsin concentration between HIV-negative vs HIV-positive groups, irrespective of pregnancy type (p = 0.6290). Additionally, there was a significant difference in adipsin concentration between HIV-negative normotensive vs HIV-negative preeclampsia (p < 0.05), as well as a difference between HIV-negative preeclampsia vs HIV-positive preeclampsia (p < 0.05). C9 protein expression was not statistically different between the normotensive and PE groups, regardless of HIV status (p = 0.5365). No statistical significance in C9 expression was found between HIV-positive vs HIV-negative groups, regardless of pregnancy type (p = 0.3166). Similarly, no statistical significance was noted across all study groups (p = 0.0774). CONCLUSION This study demonstrates that there is a strong correlation between the up-regulation of adipsin and PE and that adipsin is a promising biomarker to use as a diagnostic tool for PE.
Collapse
|
|
14
|
Feng X, Liu Y, Zhang Y, Zhang Y, Li H, Zheng Q, Li N, Tang J, Xu Z. New views on endothelial dysfunction in gestational hypertension and potential therapy targets. Drug Discov Today 2021; 26:1420-1436. [PMID: 33677145 DOI: 10.1016/j.drudis.2021.03.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 09/10/2020] [Accepted: 03/01/2021] [Indexed: 12/14/2022]
Abstract
The placenta has vital roles in metabolite exchange, fetal growth, and pre-eclampsia (PE). In this review, we discuss the pathogenesis of hypertension in pregnancy, focusing on four major theories to explain PE, discussing endothelial roles in those theories. We focus in particular on the roles of nitric oxide (NO) and prostacyclin (PGI2) in placental endothelium, and propose new hypotheses for the influence and mechanisms of endothelial NO and PGI2 signaling pathways in PE.
Collapse
Affiliation(s)
- Xueqin Feng
- First Hospital of Soochow University & Maternal and Child Health Care Hospital of Wuxi, Jiangsu, China; Department of Obstetrics, Affiliated Hospital of Jining Medical University, Shandong, China
| | - Yanping Liu
- First Hospital of Soochow University & Maternal and Child Health Care Hospital of Wuxi, Jiangsu, China
| | - Yingying Zhang
- First Hospital of Soochow University & Maternal and Child Health Care Hospital of Wuxi, Jiangsu, China
| | - Yumeng Zhang
- First Hospital of Soochow University & Maternal and Child Health Care Hospital of Wuxi, Jiangsu, China
| | - Huan Li
- First Hospital of Soochow University & Maternal and Child Health Care Hospital of Wuxi, Jiangsu, China
| | - Qiutong Zheng
- First Hospital of Soochow University & Maternal and Child Health Care Hospital of Wuxi, Jiangsu, China
| | - Na Li
- First Hospital of Soochow University & Maternal and Child Health Care Hospital of Wuxi, Jiangsu, China
| | - Jiaqi Tang
- First Hospital of Soochow University & Maternal and Child Health Care Hospital of Wuxi, Jiangsu, China.
| | - Zhice Xu
- First Hospital of Soochow University & Maternal and Child Health Care Hospital of Wuxi, Jiangsu, China.
| |
Collapse
|
|
15
|
Bakrania BA, Spradley FT, Drummond HA, LaMarca B, Ryan MJ, Granger JP. Preeclampsia: Linking Placental Ischemia with Maternal Endothelial and Vascular Dysfunction. Compr Physiol 2020; 11:1315-1349. [PMID: 33295016 PMCID: PMC7959189 DOI: 10.1002/cphy.c200008] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Preeclampsia (PE), a hypertensive disorder, occurs in 3% to 8% of pregnancies in the United States and affects over 200,000 women and newborns per year. The United States has seen a 25% increase in the incidence of PE, largely owing to increases in risk factors, including obesity and cardiovascular disease. Although the etiology of PE is not clear, it is believed that impaired spiral artery remodeling of the placenta reduces perfusion, leading to placental ischemia. Subsequently, the ischemic placenta releases antiangiogenic and pro-inflammatory factors, such as cytokines, reactive oxygen species, and the angiotensin II type 1 receptor autoantibody (AT1-AA), among others, into the maternal circulation. These factors cause widespread endothelial activation, upregulation of the endothelin system, and vasoconstriction. In turn, these changes affect the function of multiple organ systems including the kidneys, brain, liver, and heart. Despite extensive research into the pathophysiology of PE, the only treatment option remains early delivery of the baby and importantly, the placenta. While premature delivery is effective in ameliorating immediate risk to the mother, mounting evidence suggests that PE increases risk of cardiovascular disease later in life for both mother and baby. Notably, these women are at increased risk of hypertension, heart disease, and stroke, while offspring are at risk of obesity, hypertension, and neurological disease, among other complications, later in life. This article aims to discuss the current understanding of the diagnosis and pathophysiology of PE, as well as associated organ damage, maternal and fetal outcomes, and potential therapeutic avenues. © 2021 American Physiological Society. Compr Physiol 11:1315-1349, 2021.
Collapse
Affiliation(s)
- Bhavisha A. Bakrania
- Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi, USA
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Frank T. Spradley
- Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi, USA
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA
- Department of Surgery, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Heather A. Drummond
- Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi, USA
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Babbette LaMarca
- Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi, USA
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Michael J. Ryan
- Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi, USA
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Joey P. Granger
- Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi, USA
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA
| |
Collapse
|
|
16
|
Ayers CD, Carlson KS. Spontaneous Pregnancy in the Setting of Primary Ovarian Insufficiency and Breastfeeding: Does Immunosuppression Play a Role? AMERICAN JOURNAL OF CASE REPORTS 2020; 21:e926980. [PMID: 33127872 PMCID: PMC7643410 DOI: 10.12659/ajcr.926980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Patient: Female, 34-year-old Final Diagnosis: Pregnancy • premature ovarian insufficiency Symptoms: Amenorrhea • pregnancy Medication: — Clinical Procedure: — Specialty: Obstetrics and Gynecology
Collapse
Affiliation(s)
- Caleb D Ayers
- College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Karen S Carlson
- Department of Obstetrics and Gynecology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| |
Collapse
|
|
17
|
Zhao Y, Zhang X, Du N, Sun H, Chen L, Bao H, Zhao Q, Qu Q, Ma D, Kwak-Kim J, Wang WJ. Immune checkpoint molecules on T cell subsets of pregnancies with preeclampsia and gestational diabetes mellitus. J Reprod Immunol 2020; 142:103208. [PMID: 33002799 DOI: 10.1016/j.jri.2020.103208] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 09/01/2020] [Accepted: 09/08/2020] [Indexed: 12/11/2022]
Abstract
Immune checkpoint molecules may play a crucial role in safeguarding pregnancy by regulating immune responses at the maternal-fetal interface. In this study, we aim to investigate the expression of PD-1, GITR, HLA-G, and CTLA-4 on T cell subsets in peripheral blood (PB), retroplacental blood (RPB), and cord blood (CB) in normal pregnancy (NP), preeclampsia (PE) and gestational diabetes mellitus (GDM). PB, RPB, and CB were collected immediately after delivery, and the expression of PD-1, GITR, HLA-G, and CTLA-4 on T cell subsets were measured by flow cytometric analysis. The proportions of Tregs in PB, RPB, and CB from NP were significantly higher than those of PE and GDM (P < 0.01, respectively). PD-1+ and GITR+ T cell subsets (CD3+, CD4+, and CD8+ T cells, and Tregs) in PB, as well as PD-1+ T cell subsets in RPB from NP, were significantly higher than those of PE and GDM (P < 0.01, respectively). In NP, PE, and GDM, the proportion of PD-1+ Tregs was significantly decreased in CB as compared to those of PB and RPB (P < 0.05, respectively) and the proportion of GITR+ Tregs was significantly higher in PB as compared to those of CB and RPB (P < 0.01, respectively). The proportion of HLA-G+ Tregs in PB was significantly lower than those of CB and RPB (P < 0.01, respectively). In conclusion, decreased PD-1+ and GITR+ T cell subsets and decreased proportion of Tregs in PB and RPB may play a role in chronic inflammatory immune activation of effector T cells in PE and GDM.
Collapse
Affiliation(s)
- Yuanyuan Zhao
- Reproduction Medical Center, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, 20 Yuhuangding East Road, Yantai, 264000, PR China; Qilu Medical University, 2018 Jiang Meng Road, Zibo, 255300, PR China
| | - Xiaolu Zhang
- Department of Clinical Laboratory, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, 20 Yuhuangding East Road, Yantai, 264000, PR China
| | - Ning Du
- Department of Clinical Pharmacy, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, 20 Yuhuangding East Road, Yantai, 264000, PR China
| | - Hong Sun
- Department of Obstetrics and Gynecology, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, 20 Yuhuangding East Road, Yantai, 264000, PR China
| | - Lei Chen
- Department of Clinical Laboratory, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, 20 Yuhuangding East Road, Yantai, 264000, PR China
| | - Hongchu Bao
- Reproduction Medical Center, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, 20 Yuhuangding East Road, Yantai, 264000, PR China
| | - Quan Zhao
- Department of Clinical Pharmacy, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, 20 Yuhuangding East Road, Yantai, 264000, PR China
| | - Qinglan Qu
- Reproduction Medical Center, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, 20 Yuhuangding East Road, Yantai, 264000, PR China
| | - Ding Ma
- Reproduction Medical Center, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, 20 Yuhuangding East Road, Yantai, 264000, PR China
| | - Joanne Kwak-Kim
- Department of Obstetrics and Gynecology, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, 20 Yuhuangding East Road, Yantai, 264000, PR China; Microbiology and Immunology, Department of Foundational Science and Humanities, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA
| | - Wen-Juan Wang
- Reproduction Medical Center, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, 20 Yuhuangding East Road, Yantai, 264000, PR China; Reproductive Medicine and Immunology, Obstetrics and Gynecology, Department of Clinical Sciences, Chicago Medical School, Rosalind Franklin University of Medicine and Science, Vernon Hills, IL, 60061, USA.
| |
Collapse
|
|
18
|
Wang W, Sung N, Gilman-Sachs A, Kwak-Kim J. T Helper (Th) Cell Profiles in Pregnancy and Recurrent Pregnancy Losses: Th1/Th2/Th9/Th17/Th22/Tfh Cells. Front Immunol 2020; 11:2025. [PMID: 32973809 PMCID: PMC7461801 DOI: 10.3389/fimmu.2020.02025] [Citation(s) in RCA: 256] [Impact Index Per Article: 51.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 07/27/2020] [Indexed: 12/15/2022] Open
Abstract
During pregnancy, various immune effectors and molecules participating in the immune-microenvironment establish specific maternal tolerance toward the semi-allogeneic fetus. Activated maternal immune effectors by the trophoblast antigens, such as T helper (Th), T cytotoxic (Tc), T regulatory (Treg), and B cells, are involved in the regulation of adaptive immunity. Recognition of active signal through the T cell receptors stimulate the differentiation of naive CD3+CD4+ T cells into specific T cell subsets, such as Th1, Th2, Th9, Th17, Th22, and follicular Th cells (Tfh). Each of these subsets has a significant and distinct role in human pregnancy. Th1 immunity, characterized by immune-inflammatory responses, becomes dominant during the peri-implantation period, and the “controlled” Th1 immunity benefits the invading trophoblasts rather than harm. Quickly after the placental implantation, the early inflammatory Th1 immunity is shifted to the Th2 anti-inflammatory immune responses. The predominant Th2 immunity, which overrules the Th1 immunity at the placental implantation site, protects a fetus by balancing Th1 immunity and accommodate fetal and placental development. Moreover, Treg and Th9 cells regulate local inflammatory immune responses, potentially detrimental to the fetus. Th17 cells induce protective immunity against extracellular microbes during pregnancy. However, excessive Th17 immunity may induce uncontrolled neutrophil infiltration at the maternal-fetal interface. Other Th cell subsets such as Tfh cells, also contribute to pregnancy by setting up favorable humoral immunity during pregnancy. However, dysregulation of Th cell immunity during pregnancy may result in obstetrical complications, such as recurrent pregnancy losses (RPL) and preeclampsia (PE). With this review, we intend to deliver a comprehensive overview of CD4+ Th cell subsets, including Th1, Th2, Th9, Th17, Th22, and Tfh cells, in human pregnancy by reviewing their roles in normal and pathological pregnancies.
Collapse
Affiliation(s)
- Wenjuan Wang
- Reproductive Medicine and Immunology, Obstetrics and Gynecology, Department of Clinical Sciences, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States.,Reproductive Medicine Center, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Nayoung Sung
- Reproductive Medicine and Immunology, Obstetrics and Gynecology, Department of Clinical Sciences, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Alice Gilman-Sachs
- Center for Cancer Cell Biology, Immunology and Infection, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States.,Clinical Immunology Laboratory, Center for Cancer Cell Biology, Immunology and Infection, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Joanne Kwak-Kim
- Reproductive Medicine and Immunology, Obstetrics and Gynecology, Department of Clinical Sciences, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States.,Center for Cancer Cell Biology, Immunology and Infection, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| |
Collapse
|
|
19
|
Orlovic Vlaho M, Tomic V, Vukojevic K, Vasilj A, Pejic R, Lesko J, Soljic V. CD25 + FOXP3 + and CD4 + CD25 + cells distribution in decidual departments of women with severe and mild pre-eclampsia: Comparison with healthy pregnancies. Am J Reprod Immunol 2020; 84:e13281. [PMID: 32485016 DOI: 10.1111/aji.13281] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 05/01/2020] [Accepted: 05/26/2020] [Indexed: 01/07/2023] Open
Abstract
PROBLEM The aim of this study was to quantify and compare the distribution of regulatory CD25+ FOXP3+ and activated CD4+ CD25+ T cells in decidua basalis and parietalis of severe and mild pre-eclampsia (PE) to normal healthy pregnancies. METHOD OF STUDY Decidual tissue (decidua basalis and parietalis) of 13 women with mild PE, 15 women with severe PE, and 19 women with healthy term pregnancies were analyzed by immunohistochemistry and double immunofluorescence. RESULTS The total number of CD25+ FOXP3+ cells/mm2 in decidua basalis was decreased in the severe and mild PE versus normal pregnancy group. The total number of CD4+ CD25+ cells/mm2 in decidua basalis was decreased in the severe PE versus normal pregnancy group. The number of CD25+ FOXP3+ and CD4+ CD25+ cells in decidua parietalis was decreased in both PE groups. CONCLUSION Our data suggest that immunological changes of PE reflect on decidua basalis and parietalis and emphasize the importance of characterizing T cells in both decidual departments.
Collapse
Affiliation(s)
- Martina Orlovic Vlaho
- Department of Obstetrics, Gynecology University Clinical Hospital Mostar, Mostar, Bosnia and Herzegovina
| | - Vajdana Tomic
- Department of Obstetrics, Gynecology University Clinical Hospital Mostar, Mostar, Bosnia and Herzegovina.,Faculty of Health Studies, University of Mostar, Mostar, Bosnia and Herzegovina
| | - Katarina Vukojevic
- Laboratory of Morphology, Department of Histology and Embryology, School of Medicine, University of Mostar, Mostar, Bosnia and Herzegovina.,Laboratory for Early Human Development, Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, Split, Croatia
| | - Anja Vasilj
- Department of Obstetrics, Gynecology University Clinical Hospital Mostar, Mostar, Bosnia and Herzegovina
| | - Renato Pejic
- University Clinical Hospital Mostar, Mostar, Bosnia and Herzegovina
| | - Josip Lesko
- University Clinical Hospital Mostar, Mostar, Bosnia and Herzegovina
| | - Violeta Soljic
- Laboratory of Morphology, Department of Histology and Embryology, School of Medicine, University of Mostar, Mostar, Bosnia and Herzegovina
| |
Collapse
|
|
20
|
Ma Y, Yang Q, Fan M, Zhang L, Gu Y, Jia W, Li Z, Wang F, Li YX, Wang J, Li R, Shao X, Wang YL. Placental endovascular extravillous trophoblasts (enEVTs) educate maternal T-cell differentiation along the maternal-placental circulation. Cell Prolif 2020; 53:e12802. [PMID: 32291850 PMCID: PMC7260064 DOI: 10.1111/cpr.12802] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 03/04/2020] [Accepted: 03/11/2020] [Indexed: 12/27/2022] Open
Abstract
Objectives During human pregnancy, the endothelial cells of the uterine spiral arteries (SPA) are extensively replaced by a subtype of placental trophoblasts, endovascular extravillous trophoblasts (enEVTs), thus establishing a placental‐maternal circulation. On this pathway, foetus‐derived placental villi and enEVTs bath into the maternal blood that perfuses along SPA being not attacked by the maternal lymphocytes. We aimed to reveal the underlying mechanism of such immune tolerance. Methods In situ hybridization, immunofluorescence, ELISA and FCM assay were performed to examine TGF‐β1 expression and distribution of regulatory T cells (Tregs) along the placental‐maternal circulation route. The primary enEVTs, interstitial extravillous trophoblasts (iEVTs) and decidual endothelial cells (dECs) were purified by FACS, and their conditioned media were collected to treat naïve CD4+ T cells. Treg differentiation was measured by FLOW and CFSE assays. Results We found that enEVTs but not iEVTs or dECs actively produced TGF‐β1. The primary enEVTs significantly promoted naïve CD4+ T‐cell differentiation into immunosuppressive FOXP3+ Tregs, and this effect was dependent on TGF‐β1. In recurrent spontaneous abortion (RSA) patients, an evidently reduced proportion of TGF‐β1–producing enEVTs and their ability to educate Tregs differentiation were observed. Conclusions Our findings demonstrate a unique immune‐regulatory characteristic of placental enEVTs to develop immune tolerance along the placental‐maternal circulation. New insights into the pathogenesis of RSA are also suggested.
Collapse
Affiliation(s)
- Yeling Ma
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Qian Yang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, China
| | - Mengjie Fan
- Department of Gynecology and Obstetrics, Peking University Third Hospital, Beijing, China
| | - Lanmei Zhang
- Department of Gynecology and Obstetrics, The 306 Hospital of PLA, Beijing, China
| | - Yan Gu
- Second Hospital Affiliated to Tianjin Medical University, Tianjin, China
| | - Wentong Jia
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Zhilang Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Feiyang Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Yu-Xia Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Jian Wang
- NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, China
| | - Rong Li
- Department of Gynecology and Obstetrics, Peking University Third Hospital, Beijing, China
| | - Xuan Shao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Yan-Ling Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| |
Collapse
|
|
21
|
Zhang Y, Zhang Y, Li C, Fu S, Yang C, Song Y, Liu M, Wang Z, Liang P, Zhang J. NOD1 modulates decidual stromal cell function to maintain pregnancy in the early trimester. Cell Biochem Funct 2019; 37:464-473. [PMID: 31396989 DOI: 10.1002/cbf.3417] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Revised: 04/06/2019] [Accepted: 05/08/2019] [Indexed: 12/14/2022]
Abstract
We sought to explore the functions and modulated factors of NOD1 in normal decidual stromal cells (DSCs) derived from the first trimester pregnancy and whether existed different expression of NOD1 between normal and unexplained recurrent pregnancy loss (URPL) in DSCs. Twenty-six patients with normal pregnancies that required abortion and 12 URPL patients at first trimester were enrolled for the study. As a result, we found lower levels of NOD1 in the DSCs derived from URPL compared with those from normal early trimester pregnancy. Furthermore, increased NOD1 expression in the normal DSCs induced apoptosis and increased monocyte chemotactic protein-1 (MCP-1) and IL-1β (interleukin 1 beta) secretion but decreased their invasion capacity. In addition, several cytokines such as IL-1β, tumour necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and interleukin-17 (IL-17) were present at the maternal-fetal interface in RPL and were found to regulate NOD1 expression in primary DSCs. Our study indicates that RPL may be associated with NOD1 aberrant expression in DSCs, which plays a significant role in maintaining pregnancy via infection control and regulation of immune responses that might affect the pregnancy outcome. We expect that our results will bring more comprehensively understanding about the connection between NOD1 and RPL for researchers.
Collapse
Affiliation(s)
- Yuanyuan Zhang
- Department of Gynecologic Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Panjiayuan, Chaoyang District, 100021, Beijing, P.R. China
| | - Yuhui Zhang
- Department of Reproductive Center, Gynecology and Obstetric, Henan Provincial People's Hospital of Zhengzhou University, Jinshui Area, 450003, Zhengzhou, Henan, P.R. China
| | - Chunmei Li
- Department of Reproductive Center, Gynecology and Obstetric, Henan Provincial People's Hospital of Zhengzhou University, Jinshui Area, 450003, Zhengzhou, Henan, P.R. China
| | - Shuai Fu
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Chunfeng Yang
- Department of Obstetrics and Gynecology, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yan Song
- Department of Reproductive Center, Gynecology and Obstetric, Henan Provincial People's Hospital of Zhengzhou University, Jinshui Area, 450003, Zhengzhou, Henan, P.R. China
| | - Meilan Liu
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zhenhua Wang
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Peili Liang
- Department of Obstetrics and Gynecology, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jianping Zhang
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| |
Collapse
|
|
22
|
Pillay P, Moodley K, Vatish M, Moodley J, Duarte R, Mackraj I. Exosomal Th1/Th2 cytokines in preeclampsia and HIV-positive preeclamptic women on highly active anti-retroviral therapy. Cytokine 2019; 125:154795. [PMID: 31398625 DOI: 10.1016/j.cyto.2019.154795] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 07/02/2019] [Accepted: 07/27/2019] [Indexed: 01/19/2023]
Abstract
Preeclampsia (PE) is a hypertensive disorder of pregnancy which is a leading cause of maternal and foetal morbidity and mortality. Furthermore, HIV/Highly Active Anti-Retroviral Treatment has been associated with the increased risk of preeclampsia due to maternal immune reconstitution, which complicates the clinical diagnosis of PE in these patients. It is therefore necessary to identify biomarkers involved in the pathology of both disorders with the intent to diagnose. Exosomal cytokines represent ideal biomarkers of PE and inflammatory conditions due to their immunomodulatory role in pregnancy. We therefore quantified exosomal Th1 (IL-2 and TNF-α) and Th2 cytokines (IL-10) in maternal circulation. A significant dysregulation in total exosomes, placental-derived exosomes and exosomal cytokines in PE and HIV-positive PE pregnant woman on Highly Active Antiretroviral Treatment (HAART) was observed (p < 0.01). Additionally, we observed a significant shift towards Th1 immunity in PE which becomes amplified in HIV-positive PE pregnant woman on HAART (p < 0.01). Moreover, we show the potential application of exosomal Tumor necrosis factor alpha (TNF-α) as a biomarker of PE and PE in HIV-positive pregnant women on HAART (CI: 95%, LHR > 10, sensitivity of 100% and specificity of 90%). These findings are in support of exosome release and exosome cytokine encapsulation as a tightly regulated process in favour of maintaining the immune microenvironment, which can orchestrate either normal pregnancy, or the pathogenesis of preeclampsia and preeclampsia in HIV/HAART pregnancies.
Collapse
Affiliation(s)
- Preenan Pillay
- Discipline of Human Physiology, School of Laboratory Medicine & Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Kogi Moodley
- Discipline of Human Physiology, School of Laboratory Medicine & Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Manu Vatish
- Nuffield Department of Women's & Reproductive Health, Women's Centre, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Jagidesa Moodley
- Women's Health and HIV Research Group, Department of Obstetrics and Gynaecology, University of KwaZulu-Natal, Durban, South Africa
| | - Raquel Duarte
- Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Irene Mackraj
- School of Laboratory Medicine & Medical Sciences, University of KwaZulu-Natal, Durban, South Africa.
| |
Collapse
|
|
23
|
Naicker T, Phoswa WN, Onyangunga OA, Gathiram P, Moodley J. Angiogenesis, Lymphangiogenesis, and the Immune Response in South African Preeclamptic Women Receiving HAART. Int J Mol Sci 2019; 20:ijms20153728. [PMID: 31366152 PMCID: PMC6696390 DOI: 10.3390/ijms20153728] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 05/15/2019] [Accepted: 05/22/2019] [Indexed: 02/06/2023] Open
Abstract
Purpose of the review: This review highlights the role of angiogenesis, lymphangiogenesis, and immune markers in human immunodeficiency virus (HIV)-associated preeclamptic (PE) pregnancies in an attempt to unravel the mysteries underlying the duality of both conditions in South Africa. Recent findings: Studies demonstrate that HIV-infected pregnant women develop PE at a lower frequency than uninfected women. In contrast, women receiving highly active anti-retroviral therapy (HAART) are more inclined to develop PE, stemming from an imbalance of angiogenesis, lymphangiogenesis, and immune response. Summary: In view of the paradoxical effect of HIV infection on PE development, this study examines angiogenesis, lymphangiogenesis, and immune markers in the highly HIV endemic area of KwaZulu-Natal. We believe that HAART re-constitutes the immune response in PE, thereby predisposing women to PE development. This susceptibility is due to an imbalance in the angiogenic/lymphangiogenic/immune response as compared to normotensive pregnant women. Further large-scale studies are urgently required to investigate the effect of the duration of HAART on PE development.
Collapse
Affiliation(s)
- Thajasvarie Naicker
- Optics and Imaging Centre, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban 4013, South Africa.
| | - Wendy N Phoswa
- Discipline of Obstetrics and Gynecology, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban 4013, South Africa.
| | - Onankoy A Onyangunga
- Optics and Imaging Centre, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban 4013, South Africa
| | - Premjith Gathiram
- Women's Health and HIV Research Group. Department of Obstetrics and Gynecology, School of Clinical Medicine, University of KwaZulu-Natal, Durban 4013, South Africa
| | - Jagidesa Moodley
- Women's Health and HIV Research Group. Department of Obstetrics and Gynecology, School of Clinical Medicine, University of KwaZulu-Natal, Durban 4013, South Africa
| |
Collapse
|
|
24
|
Balogh A, Toth E, Romero R, Parej K, Csala D, Szenasi NL, Hajdu I, Juhasz K, Kovacs AF, Meiri H, Hupuczi P, Tarca AL, Hassan SS, Erez O, Zavodszky P, Matko J, Papp Z, Rossi SW, Hahn S, Pallinger E, Than NG. Placental Galectins Are Key Players in Regulating the Maternal Adaptive Immune Response. Front Immunol 2019; 10:1240. [PMID: 31275299 PMCID: PMC6593412 DOI: 10.3389/fimmu.2019.01240] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 05/16/2019] [Indexed: 12/12/2022] Open
Abstract
Galectins are potent immunomodulators that regulate maternal immune responses in pregnancy and prevent the rejection of the semi-allogeneic fetus that also occurs in miscarriages. We previously identified a gene cluster on Chromosome 19 that expresses a subfamily of galectins, including galectin-13 (Gal-13) and galectin-14 (Gal-14), which emerged in anthropoid primates. These galectins are expressed only by the placenta and induce the apoptosis of activated T lymphocytes, possibly contributing to a shifted maternal immune balance in pregnancy. The placental expression of Gal-13 and Gal-14 is decreased in preeclampsia, a life-threatening obstetrical syndrome partly attributed to maternal anti-fetal rejection. This study is aimed at revealing the effects of Gal-13 and Gal-14 on T cell functions and comparing the expression of these galectins in placentas from healthy pregnancies and miscarriages. First-trimester placentas were collected from miscarriages and elective termination of pregnancies, tissue microarrays were constructed, and then the expression of Gal-13 and Gal-14 was analyzed by immunohistochemistry and immunoscoring. Recombinant Gal-13 and Gal-14 were expressed and purified, and their effects were investigated on primary peripheral blood T cells. The binding of Gal-13 and Gal-14 to T cells and the effects of these galectins on apoptosis, activation marker (CD25, CD71, CD95, HLA-DR) expression and cytokine (IL-1β, IL-6, IL-8, IL-10, IFNγ) production of T cells were examined by flow cytometry. Gal-13 and Gal-14 are primarily expressed by the syncytiotrophoblast at the maternal-fetal interface in the first trimester, and their placental expression is decreased in miscarriages compared to first-trimester controls. Recombinant Gal-13 and Gal-14 bind to T cells in a population- and activation-dependent manner. Gal-13 and Gal-14 induce apoptosis of Th and Tc cell populations, regardless of their activation status. Out of the investigated activation markers, Gal-14 decreases the cell surface expression of CD71, Gal-13 increases the expression of CD25, and both galectins increase the expression of CD95 on T cells. Non-activated T cells produce larger amounts of IL-8 in the presence of Gal-13 or Gal-14. In conclusion, these results show that Gal-13 and Gal-14 already provide an immunoprivileged environment at the maternal-fetal interface during early pregnancy, and their reduced expression is related to miscarriages.
Collapse
Affiliation(s)
- Andrea Balogh
- Systems Biology of Reproduction Momentum Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.,Department of Immunology, Eotvos Lorand University, Budapest, Hungary
| | - Eszter Toth
- Systems Biology of Reproduction Momentum Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
| | - Roberto Romero
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, MD and Detroit, MI, United States.,Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, United States.,Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, United States.,Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, United States
| | - Katalin Parej
- Systems Biology of Reproduction Momentum Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.,Structural Biophysics Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
| | - Diana Csala
- Systems Biology of Reproduction Momentum Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
| | - Nikolett L Szenasi
- Systems Biology of Reproduction Momentum Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
| | - Istvan Hajdu
- Structural Biophysics Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
| | - Kata Juhasz
- Systems Biology of Reproduction Momentum Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
| | - Arpad F Kovacs
- Department of Genetics, Cell and Immunobiology, Semmelweis University, Budapest, Hungary
| | | | - Petronella Hupuczi
- Maternity Private Clinic of Obstetrics and Gynecology, Budapest, Hungary
| | - Adi L Tarca
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, MD and Detroit, MI, United States.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, United States.,Department of Computer Science, Wayne State University College of Engineering, Detroit, MI, United States
| | - Sonia S Hassan
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, MD and Detroit, MI, United States.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, United States.,Department of Physiology, Wayne State University School of Medicine, Detroit, MI, United States
| | - Offer Erez
- Division of Obstetrics and Gynecology, Maternity Department "D", Faculty of Health Sciences, Soroka University Medical Center, School of Medicine, Ben Gurion University of the Negev, Beer-Sheva, Israel
| | - Peter Zavodszky
- Structural Biophysics Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
| | - Janos Matko
- Department of Immunology, Eotvos Lorand University, Budapest, Hungary
| | - Zoltan Papp
- Maternity Private Clinic of Obstetrics and Gynecology, Budapest, Hungary.,Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary
| | - Simona W Rossi
- Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland
| | - Sinuhe Hahn
- Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland
| | - Eva Pallinger
- Department of Genetics, Cell and Immunobiology, Semmelweis University, Budapest, Hungary
| | - Nandor Gabor Than
- Systems Biology of Reproduction Momentum Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.,Maternity Private Clinic of Obstetrics and Gynecology, Budapest, Hungary.,First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| |
Collapse
|
|
25
|
Bos-Mikich A, Ferreira MO, de Oliveira R, Frantz N. Platelet-rich plasma or blood-derived products to improve endometrial receptivity? J Assist Reprod Genet 2019; 36:613-620. [PMID: 30610660 PMCID: PMC6504981 DOI: 10.1007/s10815-018-1386-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 12/14/2018] [Indexed: 02/07/2023] Open
Abstract
The use of platelet-rich plasma (PRP) to improve endometrial receptivity is gaining increasing attention in assisted reproduction technologies. The authors report that autologous PRP intrauterine administration improves pregnancy and birth rates, particularly in cases of patients presenting poor endometrial growth. Different groups of scientists proposed a similar approach years ago using whole blood-derived products also to improve endometrial receptivity. The important role played by cytokines and growth factors during embryo implantation has been well-known for a long time. These signaling molecules are present and released by blood cells during physiological, normal endometrial growth and implantation. Similar blood mediators are released from platelet granules upon a blood vessel injury. Methods described for PRP preparation for intrauterine administration are not precise, and they seem to be similar to those used to prepare peripheral blood-derived products. Thus, it is possible that when preparing PRP from whole blood, the final plasma product used as "PRP" contains platelets in addition to the important cytokines and growth factors released by the peripheral blood mononuclear cells present in the whole blood. Precise knowledge of the identity, concentration, and effects of the individual blood factors, their origin, whether platelets or blood mononuclear cells, will greatly contribute to improve and to make results obtained in fertility treatments more repeatable.
Collapse
Affiliation(s)
- Adriana Bos-Mikich
- Department of Morphological Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
| | | | | | - Nilo Frantz
- nilo.frantz Medicina Reprodutiva, Porto Alegre, RS, Brazil
| |
Collapse
|
|
26
|
Travis OK, White D, Pierce WA, Ge Y, Stubbs CY, Spradley FT, Williams JM, Cornelius DC. Chronic infusion of interleukin-17 promotes hypertension, activation of cytolytic natural killer cells, and vascular dysfunction in pregnant rats. Physiol Rep 2019; 7:e14038. [PMID: 30963715 PMCID: PMC6453821 DOI: 10.14814/phy2.14038] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 03/03/2019] [Indexed: 01/06/2023] Open
Abstract
Previous studies by our lab have established that placental-ischemia stimulated T-helper 17 cells (TH 17s) cause increased cytolytic natural killer (cNK) cell proliferation and activation during pregnancy; however, the exact mechanism is unknown. The objective of this study was to investigate the role of interlukin 17 (IL-17) in inducing cNK cell activation in pregnancy. We infused 150 pg/day of recombinant IL-17 into a subset of normal pregnant (NP) Sprague Dawley rats from gestation day (GD) 12-19 (NP+IL-17). On GD 19, mean arterial pressure (MAP), fetal and placental weights, cytokines, cNK cell activation, cytotoxic enzymes, and vascular reactivity were assessed. MAP significantly increased from 99 ± 3 mmHg in NP to 120 ± 1 mmHg in NP+IL-17 (P < 0.05). Fetal weight significantly decreased from 2.52 ± 0.04 g in NP to 2.32 ± 0.03 g in NP+IL-17 as did placental weight (NP: 0.65 ± 0.03 g; NP+IL-17: 0.54 ± 0.01 g, P < 0.05). Plasma levels of TNF-α increased to 281.4 ± 55.07 pg/mL in NP+IL-17 from 145.3 ± 16.03 pg/mL in NP (P < 0.05) while placental levels of VEGF decreased from 74.2 ± 6.48 pg/mg in NP to 54.2 ± 3.19 pg/mg in NP+IL-17. Total NK cells were increased in the placenta (NP: 14.3 ± 3.49%; NP+IL-17: 29.33 ± 2.76%, P < 0.05) as were cytolytic NK cells (NP: 3.31 ± 1.25%; NP+IL-17: 13.41 ± 1.81%, P < 0.05). A similar trend was observed in circulating NK cells. Plasma granzyme K increased from 3.55 ± 2.29 pg/mL in NP to 20.9 ± 7.76 pg/mL in NP+IL-17 (P < 0.05), and plasma granzyme B increased from 10.95 ± 0.64 pg/mL in NP to 14.9 ± 0.98 pg/mL in NP+IL-17(P < 0.05). In the placenta, both granzyme A (NP: 246.1 ± 16.7 pg/mg; NP+IL-17: 324.3 ± 15.07 pg/mg, P < 0.05) and granzyme B (NP: 15.18 ± 3.79 pg/mg; NP+IL-17: 27.25 ± 2.34 pg/mg, P < 0.05) increased in response to IL-17 infusion. Finally, vascular reactivity of uterine arteries was significantly impaired in response to IL-17 infusion. The results of this study suggest that IL-17 plays a significant role in the activation of cNK cells during pregnancy.
Collapse
Affiliation(s)
- Olivia K. Travis
- Department of Experimental Therapeutics and PharmacologyogyUniversity of Mississippi Medical CenterJacksonMississippi
| | - Dakota White
- Department of Emergency MedicineUniversity of Mississippi Medical CenterJacksonMississippi
| | - W. Austin Pierce
- Department of Emergency MedicineUniversity of Mississippi Medical CenterJacksonMississippi
| | - Ying Ge
- Department of SurgeryUniversity of Mississippi Medical CenterJacksonMississippi
| | - Cassandra Y. Stubbs
- Department of Experimental Therapeutics and PharmacologyogyUniversity of Mississippi Medical CenterJacksonMississippi
| | - Frank T. Spradley
- Department of SurgeryUniversity of Mississippi Medical CenterJacksonMississippi
| | - Jan M. Williams
- Department of Experimental Therapeutics and PharmacologyogyUniversity of Mississippi Medical CenterJacksonMississippi
| | - Denise C. Cornelius
- Department of Experimental Therapeutics and PharmacologyogyUniversity of Mississippi Medical CenterJacksonMississippi
- Department of Emergency MedicineUniversity of Mississippi Medical CenterJacksonMississippi
| |
Collapse
|
|
27
|
Vaka VR, McMaster KM, Cornelius DC, Ibrahim T, Jayaram A, Usry N, Cunningham MW, Amaral LM, LaMarca B. Natural killer cells contribute to mitochondrial dysfunction in response to placental ischemia in reduced uterine perfusion pressure rats. Am J Physiol Regul Integr Comp Physiol 2019; 316:R441-R447. [PMID: 30811248 DOI: 10.1152/ajpregu.00279.2018] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Preeclampsia (PE) is characterized by new-onset hypertension during pregnancy and is associated with immune activation and placental oxidative stress. Mitochondrial dysfunction is a major source of oxidative stress and may play a role in the pathology of PE. We (Vaka VR, et al. Hypertension 72: 703-711, 2018. doi: 10.1161/HYPERTENSIONAHA.118.11290 .) have previously shown that placental ischemia is associated with mitochondrial oxidative stress in the reduced uterine perfusion pressure (RUPP) model of PE. Furthermore, we have also shown that placental ischemia induces natural killer (NK) cell activation in RUPP. Thus, we hypothesize that NK cell depletion could improve mitochondrial function associated with hypertension in the RUPP rat model of PE. Pregnant Sprague-Dawley rats were divided into three groups: normal pregnant (NP), RUPP, and RUPP+NK cell depletion rats (RUPP+NKD). On gestational day (GD)14, RUPP surgery was performed, and NK cells were depleted by administering anti-asialo GM1 antibodies (3.5 µg/100 µl ip) on GD15 and GD17. On GD19, mean arterial pressure (MAP) was measured, and placental mitochondria were isolated and used for mitochondrial assays. MAP was elevated in RUPP versus NP rats (119 ± 1 vs.104 ± 2 mmHg, P = 0.0004) and was normalized in RUPP+NKD rats (107 ± 2 mmHg, P = 0.002). Reduced complex IV activity and state 3 respiration rate were improved in RUPP+NKD rats. Human umbilical vein endothelial cells treated with RUPP+NKD serum restored respiration with reduced mitochondrial reactive oxygen species (ROS). The restored placental or endothelial mitochondrial function along with attenuated endothelial cell mitochondrial ROS with NK cell depletion indicate an important role of NK cells in mediating mitochondrial oxidative stress in the pathology of PE.
Collapse
Affiliation(s)
- Venkata Ramana Vaka
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center , Jackson, Mississippi
| | - Kristen M McMaster
- Department of Obstetrics and Gynecology, University of Mississippi Medical Center , Jackson, Mississippi
| | - Denise C Cornelius
- Department of Emergency Medicine, University of Mississippi Medical Center , Jackson, Mississippi
| | - Tarek Ibrahim
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center , Jackson, Mississippi
| | - Aswathi Jayaram
- Department of Obstetrics and Gynecology, University of Mississippi Medical Center , Jackson, Mississippi
| | - Nathan Usry
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center , Jackson, Mississippi
| | - Mark W Cunningham
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center , Jackson, Mississippi
| | - Lorena M Amaral
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center , Jackson, Mississippi
| | - Babbette LaMarca
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center , Jackson, Mississippi.,Department of Obstetrics and Gynecology, University of Mississippi Medical Center , Jackson, Mississippi
| |
Collapse
|
|
28
|
Caruso MP, Falivene J, Holgado MP, Zurita DH, Laufer N, Castro C, Nico Á, Maeto C, Salido J, Pérez H, Salomón H, Cahn P, Sued O, Fink V, Turk G, Gherardi MM. Impact of HIV-ART on the restoration of Th17 and Treg cells in blood and female genital mucosa. Sci Rep 2019; 9:1978. [PMID: 30760809 PMCID: PMC6374372 DOI: 10.1038/s41598-019-38547-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Accepted: 01/02/2019] [Indexed: 12/28/2022] Open
Abstract
The aim of this study was to evaluate the effectiveness of antiretroviral treatment (ART) on the proportion and functions of Th17 and Treg cells in peripheral blood and female genital tract (FGT) respectively. To this aim, samples from 41 HIV-neg, 33 HIV+ ART-naïve and 32 HIV+ ART+ subjects were obtained. In peripheral blood, altered Th17 and Th17/Treg proportions were normalized in HIV+ ART+, but certain abnormal Treg and activated T-cell proportions were still observed. In FGT, abnormal patterns of secretion for Th17-related cytokines were observed in cervical mononuclear cells (CMCs) from HIV+ women, even in those from HIV+ ART+, compared to the HIV-neg group. Moreover, these altered patterns of secretion were associated with diminished levels of CXCL5 and CXCL1 chemokines and with an immunoregulatory skew in the CCL17/CCL20 ratio in ectocervix samples of these women. Finally, ART did not restore proportions of Th17-precursor cells with gut-homing potential in PBMCs, and positive correlations between these cells and the levels of IL-17F and IL-21 production by CMCs may suggest that a better homing of these cells to the intestine could also imply a better restoration of these cells in the female genital tract. These results indicate that antiretroviral treatment did not restore Th17-related immune functions completely at the female mucosal level.
Collapse
Affiliation(s)
- María Paula Caruso
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
| | - Juliana Falivene
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
| | - María Pía Holgado
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
| | | | - Natalia Laufer
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
- Hospital J.A. Fernández, Buenos Aires, Argentina
| | | | - Ángeles Nico
- Hospital J.A. Fernández, Buenos Aires, Argentina
| | - Cynthia Maeto
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
| | - Jimena Salido
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
| | - Héctor Pérez
- Hospital J.A. Fernández, Buenos Aires, Argentina
| | - Horacio Salomón
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
| | - Pedro Cahn
- Hospital J.A. Fernández, Buenos Aires, Argentina
- Fundación Huésped, Buenos Aires, Argentina
| | - Omar Sued
- Fundación Huésped, Buenos Aires, Argentina
| | - Valeria Fink
- Hospital J.A. Fernández, Buenos Aires, Argentina
- Fundación Huésped, Buenos Aires, Argentina
| | - Gabriela Turk
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
| | - María Magdalena Gherardi
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina.
| |
Collapse
|
|
29
|
Cunningham MW, Vaka VR, McMaster K, Ibrahim T, Cornelius DC, Amaral L, Campbell N, Wallukat G, McDuffy S, Usry N, Dechend R, LaMarca B. Renal natural killer cell activation and mitochondrial oxidative stress; new mechanisms in AT1-AA mediated hypertensive pregnancy. Pregnancy Hypertens 2018; 15:72-77. [PMID: 30825931 DOI: 10.1016/j.preghy.2018.11.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 11/26/2018] [Accepted: 11/30/2018] [Indexed: 12/21/2022]
Abstract
Women with preeclampsia (PE) have increased mean arterial pressure (MAP), natural killer (NK) cells, reactive oxygen species (ROS), and agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA). AT1-AA's administered to pregnant rodents produces a well-accepted model of PE. However, the role of NK cells and mitochondrial reactive oxygen species (mtROS) in AT1-AA mediated hypertension during pregnancy is unknown. We hypothesize that AT1-AA induced model of PE will exhibit elevated MAP, NK cells, and mtROS; while inhibition of the AT1-AA binding to the AT1R would be preventative. Pregnant rats were divided into 4 groups: normal pregnant (NP) (n = 5), NP + AT1-AA inhibitory peptide (NP +'n7AAc') (n = 3), NP + AT1-AA infused (NP + AT1-AA) (n = 10), and NP + AT1-AA +'n7AAc' (n = 8). Day 13, rats were surgically implanted with mini-pumps infusing either AT1-AA or AT1-AA +'n7AAc'. Day 19, tissue and blood was collected. MAP was elevated in AT1-AA vs. NP (119 ± 1 vs. 102 ± 2 mmHg, p < 0.05) and this was prevented by 'n7AAc' (108 ± 3). There was a 6 fold increase in renal activated NK cells in AT1-AA vs NP (1.2 ± 0.4 vs. 0.2 ± 0.1% Gated, p = 0.05) which returned to NP levels in AT1-AA +'n7AAc' (0.1 ± 0.1% Gated). Renal mtROS (317 ± 49 vs. 101 ± 13% Fold, p < 0.05) was elevated with AT1-AA vs NP and was decreased in AT1-AA +'n7AAc' (128 ± 16, p < 0.05). In conclusion, AT1-AA's increased MAP, NK cells, and mtROS which were attenuated by AT1-AA inhibition, thus highlighting new mechanisms of AT1-AA and the importance of drug therapy targeted to AT1-AAs in hypertensive pregnancies.
Collapse
Affiliation(s)
- Mark W Cunningham
- Depart. of Pharmacology & Toxicology, University of Mississippi Medical Center, Jackson, MS, United States
| | - Venkata Ramana Vaka
- Depart. of Pharmacology & Toxicology, University of Mississippi Medical Center, Jackson, MS, United States
| | - Kristen McMaster
- Depart. of Pharmacology & Toxicology, University of Mississippi Medical Center, Jackson, MS, United States
| | - Tarek Ibrahim
- Depart. of Pharmacology & Toxicology, University of Mississippi Medical Center, Jackson, MS, United States
| | - Denise C Cornelius
- Depart. of Emergency Medicine, University of Mississippi Medical Center, Jackson, MS, United States
| | - Lorena Amaral
- Depart. of Pharmacology & Toxicology, University of Mississippi Medical Center, Jackson, MS, United States
| | - Nathan Campbell
- Depart. of Pharmacology & Toxicology, University of Mississippi Medical Center, Jackson, MS, United States
| | - Gerd Wallukat
- Experimental and Clinical Research Center, Charité Campus Buch, Max-Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Shyanne McDuffy
- Depart. of Pharmacology & Toxicology, University of Mississippi Medical Center, Jackson, MS, United States
| | - Nathan Usry
- Depart. of Pharmacology & Toxicology, University of Mississippi Medical Center, Jackson, MS, United States
| | - Ralf Dechend
- Experimental and Clinical Research Center, HELIOS Clinic, Berlin, Germany
| | - Babbette LaMarca
- Depart. of Pharmacology & Toxicology, University of Mississippi Medical Center, Jackson, MS, United States; Depart. of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS, United States.
| |
Collapse
|
|
30
|
Natural killer cells mediate pathophysiology in response to reduced uterine perfusion pressure. Clin Sci (Lond) 2017; 131:2753-2762. [PMID: 29042488 DOI: 10.1042/cs20171118] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Revised: 09/28/2017] [Accepted: 10/13/2017] [Indexed: 01/09/2023]
Abstract
Preeclampsia is associated with hypertension, small-for-gestational-age babies, and increased cytolytic natural killer (NK) cells. The specific role of cytolytic NK cells in the pathophysiology of preeclampsia has not been clearly defined. We hypothesized that Reduced Uterine Perfusion Pressure (RUPP) stimulates proliferation and cytolytic activation of NK cells, and that reducing NK cells in RUPP would prevent hypertension, intrauterine growth restriction, and inflammation in response to placental ischemia. RUPP was induced on gestation day (GD) 14 in pregnant rats. NK cells were depleted by i.p. administration of anti-asialo GM1 antibody on GDs 15 and 17. Placental and circulating NK cells were quantified via flow cytometry, mean arterial pressure (MAP), fetal weights, and cytokines were measured on GD 19. Total placental NK cells were 7.4 ± 2% of gated cells in normal pregnant (NP; n=10) and 16.5 ± 3% of gated cells in RUPP (n=10) rats. Furthermore, cytolytic placental NK cells also increased in RUPP. Depletion of NK cells in RUPP (RUPP + anti-ASGM1) significantly improved MAP and fetal weights. MAP was 108 ± 2 mmHg in NP, 125 ± 2 mmHg in RUPP, and 112 ± 2 mmHg in RUPP + anti-ASGM1 (n=12). Fetal weight was 2.32 ± 0.05 in NP, 1.8 ± 0.04g in RUPP, and increased to 2.0 ± 0.04g in RUPP + anti-ASGM1. Placental interferon-γ (IFN-γ) was 40.4 ± 5.2 pg/mg in NP, 72.17 ± 3.2 pg/mg in RUPP, and 44.0 ± 6.5 pg/mg in RUPP + anti-ASGM1 (P<0.05). Placental tumor necrosis factor-α (TNF-α) was 17.9 ± 1.7 pg/mg in NP, 23.9 ± 2.2 pg/mg in RUPP, and 12.9 ± 2.3 pg/mg in RUPP + anti-ASGM1 (P<0.05). Depletion of NK cells significantly lowered MAP, intrauterine growth restriction, and inflammation in RUPP rats indicating that cytolytic NK cells are important in preeclampsia pathophysiology.
Collapse
|
|
31
|
Zhu L, Aly M, Wang H, Karakizlis H, Weimer R, Morath C, Kuon RJ, Toth B, Opelz G, Daniel V. Decreased NK cell immunity in kidney transplant recipients late post-transplant and increased NK-cell immunity in patients with recurrent miscarriage. PLoS One 2017; 12:e0186349. [PMID: 29040297 PMCID: PMC5645130 DOI: 10.1371/journal.pone.0186349] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 10/01/2017] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND There is evidence that NK-cell reactivity might affect graft outcome in transplant recipients and pregnancy in women. METHOD NK-cell subsets were determined in whole blood using eight-colour-fluorescence flow cytometry in patients before and after renal transplantation, patients with recurrent miscarriage (RM) and healthy controls (HC). RESULTS Patients late post-transplant (late-Tx) with functioning renal transplants showed abnormally low CD56dimCD16+ NK-cells containing both perforin and granzyme (vs HC p = 0.021) whereas RM patients exhibited abnormally high numbers of these cells (vs HC p = 0.043). CD56dimCD16+perforin+granzyme+ NK-cell counts were strikingly different between the two patient groups (p<0.001). In addition, recipients late-Tx showed abnormally low CD8+ NK-cells (vs HC p<0.001) in contrast to RM patients who showed an abnormal increase (vs HC p = 0.008). CD8+ NK-cell counts were strongly different between the two patient groups (p<0.001). Higher perforin+granzyme+CD56dimCD16+ and CD8+ NK-cells were associated with impaired graft function (p = 0.044, p = 0.032). After in-vitro stimulation, CD56dimCD16+ and CD56brightCD16dim/- NK-cells showed strong upregulation of CD107a and IFNy, whereas the content of perforin decreased dramatically as a consequence of perforin release. Recipients late post-Tx showed less in-vitro perforin release (= less cytotoxicity) than HC (p = 0.037) and lower perforin release was associated with good graft function (r = 0.738, p = 0.037). Notably, we observed strong in-vitro perforin release in 2 of 6 investigated RM patients. When circulating IL10+CD56bright NK-cells were analyzed, female recipients late post-Tx (n = 9) showed significantly higher relative and absolute cell numbers than RM patients (p = 0.002 and p = 0.018, respectively); and high relative and absolute IL10+CD56bright NK-cell numbers in transplant recipients were associated with low serum creatinine (p = 0.004 and p = 0.012) and high glomerular filtration rate (p = 0.011 and p = 0.002, respectively). Female recipients late post-Tx exhibited similar absolute but higher relative numbers of IL10+IFNy- NK-cells than RM patients (p>0.05 and p = 0.016, respectively). CONCLUSION NK-cells with lower cytotoxicity and immunoregulatory function might contribute to good long-term graft outcome, whereas circulating NK-cells with normal or even increased cytotoxicity and less immunoregulatory capacity are observed in patients with RM.
Collapse
Affiliation(s)
- Li Zhu
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 305, Heidelberg, Germany
- Department of Hematology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Mostafa Aly
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 305, Heidelberg, Germany
- Nephrology unit, Internal Medicine Department, Assiut University, Âssiut, Egypt
| | - Haihao Wang
- Department of Cardiovascular Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Hristos Karakizlis
- Department of Internal Medicine, University of Giessen, Klinikstraße 33, Giessen, Germany
| | - Rolf Weimer
- Department of Internal Medicine, University of Giessen, Klinikstraße 33, Giessen, Germany
| | - Christian Morath
- Department of Nephrology, University of Heidelberg, Heidelberg, Germany
| | - Ruben Jeremias Kuon
- Department of Obstetrics and Gynecology, University Hospital Heidelberg, Im Neuenheimer Feld 440, Heidelberg, Germany
| | - Bettina Toth
- Department of Gynecological Endocrinology and Reproductive Medicine, Medical University Innsbruck, Anichstraße 35, Innsbruck, Austria
| | - Gerhard Opelz
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 305, Heidelberg, Germany
| | - Volker Daniel
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 305, Heidelberg, Germany
- * E-mail:
| |
Collapse
|
|
32
|
Sho T, Hachisuga T, Koi C, Kurita T, Kagami S, Kawagoe T, Matsuura Y, Yoshimura K, Hisaoka M. 17β-Estradiol induces proliferation of endometrial NK cells (CD56+) in postmenopausal women. Climacteric 2017; 20:571-576. [PMID: 28933961 DOI: 10.1080/13697137.2017.1377173] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVE The aim of this report was to evaluate the impact of hormone replacement therapy (HRT) on lymphocytic infiltration of the endometrium in postmenopausal women. METHOD This study included 58 Japanese patients who had undergone hysterectomy at the University Hospital of Occupational and Environmental Health, Japan. Before surgery, nine patients had received 17β-estradiol (E2), 0.72 mg transdermally for 2-8 weeks (E2 group); 16 patients had received an Estra-1,3,5(10)-triene-3,16α, 17β-triol (E3) vaginal tablet 0.5 mg per month five times (E3 group); and 19 patients had received 17β-estradiol, 0.62 mg, and norethindrone acetate (P), 2.70 mg for 3-16 weeks (E2 + P group). Fourteen patients received no HRT (control group). We examined uterine tissue specimens immunohistochemically for CD45+, CD3+, CD4+, CD8+, CD20+, CD56+, and Ki67 antigen-positive cells. RESULTS The numbers of CD56 + cells were significantly increased in the E2 group compared with all other groups (E2 vs. E3: 7.0 vs. 0.75, p = 0.017; E2 vs. E2 + P: 7.0 vs. 0.58, p = 0.009; E2 vs. CONTROL 7.0 vs. 0.43, p = 0.010). The numbers of CD3+ cells were significantly increased in the E2 group compared with the control group (149.3 vs. 42.6, p = 0.008). CONCLUSION 17β-Estradiol induced the proliferation of endometrial uterine natural killer cells (CD56+) in postmenopausal women.
Collapse
Affiliation(s)
- T Sho
- a Department of Obstetrics and Gynecology , University of Occupational and Environmental Health, School of Medicine , Kitakyushu , Japan
| | - T Hachisuga
- a Department of Obstetrics and Gynecology , University of Occupational and Environmental Health, School of Medicine , Kitakyushu , Japan
| | - C Koi
- a Department of Obstetrics and Gynecology , University of Occupational and Environmental Health, School of Medicine , Kitakyushu , Japan
| | - T Kurita
- a Department of Obstetrics and Gynecology , University of Occupational and Environmental Health, School of Medicine , Kitakyushu , Japan
| | - S Kagami
- a Department of Obstetrics and Gynecology , University of Occupational and Environmental Health, School of Medicine , Kitakyushu , Japan
| | - T Kawagoe
- a Department of Obstetrics and Gynecology , University of Occupational and Environmental Health, School of Medicine , Kitakyushu , Japan
| | - Y Matsuura
- a Department of Obstetrics and Gynecology , University of Occupational and Environmental Health, School of Medicine , Kitakyushu , Japan
| | - K Yoshimura
- b Department of Obstetrics and Gynecology , Wakamatsu Hospital of the University of Occupational and Environmental Health , Kitakyushu , Japan
| | - M Hisaoka
- c Department of Pathology and Oncology , University of Occupational and Environmental Health, School of Medicine , Kitakyushu , Japan
| |
Collapse
|
|
33
|
Shah NM, Herasimtschuk AA, Boasso A, Benlahrech A, Fuchs D, Imami N, Johnson MR. Changes in T Cell and Dendritic Cell Phenotype from Mid to Late Pregnancy Are Indicative of a Shift from Immune Tolerance to Immune Activation. Front Immunol 2017; 8:1138. [PMID: 28966619 PMCID: PMC5605754 DOI: 10.3389/fimmu.2017.01138] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2017] [Accepted: 08/29/2017] [Indexed: 12/12/2022] Open
Abstract
During pregnancy, the mother allows the immunologically distinct fetoplacental unit to develop and grow. Opinions are divided as to whether this represents a state of fetal-specific tolerance or of a generalized suppression of the maternal immune system. We hypothesized that antigen-specific T cell responses are modulated by an inhibitory T cell phenotype and modified dendritic cell (DC) phenotype in a gestation-dependent manner. We analyzed changes in surface markers of peripheral blood T cells, ex vivo antigen-specific T cell responses, indoleamine 2,3-dioxygenase (IDO) activity (kynurenine/tryptophan ratio, KTR), plasma neopterin concentration, and the in vitro expression of progesterone-induced blocking factor (PIBF) in response to peripheral blood mononuclear cell culture with progesterone. We found that mid gestation is characterized by reduced antigen-specific T cell responses associated with (1) predominance of effector memory over other T cell subsets; (2) upregulation of inhibitory markers (programmed death ligand 1); (3) heightened response to progesterone (PIBF); and (4) reduced proportions of myeloid DC and concurrent IDO activity (KTR). Conversely, antigen-specific T cell responses normalized in late pregnancy and were associated with increased markers of T cell activation (CD38, neopterin). However, these changes occur with a simultaneous upregulation of immune suppressive mechanisms including apoptosis (CD95), coinhibition (TIM-3), and immune regulation (IL-10) through the course of pregnancy. Together, our data suggest that immune tolerance dominates in the second trimester and that it is gradually reversed in the third trimester in association with immune activation as the end of pregnancy approaches.
Collapse
Affiliation(s)
- Nishel Mohan Shah
- Department of Surgery and Cancer, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom
| | - Anna A Herasimtschuk
- Department of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom
| | - Adriano Boasso
- Department of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom
| | - Adel Benlahrech
- Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine and Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Dietmar Fuchs
- Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria
| | - Nesrina Imami
- Department of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom
| | - Mark R Johnson
- Department of Surgery and Cancer, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom
| |
Collapse
|
|
34
|
Lopez Gelston CA, Mitchell BM. Recent Advances in Immunity and Hypertension. Am J Hypertens 2017; 30:643-652. [PMID: 28200062 DOI: 10.1093/ajh/hpx011] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 01/18/2017] [Indexed: 01/01/2023] Open
Abstract
Persistent immune system activation plays an important role in the development of various forms of hypertension. Activation of the innate immune system, inflammation, and subsequent adaptive immune system response causing end-organ injury and dysfunction ultimately leads to hypertension and its associated sequelae including coronary artery disease, heart failure, stroke, and chronic kidney disease. In this review, we will provide updates on the innate and adaptive immune cells involved in hypertension, the current understanding of how the immune system gets activated, and examine the recently discovered mechanisms involved in several forms of experimental hypertension.
Collapse
Affiliation(s)
- Catalina A Lopez Gelston
- Department of Medical Physiology, Texas A&M University Health Science Center, College Station, Texas, USA
| | - Brett M Mitchell
- Department of Medical Physiology, Texas A&M University Health Science Center, College Station, Texas, USA
| |
Collapse
|
|
35
|
Orlovic M, Tomic V, Vukojevic K, Hudic I, Mandic V, Azinovic I, Soldo D, Kajic M, Soljic V. Decreased expression of MMP-9 in CD8 + cells in placenta with severe preeclampsia. Biotech Histochem 2017; 92:288-296. [PMID: 28498052 DOI: 10.1080/10520295.2017.1309069] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
We compared the number of CD4-positive (CD4+) and CD8-positive (CD8+) cells in severe and non-severe preeclampsia (PE), and in normal pregnancy. We also evaluated the expression of matrix metalloproteinase 9 (MMP-9) in CD4+ and CD8+ cells. Immunohistochemistry for CD4+ and CD8+ was performed on the decidua basalis of 15 severe and 13 non-severe PE women and compared to decidual tissue of 19 normal pregnancies (control group). Co-expression of MMP-9 with CD8+ and CD4+ cells was determined by double immunofluorescence staining. The median number of CD8+ cells/mm2 was significantly lower for the severe PE group than for the normal pregnancy group, as was the number of CD4+ cells and MMP-9+CD8+ cells. No statistical difference was found between the non-severe PE group and the normal pregnancy group. The significant decrease of CD4+, CD8+ and MMP-9+CD8+ cells at the fetal-maternal interface only in the severe PE group suggests that immunological disorders play a role in the pathophysiology of severe PE.
Collapse
Affiliation(s)
- M Orlovic
- a Department of Gynecology , University Hospital in Mostar
| | - V Tomic
- a Department of Gynecology , University Hospital in Mostar.,b Faculty of Health Studies , University of Mostar
| | - K Vukojevic
- c Laboratory of Morphology, Department of Histology and Embryology , School of Medicine, University of Mostar , Mostar , Bosnia and Herzegovina.,d Laboratory for Early Human Development, Department of Anatomy , Histology and Embryology, School of Medicine, University of Split , Split , Croatia
| | - I Hudic
- e Clinic of Gynecology and Obstetrics, University Clinical Center , Tuzla
| | - V Mandic
- a Department of Gynecology , University Hospital in Mostar
| | - I Azinovic
- c Laboratory of Morphology, Department of Histology and Embryology , School of Medicine, University of Mostar , Mostar , Bosnia and Herzegovina
| | - D Soldo
- a Department of Gynecology , University Hospital in Mostar
| | - M Kajic
- a Department of Gynecology , University Hospital in Mostar
| | - V Soljic
- c Laboratory of Morphology, Department of Histology and Embryology , School of Medicine, University of Mostar , Mostar , Bosnia and Herzegovina.,f Department of Pathology , Cytology and Forensic Medicine, University Hospital in Mostar , Mostar , Bosnia and Herzegovina
| |
Collapse
|
|
36
|
Hickey MJ, Chow Z. Viewing immune regulation as it happens: in vivo imaging for investigation of regulatory T-cell function. Immunol Cell Biol 2017; 95:514-519. [PMID: 28420873 DOI: 10.1038/icb.2017.33] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 04/10/2017] [Accepted: 04/10/2017] [Indexed: 12/12/2022]
Abstract
Regulatory T cells (Tregs) play indispensable roles in the immune system, in limiting excessive or inappropriate immune and inflammatory responses. They achieve this function via effects on other immune cells in the secondary lymphoid system, and in peripheral locations such as skin, gut and bone marrow. As for the more extensively studied cellular players in the immune system, particularly dendritic cells and conventional T cells, in vivo imaging of Tregs via two-photon (or multiphoton) microscopy (MPM) has been central to the development of understanding how these cells function. In this brief review, we will describe the studies that have utilised MPM to examine Treg behaviour in vivo. These studies have investigated Treg behaviour in lymph nodes and spleen, as well as in peripheral organs such as skin, small intestine and bone marrow. The findings from these experiments underline how assumptions made about Treg function based on results of in vitro experiments are often not supported by direct visualisation of these cells in their normal in vivo settings. Together this work reveals that only via MPM analysis can Treg function be investigated in the complicated multicellular environments where conventional T cells, antigen-presenting cells and other potential cellular targets of Tregs are present with each undergoing their own specific actions.
Collapse
Affiliation(s)
- Michael J Hickey
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Victoria, Australia
| | - Zachary Chow
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Victoria, Australia
| |
Collapse
|
|
37
|
Trojan K, Zhu L, Aly M, Weimer R, Bulut N, Morath C, Opelz G, Daniel V. Association of peripheral NK cell counts with Helios + IFN-γ - T regs in patients with good long-term renal allograft function. Clin Exp Immunol 2017; 188:467-479. [PMID: 28194759 DOI: 10.1111/cei.12945] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/09/2017] [Indexed: 12/16/2022] Open
Abstract
Little is known about a possible interaction of natural killer (NK) cells with regulatory T cells (Treg ) in long-term stable kidney transplant recipients. Absolute counts of lymphocyte and Treg subsets were studied in whole blood samples of 136 long-term stable renal transplant recipients and 52 healthy controls using eight-colour fluorescence flow cytometry. Patients were 1946 ± 2201 days (153-10 268 days) post-transplant and showed a serum creatinine of 1·7 ± 0·7 mg/dl. Renal transplant recipients investigated > 1·5 years post-transplant showed higher total NK cell counts than recipients studied < 1·5 years after transplantation (P = 0·006). High NK cells were associated with high glomerular filtration rate (P = 0·002) and low serum creatinine (P = 0·005). Interestingly, high NK cells were associated with high CD4+ CD25+ CD127- forkhead box protein 3 (FoxP3+ ) Treg that co-express the phenotype Helios+ interferon (IFN)-γ- and appear to have stable FoxP3 expression and originate from the thymus. Furthermore, high total NK cells were associated with Treg that co-express the phenotypes interleukin (IL)-10- transforming growth factor (TGF)-β+ (P = 0·013), CD183+ CD62L- (P = 0·003), CD183+ CD62+ (P = 0·001), CD183- CD62L+ (P = 0·002), CD252- CD152+ (P < 0·001), CD28+ human leucocyte antigen D-related (HLA-DR- ) (P = 0·002), CD28+ HLA-DR+ (P < 0·001), CD95+ CD178- (P < 0·001) and CD279- CD152+ (P < 0·001), suggesting that these activated Treg home in peripheral tissues and suppress effector cells via TGF-β and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). The higher numbers of NK and Treg cell counts in patients with long-term good allograft function and the statistical association of these two lymphocyte subsets with each other suggest a direct or indirect (via DC) interaction of these cell subpopulations that contributes to good long-term allograft acceptance. Moreover, we speculate that regulatory NK cells are formed late post-transplant that are able to inhibit graft-reactive effector cells.
Collapse
Affiliation(s)
- K Trojan
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | - L Zhu
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany.,Department of Hematology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - M Aly
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany.,Nephrology Unit, Internal Medicine Department, Assiut University, Egypt
| | - R Weimer
- Department of Internal Medicine, University of Giessen, Giessen, Germany
| | - N Bulut
- Department of Internal Medicine, University of Giessen, Giessen, Germany
| | - C Morath
- Department of Nephrology, University of Heidelberg, Heidelberg, Germany
| | - G Opelz
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | - V Daniel
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany
| |
Collapse
|
|
38
|
Small HY, Cornelius DC, Guzik TJ, Delles C. Natural killer cells in placentation and cancer: Implications for hypertension during pregnancy. Placenta 2017; 56:59-64. [PMID: 28318556 DOI: 10.1016/j.placenta.2017.03.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2016] [Revised: 03/04/2017] [Accepted: 03/06/2017] [Indexed: 11/25/2022]
Abstract
Hypertension during pregnancy is the most common medical condition encountered during gestation. Despite this, knowledge of the mechanisms that underlie the disease and the development of new therapies are limited. Hypertension during pregnancy and some forms of cancer confer an increased risk to the development of cardiovascular disease later in life; one mechanism which may link these conditions is the involvement of natural killer (NK) cells. Whilst immunology and immunotherapy are well-developed areas in oncology; the complex mechanisms of the immune system in health and disease at the maternal-fetal interface are less well-defined. Natural killer (NK) cells have emerged as key immune cells involved in physiology and pathology of pregnancy. These small lymphocytes are present in the decidua (the uterine-specific uNK cells) and are distinct from peripheral NK cells. The uNK cell population plays a vital role in mediating trophoblast invasion and affecting decidual vascular remodelling whereas the role of the peripheral NK cell population during pregnancy is less well-defined. This review will give an overview of NK cell biology followed by a discussion of the current evidence for the role of uterine and peripheral NK cells at the maternal-fetal interface in health and disease. Furthermore, examples of NK cell research from cancer biology will be employed to inform future directions of research. By combining this knowledge from oncology where the field of immunotherapy has now matured into clinical trials; it is hopeful that new mechanisms can be elucidated to generate targets for similar therapeutic strategies for women with hypertensive pregnancies where interventions are needed.
Collapse
Affiliation(s)
- Heather Yvonne Small
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
| | - Denise C Cornelius
- Department of Emergency Medicine, University of Mississippi Medical Centre, Jackson, MS, USA
| | - Tomasz J Guzik
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Christian Delles
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
| |
Collapse
|
|
39
|
Kieffer TE, Faas MM, Scherjon SA, Prins JR. Pregnancy persistently affects memory T cell populations. J Reprod Immunol 2017; 119:1-8. [DOI: 10.1016/j.jri.2016.11.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Revised: 10/28/2016] [Accepted: 11/10/2016] [Indexed: 11/28/2022]
|
|
40
|
Sava F, Toldi G, Treszl A, Hajdú J, Harmath Á, Tulassay T, Vásárhelyi B. Expression of lymphocyte activation markers of preterm neonates is associated with perinatal complications. BMC Immunol 2016; 17:19. [PMID: 27328920 PMCID: PMC4915083 DOI: 10.1186/s12865-016-0159-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2016] [Accepted: 06/16/2016] [Indexed: 02/10/2023] Open
Abstract
Background Inappropriate activation of T lymphocytes plays an important role in perinatal complications. However, data on T lymphocyte activation markers of preterm infants is scarce. We investigated the association between gender, gestational and postnatal age, preeclampsia (PE), premature rupture of membranes (PROM) as well as prenatal steroid treatment (PS) and the frequency of activated T lymphocyte subsets (HLA-DR+, CD69+, CD25+, CD62L+) and major T lymphocyte subpopulations (CD4, CD8, Th1, Th2, naïve, memory) in peripheral blood during the first postnatal week in preterm infants. Results Cord blood and peripheral blood samples were collected from 43 preterm infants on the 1st, 3rd, and 7th days of life. We assessed the frequency of the above T lymphocyte subsets using flow cytometry. The ‘mixed effect model’ was used to analyze the effects of clinical parameters on T lymphocyte markers. The frequency of CD25+ T lymphocytes was higher in PROM. The frequency of CD4+ and CD8+ cells and the CD4+/CD8+ cell ratio was decreased in PE. The frequency of CD62L+ T lymphocytes was higher in male compared with female infants. PS did not affect the frequency of the investigated markers. CD4+ CD25+ cells had a lower frequency at birth than on day 7. Th2 lymphocytes had a lower frequency on postnatal days 1 and 3 when compared to day 7. Conclusions Our observations indicate that alterations affecting the expression of T lymphocyte activation markers are associated with the above factors and may play a role in the development of perinatal complications.
Collapse
Affiliation(s)
- Florentina Sava
- First Department of Obstetrics and Gynecology, Semmelweis University, Baross u. 27, H-1088, Budapest, Hungary
| | - Gergely Toldi
- First Department of Obstetrics and Gynecology, Semmelweis University, Baross u. 27, H-1088, Budapest, Hungary.
| | - András Treszl
- First Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Júlia Hajdú
- First Department of Obstetrics and Gynecology, Semmelweis University, Baross u. 27, H-1088, Budapest, Hungary
| | - Ágnes Harmath
- First Department of Obstetrics and Gynecology, Semmelweis University, Baross u. 27, H-1088, Budapest, Hungary
| | - Tivadar Tulassay
- First Department of Pediatrics, Semmelweis University, Budapest, Hungary.,MTA-SE Research Group of Pediatrics and Nephrology, Hungarian Academy of Sciences, Budapest, Hungary
| | - Barna Vásárhelyi
- MTA-SE Research Group of Pediatrics and Nephrology, Hungarian Academy of Sciences, Budapest, Hungary.,Department of Laboratory Medicine, Semmelweis University, Budapest, Hungary
| |
Collapse
|
|
41
|
Harmon AC, Cornelius DC, Amaral LM, Faulkner JL, Cunningham MW, Wallace K, LaMarca B. The role of inflammation in the pathology of preeclampsia. Clin Sci (Lond) 2016; 130:409-19. [PMID: 26846579 PMCID: PMC5484393 DOI: 10.1042/cs20150702] [Citation(s) in RCA: 382] [Impact Index Per Article: 42.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Preeclampsia (PE) affects 5-7% of all pregnancies in the United States and is the leading cause of maternal and prenatal morbidity. PE is associated with hypertension after week 20 of gestation, decreased renal function and small-for-gestational-age babies. Women with PE exhibit chronic inflammation and production of autoantibodies. It is hypothesized that during PE, placental ischaemia occurs as a result of shallow trophoblast invasion which is associated with an immune imbalance where pro-inflammatory CD4(+) T-cells are increased and T regulatory cells (Tregs) are decreased. This imbalance leads to chronic inflammation characterized by oxidative stress, pro-inflammatory cytokines and autoantibodies. Studies conducted in our laboratory have demonstrated the importance of this immune imbalance in causing hypertension in response to placental ischaemia in pregnant rats. These studies confirm that increased CD4(+) T-cells and decreased Tregs during pregnancy leads to elevated inflammatory cytokines, endothelin (ET-1), reactive oxygen species (ROS) and agonistic autoantibodies to the angiotensin II (Ang II), type 1 receptor (AT1-AA). All of these factors taken together play an important role in increasing the blood pressure during pregnancy. Specifically, this review focuses on the decrease in Tregs, and their associated regulatory cytokine interleukin (IL)-10, which is seen in response to placental ischaemia during pregnancy. This study will also examine the effect of regulatory immune cell repopulation on the pathophysiology of PE. These studies show that restoring the balance of the immune system through increasing Tregs, either by adoptive transfer or by infusing IL-10, reduces the blood pressure and pathophysiology associated with placental ischaemia in pregnant rats.
Collapse
Affiliation(s)
- Ashlyn C Harmon
- Departments of Pharmacology, Physiology, & Ob/Gyn, Center for Excellence in Cardiovascular and Renal Research, University of Mississippi Medical Center, Jackson, MS 39216, U.S.A
| | - Denise C Cornelius
- Departments of Pharmacology, Physiology, & Ob/Gyn, Center for Excellence in Cardiovascular and Renal Research, University of Mississippi Medical Center, Jackson, MS 39216, U.S.A
| | - Lorena M Amaral
- Departments of Pharmacology, Physiology, & Ob/Gyn, Center for Excellence in Cardiovascular and Renal Research, University of Mississippi Medical Center, Jackson, MS 39216, U.S.A
| | - Jessica L Faulkner
- Departments of Pharmacology, Physiology, & Ob/Gyn, Center for Excellence in Cardiovascular and Renal Research, University of Mississippi Medical Center, Jackson, MS 39216, U.S.A
| | - Mark W Cunningham
- Departments of Pharmacology, Physiology, & Ob/Gyn, Center for Excellence in Cardiovascular and Renal Research, University of Mississippi Medical Center, Jackson, MS 39216, U.S.A
| | - Kedra Wallace
- Departments of Pharmacology, Physiology, & Ob/Gyn, Center for Excellence in Cardiovascular and Renal Research, University of Mississippi Medical Center, Jackson, MS 39216, U.S.A
| | - Babbette LaMarca
- Departments of Pharmacology, Physiology, & Ob/Gyn, Center for Excellence in Cardiovascular and Renal Research, University of Mississippi Medical Center, Jackson, MS 39216, U.S.A.
| |
Collapse
|
|
42
|
Clark DA. Mouse is the new woman? Translational research in reproductive immunology. Semin Immunopathol 2016; 38:651-668. [DOI: 10.1007/s00281-015-0553-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 12/29/2015] [Indexed: 12/18/2022]
|
|
43
|
Shirshev SV, Nekrasova IV, Gorbunova OL, Orlova EG, Maslennikova IL. The effect of kisspeptin on the functional characteristics of isolated NK cells. DOKLADY BIOLOGICAL SCIENCES : PROCEEDINGS OF THE ACADEMY OF SCIENCES OF THE USSR, BIOLOGICAL SCIENCES SECTIONS 2015; 464:267-269. [PMID: 26530074 DOI: 10.1134/s0012496615050129] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Indexed: 06/05/2023]
Abstract
The effect of kisspeptin at concentrations typical of pregnancy on the functional activity of isolated cytokine-primed NK cells has been investigated. The hormone has been shown to promote an increase in the proportion of CD56(bright) NK cells, as well as an increase in the L-selectin expression on the cell surface. Assessment of cytokine levels has shown that kisspeptin suppresses the production of IL-4, IL-10, and IFN-γ while stimulating the production of TGF-β by isolated NK cells. The overall effect of the hormone investigated consisted in the formation of a phenotype and a cytokine spectrum characteristic of the regulatory NK3 subpopulation of NK cells in pregnancy.
Collapse
Affiliation(s)
- S V Shirshev
- Institute of Ecology and Genetics of Microorganisms, Ural Branch, Russian Academy of Sciences, ul. Goleva 13, Perm, 614081, Russia.
| | - I V Nekrasova
- Institute of Ecology and Genetics of Microorganisms, Ural Branch, Russian Academy of Sciences, ul. Goleva 13, Perm, 614081, Russia
| | - O L Gorbunova
- Institute of Ecology and Genetics of Microorganisms, Ural Branch, Russian Academy of Sciences, ul. Goleva 13, Perm, 614081, Russia
| | - E G Orlova
- Institute of Ecology and Genetics of Microorganisms, Ural Branch, Russian Academy of Sciences, ul. Goleva 13, Perm, 614081, Russia
| | - I L Maslennikova
- Institute of Ecology and Genetics of Microorganisms, Ural Branch, Russian Academy of Sciences, ul. Goleva 13, Perm, 614081, Russia
| |
Collapse
|
|
44
|
Characterization of the subsets of human NKT-like cells and the expression of Th1/Th2 cytokines in patients with unexplained recurrent spontaneous abortion. J Reprod Immunol 2015; 110:81-8. [DOI: 10.1016/j.jri.2015.05.001] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Accepted: 05/07/2015] [Indexed: 11/22/2022]
|
|
45
|
Hu WT, Huang LL, Li MQ, Jin LP, Li DJ, Zhu XY. Decidual stromal cell-derived IL-33 contributes to Th2 bias and inhibits decidual NK cell cytotoxicity through NF-κB signaling in human early pregnancy. J Reprod Immunol 2015; 109:52-65. [DOI: 10.1016/j.jri.2015.01.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Revised: 12/20/2014] [Accepted: 01/13/2015] [Indexed: 10/24/2022]
|
|
46
|
Lashley LE, van der Keur C, van Beelen E, Schaap R, van der Westerlaken LA, Scherjon SA, Claas FH. Stronger T-Cell Alloreactivity and Diminished Suppressive Capacity of Peripheral Regulatory T Cells in Infertile Women UndergoingIn VitroFertilization. Am J Reprod Immunol 2015; 74:268-78. [DOI: 10.1111/aji.12398] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Accepted: 03/31/2015] [Indexed: 12/14/2022] Open
Affiliation(s)
- Lisa E.E.L.O. Lashley
- Department of Gynecology and Obstetrics; Leiden University Medical Centre; Leiden The Netherlands
| | - Carin van der Keur
- Department of Immunohematology and Blood Transfusion; Leiden University Medical Centre; Leiden The Netherlands
| | - Els van Beelen
- Department of Immunohematology and Blood Transfusion; Leiden University Medical Centre; Leiden The Netherlands
| | - Rowena Schaap
- Department of Immunohematology and Blood Transfusion; Leiden University Medical Centre; Leiden The Netherlands
| | | | | | - Frans H.J. Claas
- Department of Immunohematology and Blood Transfusion; Leiden University Medical Centre; Leiden The Netherlands
| |
Collapse
|
|
47
|
Djurisic S, Hviid TVF. HLA Class Ib Molecules and Immune Cells in Pregnancy and Preeclampsia. Front Immunol 2014; 5:652. [PMID: 25566263 PMCID: PMC4274990 DOI: 10.3389/fimmu.2014.00652] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2014] [Accepted: 12/05/2014] [Indexed: 01/14/2023] Open
Abstract
Despite decades of research, the highly prevalent pregnancy complication preeclampsia, “the disease of theories,” has remained an enigma. Indeed, the etiology of preeclampsia is largely unknown. A compiling amount of studies indicates that the pathological basis involves a complex array of genetic predisposition and immunological maladaptation, and that a contribution from the mother, the father, and the fetus is likely to be important. The Human Leukocyte Antigen (HLA)-G is an increasing focus of research in relation to preeclampsia. The HLA-G molecule is primarily expressed by the extravillous trophoblast cells lining the placenta together with the two other HLA class Ib molecules, HLA-E and HLA-F. Soluble isoforms of HLA-G have been detected in the early endometrium, the matured cumulus–oocyte complex, maternal blood of pregnant women, in umbilical cord blood, and lately, in seminal plasma. HLA-G is believed to be involved in modulating immune responses in the context of vascular remodeling during pregnancy as well as in dampening potential harmful immune attacks raised against the semi-allogeneic fetus. In addition, HLA-G genetic variants are associated with both membrane-bound and soluble forms of HLA-G, and, in some studies, with preeclampsia. In this review, a genetic contribution from the mother, the father, and the fetus, together with the presence and function of various immune cells of relevance in pregnancy are reviewed in relation to HLA-G and preeclampsia.
Collapse
Affiliation(s)
- Snezana Djurisic
- Department of Clinical Biochemistry, Centre for Immune Regulation and Reproductive Immunology (CIRRI), Copenhagen University Hospital (Roskilde), University of Copenhagen , Roskilde , Denmark
| | - Thomas Vauvert F Hviid
- Department of Clinical Biochemistry, Centre for Immune Regulation and Reproductive Immunology (CIRRI), Copenhagen University Hospital (Roskilde), University of Copenhagen , Roskilde , Denmark
| |
Collapse
|
|
48
|
Blackburn HK, Allington DR, Procacci KA, Rivey MP. Asthma in pregnancy. World J Pharmacol 2014; 3:56-71. [DOI: 10.5497/wjp.v3.i4.56] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Revised: 08/01/2014] [Accepted: 09/17/2014] [Indexed: 02/06/2023] Open
Abstract
Asthma affects approximately 8% of women during pregnancy. Pregnancy results in a variable course for asthma control, likely contributed to by physiological changes affecting the respiratory, immune, and hormonal systems. While asthma during pregnancy has been associated with an increased risk of maternal and fetal complications including malformations, available data also suggest that active asthma management and monitoring can decrease the risk of adverse outcomes. The diagnosis, disease classification, and goals for asthma management in the pregnant woman are the same as for nonpregnant patients. However, evidence shows that pregnant asthmatics are more likely to be undertreated, resulting in asthma exacerbations occurring in approximately one third and hospitalization in one tenth of patients. Pharmacotherapeutic management of asthma exacerbations in pregnant patients follows standard treatment guidelines. In contrast, the principles of asthma maintenance therapy are slightly modified in the pregnant patient. Patients and practitioners may avoid use of asthma medications due to concern for a risk of fetal complications and malformations. A variable amount of information is available regarding the risk of a given asthma medication to cause adverse fetal outcomes, and it is preferable to use an inhaled product. Nevertheless, based on available data, the majority of asthma medications are regarded as safe for use during pregnancy. And, any increased risk to either the mother or fetus from medication use appears to be small compared to that associated with poor asthma control.
Collapse
|
|
49
|
Brazão V, Kuehn CC, dos Santos CD, da Costa CMB, Júnior JCDP, Carraro-Abrahão AA. Endocrine and immune system interactions during pregnancy. Immunobiology 2014; 220:42-7. [PMID: 25257860 DOI: 10.1016/j.imbio.2014.09.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2011] [Accepted: 09/05/2014] [Indexed: 10/24/2022]
Abstract
Pregnancy is known to induce a transient depression of maternal cell-mediated immunity, to prevent rejection of the fetus, while at the same time it keeps adequate maternal host defense mechanisms to fight infection. Presently, the aim of this paper was to investigate a possible endocrine and immunologic alteration observed during a successful pregnancy. This study consistently showed that plasma corticosterone levels were significantly higher (P<0.0001) in pregnant Wistar rats than in virgin female. An increased number of peritoneal macrophages was also detected in pregnant females when compared to non-pregnant ones. Macrophages play an important role in the production of bioactive proteins and lipids such as nitric oxide. Then, in support of the latter, the present study showed increased levels of endogenous NO in pregnant rats when compared to non-pregnant ones, thereby mediating the vasodilatation process of normal gestation. Furthermore, our FACS analysis clearly indicated the correlation between reduced CD161 expression on NK cells (P<0.0001) in pregnant rats when compared to virgin females. It was found that pregnancy appears to be associated with depressed cell immunity, as evidenced by a significant inhibition of lymphocyte proliferation. Understanding the immunological paradox of maternal tolerance, as well as the hormonal modulation of the immune environment during pregnancy is essential for future studies to investigate the potential for these processes to be modulated by diet or effective therapeutics during pregnancy.
Collapse
Affiliation(s)
- Vânia Brazão
- College of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo, Av. do Café s/n, 14040-903 Ribeirão Preto, São Paulo, Brazil.
| | - Christian Collins Kuehn
- College of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo, Av. do Café s/n, 14040-903 Ribeirão Preto, São Paulo, Brazil
| | - Carla Domingues dos Santos
- College of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo, Av. do Café s/n, 14040-903 Ribeirão Preto, São Paulo, Brazil
| | - Cássia Mariana Bronzon da Costa
- College of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo, Av. do Café s/n, 14040-903 Ribeirão Preto, São Paulo, Brazil
| | - José Clóvis do Prado Júnior
- College of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo, Av. do Café s/n, 14040-903 Ribeirão Preto, São Paulo, Brazil
| | - Ana Amélia Carraro-Abrahão
- College of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo, Av. do Café s/n, 14040-903 Ribeirão Preto, São Paulo, Brazil
| |
Collapse
|
|
50
|
Ruocco MG, Chaouat G, Florez L, Bensussan A, Klatzmann D. Regulatory T-cells in pregnancy: historical perspective, state of the art, and burning questions. Front Immunol 2014; 5:389. [PMID: 25191324 PMCID: PMC4139600 DOI: 10.3389/fimmu.2014.00389] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Accepted: 07/30/2014] [Indexed: 01/04/2023] Open
Abstract
In this review, we first revisit the original concept of "suppressor T-cells" in pregnancy, put it in a historical perspective, and then highlight the main data that licensed its resurrection and revision into the concept of "regulatory T-cells" (Tregs) in pregnancy. We review the evidence for a major role of Tregs in murine and human pregnancy and discuss Treg interactions with dendritic and uterine natural killer cells, other players of maternal-fetal tolerance. Finally, we highlight what we consider as the most important questions in the field.
Collapse
Affiliation(s)
- Maria Grazia Ruocco
- Sorbonne Université, UPMC Univ Paris 06, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), Paris, France
- INSERM, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), Paris, France
| | | | - Laura Florez
- Sorbonne Université, UPMC Univ Paris 06, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), Paris, France
- INSERM, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), Paris, France
| | | | - David Klatzmann
- Sorbonne Université, UPMC Univ Paris 06, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), Paris, France
- INSERM, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), Paris, France
- AP-HP, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (i2B), Paris, France
| |
Collapse
|