| 1. |
- Boij, Roland, 1952-
(författare)
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Aspects of inflammation, angiogenesis and coagulation in preeclampsia
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Preeclampsia is a major challenge to obstetricians, due to its impact on maternal and fetal morbidity and mortality and the lack of preventive and treatment strategies. The overall aim of this thesis is to increase the knowledge of the pathogenesis of preeclampsia including the role of inflammation, angiogenesis and coagulation, both locally at the fetomaternal interface and in the maternal circulation. Uncompensated maternal endothelial inflammatory responses to factors from stressed trophoblasts seem to be a major contributor to the syndrome, together with an imbalance in angiogenesis and an activated coagulation system. An increasing amount of data indicates an involvement of the immune system with defect tolerance to the conceptus as an integral part of the pathogenesis, at least in early-onset preeclampsia (EOP).We showed that a single administration of human preeclampsia serum in pregnant IL-10−/− mice induced the full spectrum of preeclampsia-like symptoms including hypoxic injury in uteroplacental tissues and endotheliosis in maternal kidneys. Importantly, preeclampsia serum, as early as 12 to 14 weeks of gestation, disrupted cross talk between trophoblasts and endothelial cells in an in vitro model of endovascular activity (Tube formation test). These results indicate that preeclamptic sera can be used to better understand the pathophysiology and to predict the disorder. Preeclampsia has been associated with increased inflammation, aberrant angiogenesis and activated coagulation, but their correlation and relative contribution are unknown. We found that markers for all these mechanisms were independently associated with preeclampsia. Cytokines, chemokines, and complement factors seem all to be part of a Th1-associated inflammatory reaction in preeclampsia, more pronounced in EOP than in late-onset preeclampsia (LOP), in line with a more homogeneous pathogenesis in EOP as based on placental pathology. In women with intrauterine growth restriction (IUGR), with an anticipated pathologic placentation, only differences in levels for sFlt-1 and PlGF were found in comparison with mothers without IUGR. Thus, sFlt-1 and PlGF seem to be indicators of placental pathology, while other biomarkers might also reflect maternal endothelial pathology. Chemokines, in contrast to cytokines, may prove to be useful markers in preeclampsia.A deficiency in regulatory T (Treg) cells causing reduced immune regulatory capacity has been proposed in preeclampsia. Utilizing recent advances in flow cytometry phenotyping, we found no major alterations in circulating Treg numbers in preeclamptic women compared with normal pregnant and non-pregnant women. However, preeclampsia was associated with increased fractions of CTLA-4+ and CCR4+ cells within Treg subpopulations, which is in line with a migratory defect of Treg cells, and potentially associated with a reduced number of suppressive Treg cells at the fetomaternal interface. As we found that corticosteroid treatment affected the results, it should be accounted for in studies of EOP. Chemokines are supposed to be part of the immune adaptation in pregnancy. We found a decreased expression of CCL18 (Th2/Tregassociated), in trophoblasts from preeclamptic compared to normal pregnant women, indicating a local regulatory defect in preeclampsia, in line with our finding of a possible migratory defect of circulating Treg cells. Due to increased expression of CCL20 (Th17) and CCL22 (Th2) in first trimester placenta and increased circulating levels of CXCL10 (Th1) and CCL20 (Th17) in third trimester preeclamptic women, we suggest that CCL20 and CCL22 may be important for implantation and early placentation while in third trimester of a preeclamptic pregnancy CXCL10 and CCL20 mainly mirror maternal increased endothelial inflammation and aberrant angiogenesis. In summary, we found that preeclampsia is associated with increased inflammation, aberrant angiogenesis and activated coagulation, caused by placental factors in maternal peripheral circulation, more pronounced in the early-onset form of preeclampsia. It also appears that there is a defective modulation of the immune system in preeclamptic pregnancies. The results provide a better understanding of the pathogenesis of preeclampsia and have given suggestions to predictive markers for preeclampsia in the future.
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| 2. |
- Boij, Roland, et al.
(författare)
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Biomarkers of Coagulation, Inflammation, and Angiogenesis are Independently Associated with Preeclampsia
- 2012
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Ingår i: AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY. - : John Wiley and Sons. - 1046-7408 .- 8755-8920. ; 68:3, s. 258-270
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Tidskriftsartikel (refereegranskat)abstract
- Problem Although preeclampsia has been associated with inflammation, coagulation, and angiogenesis, their correlation and relative contribution are unknown. Method of Study About 114 women with preeclampsia, 31 with early onset (EOP) and 83 with late onset preeclampsia (LOP), and 100 normal pregnant controls were included. A broad panel of 32 biomarkers reflecting coagulation, inflammation, and angiogenesis was analyzed. Results Preeclampsia was associated with decreased antithrombin, IL-4 and placental growth factor levels and with increased C3a, pentraxin-3, and sFlt-1 levels, with more marked differences in the EOP group. The Th1-associated chemokines CXCL10 and CXCL11 were significantly higher in the preeclampsia and EOP group than in controls, respectively. No correlations between the biomarkers were found in preeclampsia. Multivariate logistic regression tests confirmed the results. Conclusions Cytokines, chemokines and complement activation seem to be part of a Th1-like inflammatory reaction in preeclampsia, most pronounced in EOP, where chemokines may be more useful than cytokines as biomarkers. Biomarkers were not correlated suggesting partly independent or in time separated mechanisms.
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| 3. |
- Boij, Roland, et al.
(författare)
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Regulatory T-cell Subpopulations in Severe or Early-onset Preeclampsia
- 2015
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Ingår i: American Journal of Reproductive Immunology. - : WILEY-BLACKWELL. - 1046-7408 .- 1600-0897. ; 74:4, s. 368-378
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Tidskriftsartikel (refereegranskat)abstract
- Problem A deficiency in regulatory T (Treg) cells causing reduced immune regulatory capacity has been proposed in preeclampsia. Objective Utilizing recent advances in flow cytometry phenotyping, we aimed to assess whether a deficiency of Treg subpopulations occurs in preeclampsia. Method of study Six-color flow cytometry was used for Treg phenotyping in 18 preeclamptic women (one early-onset, one severe and 16 both), 20 women with normal pregnancy, and 20 non-pregnant controls. Results No differences were found in major Treg populations including CD127(low)CD25(+)/CD127(ow)FOXP3(+), resting (FOXP3(dim)CD45RA(+)), and activated (FOXP3(bright)CD45RA(-)) Treg cells, whereas preeclamptic women showed increased CTLA-4(+) and CCR4(+) proportions within resting/activated Treg populations. Corticosteroid treatment prior to blood sampling (n = 10) affected the distribution of Treg populations. Conclusions Although we found no major alterations in circulating Treg frequencies, differences in CTLA-4(+) and CCR4(+) frequencies suggest a migratory defect of Treg cells in preeclampsia. Corticosteroid treatment should be taken into account when evaluating Treg cells.
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| 4. |
- Kalkunte, Satyan, et al.
(författare)
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Sera from Preeclampsia Patients Elicit Symptoms of Human Disease in Mice and Provide a Basis for an in Vitro Predictive Assay
- 2010
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Ingår i: AMERICAN JOURNAL OF PATHOLOGY. - : American Society for Investigative Pathology (ASIP). - 0002-9440. ; 177:5, s. 2387-2398
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Tidskriftsartikel (refereegranskat)abstract
- Early diagnosis and treatment of preeclampsia would significantly reduce maternal and fetal morbidity and mortality. However, its etiology and prediction have remained elusive. Based on the hypothesis that sera from patients with preeclampsia could function as a "blueprint" of causative factors, we describe a serum-based pregnancy-specific mouse model that closely mirrors the human condition as well as an in vitro predictive assay. We show that a single administration of human preeclampsia serum in pregnant IL-10(-/-) mice induced the full spectrum of preeclampsia-like symptoms, caused hypoxic injury in uteroplacental tissues, and elevated soluble fins-like tyrosine kinase 1 and soluble endoglin, markers thought to be related to the disease. The same serum sample(s) induced a partial preeclampsia phenotype in wild-type mice. Importantly, preeclampsia serum disrupted cross talk between trophoblasts and endothelial cells in an in vitro model of endovascular activity. Disruption of endovascular activity could be documented in serum samples as early as 12 to 14 weeks of gestation from patients who subsequently developed preeclampsia. These results indicate that preeclampsia patient sera can be used to understand the pregnancy-specific disease pathology in mice and can predict the disorder.
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| 5. |
- Lindau, Robert, et al.
(författare)
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Interleukin-34 is present at the fetal-maternal interface and induces immunoregulatory macrophages of a decidual phenotype in vitro
- 2018
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Ingår i: Human Reproduction. - : OXFORD UNIV PRESS. - 0268-1161 .- 1460-2350. ; 33:4, s. 588-599
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Tidskriftsartikel (refereegranskat)abstract
- STUDY QUESTION: Is the newly discovered cytokine interleukin (IL)-34 expressed at the human fetal-maternal interface in order to influence polarization of monocytes into macrophages of a decidual immunoregulatory phenotype? SUMMARY ANSWER: IL-34 was found to be present at the fetal-maternal interface, in both fetal placenta and maternal decidua, and it was able to polarize monocytes into macrophages of a decidual phenotype. WHAT IS KNOWN ALREADY: IL-34 was shown to bind to the same receptor as macrophage-colony stimulating factor (M-CSF), which has an important immunomodulatory role at the fetal-maternal interface, for example by polarizing decidual macrophages to an M2-like regulatory phenotype. IL-34 is known to regulate macrophage subsets, such as microglia and Langerhans cells, but its presence at the fetal-maternal interface is unknown. STUDY DESIGN, SIZE, DURATION: The presence of IL-34 at the fetal-maternal interface was evaluated by immunohistochemistry (IHC) and ELISA in placental and decidual tissues as well as in isolated trophoblast cells and decidual stromal cells obtained from first trimester elective surgical terminations of pregnancy (n = 49). IL-34 expression was also assessed in third trimester placental biopsies from women with (n = 21) or without (n = 15) pre-eclampsia. The effect of IL-34 on macrophage polarization was evaluated in an in vitro model of blood monocytes obtained from healthy volunteers (n = 14). In this model, granulocyte macrophage-colony stimulating factor (GM-CSF) serves as a growth factor for M1-like polarization, and M-CSF as a growth factor for M2-like polarization. PARTICIPANTS/MATERIALS, SETTING, METHODS: First trimester placental and decidual tissues were obtained from elective pregnancy terminations. Placental biopsies were obtained from women with pre-eclampsia and matched controls in the delivery ward. Polarization of macrophages in vitro was determined by flow-cytometric phenotyping and secretion of cytokines and chemokines in cell-free supernatants by multiplex bead assay. MAIN RESULTS AND THE ROLE OF CHANCE: Our study shows that IL-34 is produced at the fetal-maternal interface by both placental cyto-and syncytiotrophoblasts and decidual stromal cells. We also show that IL-34, in vitro, is able to polarize blood monocytes into macrophages with a phenotype (CD14(high)CD163(+)CD209(+)) and cytokine secretion pattern similar to that of decidual macrophages. The IL-34-induced phenotype was similar, but not identical to the phenotype induced by M-CSF, and both IL-34-and M-CSF-induced macrophages were significantly different (P amp;lt; 0.05-0.0001 depending on marker) from GM-CSF-polarized M1-like macrophages. Our findings suggest that IL-34 is involved in the establishment of the tolerant milieu found at the fetal-maternal interface by skewing polarization of macrophages into a regulatory phenotype. LIMITATIONS, REASONS FOR CAUTION: Although it is clear that IL-34 is present at the fetal-maternal interface and polarizes macrophages in vitro, its precise role in vivo remains to be established. WIDER IMPLICATIONS OF THE FINDINGS: The recently discovered cytokine IL-34 is present at the fetal-maternal interface and has immunomodulatory properties with regard to induction of decidual macrophages, which are important for a healthy pregnancy. Knowledge of growth factors related to macrophage polarization can potentially be translated to treatment of pregnancy complications involving dysregulation of this process. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by grants from the Medical Research Council (Grant K2013-61X-22310-01-04), the Research Council of South-East Sweden (FORSS), and the County Council of Ostergotland, Sweden. No author has any conflicts of interest to declare.
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| 6. |
- Marie, Blomstrand, et al.
(författare)
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Systematic bladder scanning identifies more women with postpartum urinary retention than diagnosis by clinical signs and symptoms
- 2015
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Ingår i: International Journal of Nursing and Midwifery. - : Academic Journals. - 2141-2456. ; 7:6, s. 108-115
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Tidskriftsartikel (refereegranskat)abstract
- This study aims to determine if systematic use of bladder scan accurately identifies more women with postpartum urinary retention compared with diagnosis using clinical signs and symptoms, alone. A prospective, quasi experimental study was performed at the Department of Obstetrics and Gynecology, County Hospital Ryhov, Jönköping, Sweden. A total of 252 women participated in this study; they were women who gave birth between the period of March and April, 2011. One hundred and twenty-six women were included in an experimental group, they received ultrasound scanning of post-void residual bladder volume for identification of urinary retention; patients were catheterized if post-void residual bladder volume was ≥400 ml. A control group of 126 women, matched by parity and age, were also included. The latter group were catheterized on clinical signs or symptoms of urinary retention. Twenty-one women in the experimental group were identified as having post-void residual bladder volume ≥400 ml compared to 9 in the control group, verified by catheterization (p < 0.05). Eleven women in the experimental group had covert urinary retention with a post-void residual bladder volume of 400 to 1200 ml. No woman who gave birth by caesarean section was identified with postpartum urinary retention. Univariable logistic regression analyses identified seven risk indicators of postpartum urinary retention: first pregnancy, delivery with use of ventouse, oxytocin infusion, epidural analgesia, second stage of >120 min, active pushing >30 min and perineal tear. Oxytocin infusion and perineal tear were independent risk indicators in a multivariable regression analysis. Systematic bladder scanning identifies more women with postpartum urinary retention in women with vaginal delivery than diagnosis by clinical signs and symptoms, alone. Oxytocin infusion and perineal tear are independent risk indicators for urinary retention in new delivered women.
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| 7. |
- Mjösberg, Jenny, et al.
(författare)
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Circulating CD4dimCD25highFOXP3+ regulatory T cells in severe early-onset preeclampsia
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Preeclampsia is an inflammatory condition suggested to involve regulatory CD4+CD25high T helper cell (Treg) disturbances. However, the importance of Tregs in early-onset preeclampsia, associated with increased disease severity and possibly representing a more distinct placental disease, remains unclear. We recently showed that by defining Tregs as CD4dimCD25high cells, the risk of including activated non-Tregs, being more prominent in the circulation during pregnancy, is avoided. The aim of this study was to determine, using updated Treg markers and flow cytometric gating strategies, the frequency and phenotype of circulating Tregs from women with severe early-onset preeclampsia (n=10) as compared with healthy pregnant (n=20) and nonpregnant (n=20) women. The frequency of CD4dimCD25high cells and the expression of FOXP3 was similar in healthy and preeclamptic pregnancy. However, the occurrence of CTLA-4+ and HLA-DR+ cells in the Treg population from preeclamptic women tended to be higher than in healthy pregnant women, indicating alterations in Treg functionality in preeclampsia. Further, the Treg population from healthy pregnant, but not preeclamptic, women tended to be enriched for CCR4+ and CD45R0+ cells as compared with nonpregnant women. In conclusion, although the findings do not support a role for diminished circulating Treg frequency in severe early-onset preeclampsia, the study suggests functional alterations related to Treg suppression, activation and migration mechanisms in this subgroup of preeclamptic women.
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| 8. |
- Mjösberg, Jenny, et al.
(författare)
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Systemic reduction of functionally suppressive CD4dimCD25highFoxp3+ Tregs in human second trimester pregnancy is induced by progesterone and 17θ-estradiol
- 2009
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 183:1, s. 759-769
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Tidskriftsartikel (refereegranskat)abstract
- CD4+CD25high regulatory T cells (Tregs) are implicated in the maintenance of murine pregnancy. However, reports regarding circulating Treg frequencies in human pregnancy are inconsistent, and the functionality and phenotype of these cells in pregnancy have not been clarified. The aim of this study was to determine the frequency, phenotype, and function of circulating Tregs in the second trimester of human pregnancy and the influence of progesterone and 17β-estradiol on Treg phenotype and frequency. Based on expressions of Foxp3, CD127, and HLA-DR as determined by multicolor flow cytometry, we defined a proper CD4dimCD25high Treg population and showed, in contrast to most previous reports, that this population was reduced in second trimester of pregnancy. Unexpectedly, Foxp3 expression was decreased in the Treg, as well as in the CD4+ population. These changes could be replicated in an in vitro system resembling the pregnancy hormonal milieu, where 17β-estradiol, and in particular progesterone, induced, in line with the pregnancy situation, a reduction of CD4dimCD25highFoxp3+ cells in PBMC from nonpregnant women. By coculturing FACS-sorted Tregs and autologous CD4+CD25– responder cells, we showed that Tregs from pregnant women still displayed the same suppressive capacity as nonpregnant women in terms of suppressing IL-2, TNF-, and IFN- secretion from responder cells while efficiently producing IL-4 and IL-10. Our findings support the view of hormones, particularly progesterone, as critical regulators of Tregs in pregnancy. Furthermore, we suggest that in the light of the results of this study, early data on circulating Treg frequencies in pregnancy need reevaluation.The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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| 9. |
- Rasmark Roepke, E., et al.
(författare)
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Low-molecular-weight-heparin increases Th1-and Th17-associated chemokine levels during pregnancy in women with unexplained recurrent pregnancy loss: a randomised controlled trial
- 2019
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Low-molecular-weight heparin (LMWH) is widely used to treat recurrent pregnancy loss (RPL) because of its anti-coagulant effects. Although in vitro studies have suggested additional immunological effects, these are debated. We therefore investigated whether LMWH could modulate immune responses in vivo during pregnancy of women with unexplained RPL. A Swedish open multi-centre randomised controlled trial included 45 women treated with tinzaparin and 42 untreated women. Longitudinally collected plasma samples were obtained at gestational weeks (gw) 6, 18, 28 and 34 and analysed by multiplex bead technology for levels of 11 cytokines and chemokines, chosen to represent inflammation and T-helper subset-associated immunity. Mixed linear models test on LMWH-treated and untreated women showed differences during pregnancy of the Th1-associated chemokines CXCL10 (p = 0.01), CXCL11 (p amp;lt; 0.001) and the Th17-associated chemokine CCL20 (p = 0.04), while CCL2, CCL17, CCL22, CXCL1, CXCL8, CXCL12, CXCL13 and IL-6 did not differ. Subsequent Students t-test showed significantly higher plasma levels of CXCL10 and CXCL11 in treated than untreated women at gw 28 and 34. The consistent increase in the two Th1-associated chemokines suggests a potential proinflammatory and unfavourable effect of LMWH treatment during later stages of pregnancy, when Th1 immunity is known to disrupt immunological tolerance.
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| 10. |
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