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Aspects of inflammation, angiogenesis and coagulation in preeclampsia
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. , 141 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1548
National Category
Immunology Immunology in the medical area Cell and Molecular Biology Neurosciences Obstetrics, Gynecology and Reproductive Medicine
Identifiers
URN: urn:nbn:se:liu:diva-132446DOI: 10.3384/diss.diva-132446ISBN: 9789176856512 (Print)OAI: oai:DiVA.org:liu-132446DiVA: diva2:1045919
Public defence
2016-12-02, Originalet, Qulturum, Länssjukhuset Ryhov, Jönköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2016-11-11 Created: 2016-11-11 Last updated: 2016-11-11Bibliographically approved
List of papers
1. Sera from Preeclampsia Patients Elicit Symptoms of Human Disease in Mice and Provide a Basis for an in Vitro Predictive Assay
Open this publication in new window or tab >>Sera from Preeclampsia Patients Elicit Symptoms of Human Disease in Mice and Provide a Basis for an in Vitro Predictive Assay
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2010 (English)In: AMERICAN JOURNAL OF PATHOLOGY, ISSN 0002-9440, Vol. 177, no 5, 2387-2398 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Society for Investigative Pathology (ASIP), 2010
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-62755 (URN)10.2353/ajpath.2010.100475 (DOI)000284182900026 ()
Available from: 2010-12-03 Created: 2010-12-03 Last updated: 2016-11-11
2. Biomarkers of Coagulation, Inflammation, and Angiogenesis are Independently Associated with Preeclampsia
Open this publication in new window or tab >>Biomarkers of Coagulation, Inflammation, and Angiogenesis are Independently Associated with Preeclampsia
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2012 (English)In: AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, ISSN 1046-7408, Vol. 68, no 3, 258-270 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
John Wiley and Sons, 2012
Keyword
preeclampsia, coagulation, inflammation, angiogenesis, chemokines, cytokines and early onset preeclampsia
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81815 (URN)10.1111/j.1600-0897.2012.01158.x (DOI)000307440300012 ()
Note

Funding Agencies|FORSS (Medical Research Council of Southeast Sweden)||Futurum (the Research department of County of Jonkoping)||Swedish Research Council|2007-15809-48800-58|Linneaus University (Sweden)||

Available from: 2012-09-26 Created: 2012-09-24 Last updated: 2016-11-11
3. Regulatory T-cell Subpopulations in Severe or Early-onset Preeclampsia
Open this publication in new window or tab >>Regulatory T-cell Subpopulations in Severe or Early-onset Preeclampsia
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2015 (English)In: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 74, no 4, 368-378 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
WILEY-BLACKWELL, 2015
Keyword
Early-onset preeclampsia; preeclampsia; pregnancy; regulatory T cells
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:liu:diva-122528 (URN)10.1111/aji.12410 (DOI)000362664200009 ()26118401 (PubMedID)
Note

Funding Agencies|FORSS (Medical Research Council of Southeast Sweden); Futurum, academy for Health and Care Jonkoping County Council, Sweden

Available from: 2015-11-09 Created: 2015-11-06 Last updated: 2016-11-11

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