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Cytokines and immune balance in preeclampsia: a survey of some immunological variables and methods in the study of preeclampsia
Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Preeclampsia is one of the most feared pregnancy complications, with a risk of maternal and fetal death and with no ideal therapy readily available. The cause of this strictly pregnancyrelated disease is still unknown and is therefore a great challenge to all researchers in the field of pregnancy-related pathophysiology.

Today, the dominating theory of the origin of preeclampsia is defective initial placentation with insufficient penetration of the trophoblasts, leading to impaired maternal blood flow through narrow spiral arteries. However, the cause of this defective trophoblast behavior is not known. The maternal immune system has been proposed to have an influence on both the placentation and the subsequent systemic reactions. Therefore, it is very interesting to study the maternal immune system during preeclampsia, in hope of achieving a better understanding of this puzzling disease.

Earlier studies have suggested that normal pregnancy requires a shift to a Th2/antiinflammatory type of immunity, at least directed towards the fetus and placenta, while some pregnancy complications, such as preeclampsia, could be due to a skewed Th1/proinflammatory type of immunity. However, the results from earlier studies designed to test the Th1/Th2 hypothesis in preeclampsia have not been consistent. Therefore, the aim of this thesis was to examine if established preeclampsia is associated with increased innate inflammatory responses and a deviation of adaptive responses towards Th1 when compared with normal pregnancy.

Enumerations of cytokine-producing cells from peripheral blood did not show any difference in the production of IFN-γ, IL-4, IL-10 and IL-12 between women with preeclampsia and normal pregnancies. However, a decrease in the spontaneously produced levels of IL-5 was detected in cell cultures on peripheral blood mononuclear cells in women with preeclampsia. Furthermore, a decreased production of IL-10 in response to paternal antigens, believed to represent the fetus, was also detected for the preeclamptic women.

Serum analysis showed increased levels of the pro-inflammatory mediators IL-6 and IL-8 during preeclampsia. Also, preeclamptic women displayed increased serum levels of the soluble IL-4 receptor, but no difference in the levels of IL-4 compared to normal pregnant women. This was an elusive finding, since the receptor was originally thought to reflect the levels of IL-4, but has recently been shown to have both agonistic and antagonistic properties on the IL-4 levels. Further studies of the local immune responses in the placenta showed no difference in the immunohistochemical staining of IL-4 and TNF-α between women with preeclampsia and women with normal pregnancies. In general, there were no hallmarks of abnormal morphology in the placental sections examined, regardless of diagnosis.

In conclusion, the decreased levels of IL-10 in response to paternal antigens and the systemically increased levels of IL-6 and IL-8 suggest a specific decrease in antiinflammatory responses towards fetal antigens, together with a systemic activation of proinflammatory mediators during preeclampsia. Furthermore, the decreased production of IL-5 also indicates, at least partly, decreased Th2 responses in the established preeclampsia.

Place, publisher, year, edition, pages
Institutionen för molekylär och klinisk medicin , 2005.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 924
Keyword [en]
Preeclampsia, Cytokines, Leukocytes, Immunology, Placenta, Th1/Th2 balance, Inflammation
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:liu:diva-8602ISBN: 91-85497-60-6 (print)OAI: oai:DiVA.org:liu-8602DiVA: diva2:23354
Public defence
2005-12-09, Berzeliussalen, Campus Valla, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Note
Figure 1 on page 6 is republished in the Ph.D. thesis with the kind permisson of Blackwell Publishing (http://www.blackwellpublishing.com). Figure IX on page38, figure XB on page 41, figure XI on page 46 and figure XII on page 47 are all published in the Journal of Reproductive Immunology and republished with kind permisson from Elsevier (http://www.elsevier.com/) in the Ph.D. thesis.Available from: 2007-03-23 Created: 2007-03-23 Last updated: 2013-08-29
List of papers
1. Systemic Th1/Th2 cytokine responses to paternal and vaccination antigens in preeclampsia: no differences compared with normal pregnancy
Open this publication in new window or tab >>Systemic Th1/Th2 cytokine responses to paternal and vaccination antigens in preeclampsia: no differences compared with normal pregnancy
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2004 (English)In: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 51, no 4, 302-310 p.Article in journal (Refereed) Published
Abstract [en]

Problem: A Th1-shift has been suggested to be involved in the pathogenesis of preeclampsia. This study was designed to compare Th1/Th2 related cytokine secretion in blood between women with preeclampsia (n = 15) and normal pregnancies (n = 15), using a high-sensitivity technique for cytokine detection.

Methods of study: Spontaneous as well as 'fetus-specific' and recall antigen-specific (purified protein derivate of Mycobacterium tuberculosis, tetanus toxoid and lipopolysaccharide) secretion of interferon-γ, interleukin (IL)-4, IL-10 and IL-12 in peripheral blood mononuclear cells (PBMC) was detected by enzyme-linked immunosorbent spot-forming cell assay (ELISPOT). Fetus-specific secretion was induced by stimulation with paternal PBMC in a mixed leukocyte culture assay.

Results: All cytokines were secreted by PBMCs both from women with preeclampsia and women with normal pregnancies. No differences in the number of cytokine-secreting cells were found between the two groups.

Conclusions: No evidence was found for a shift in the systemic Th1/Th2 responses, in preeclampsia compared with normal pregnancy. This does, however, not exclude differences in the local immune responses related to the fetoplacental unit.

Place, publisher, year, edition, pages
John Wiley & Sons, 2004
Keyword
ELISPOT, interferon-γ, interleukin-10, interleukin-12, interleukin-4, preeclampsia
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14372 (URN)10.1111/j.1600-0897.2004.00161.x (DOI)
Available from: 2007-03-23 Created: 2007-03-23 Last updated: 2017-02-09Bibliographically approved
2. Indications of an altered immune balance in preeclampsia: A decrease in in vitro secretion of IL-5 and IL-10 from blood mononuclear cells and in blood basophil counts compared with normal pregnancy
Open this publication in new window or tab >>Indications of an altered immune balance in preeclampsia: A decrease in in vitro secretion of IL-5 and IL-10 from blood mononuclear cells and in blood basophil counts compared with normal pregnancy
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2005 (English)In: Journal of Reproductive Immunology, ISSN 0165-0378, Vol. 66, no 1, 69-84 p.Article in journal (Refereed) Published
Abstract [en]

It has been suggested that maladaptation of the maternal immune response during pregnancy might be a causal factor for preeclampsia. This study was designed to examine the systemic immune status at both the innate level and the adaptive level in pregnancies complicated by preeclampsia (n = 15) and normal pregnancies (n = 15). Spontaneous and in vitro-induced secretion of IL-5, IL-6, IL-10, IL-12, IL-13 and TNF-α, in response to paternal blood cells and the vaccination antigens purified protein derivate of tuberculin (PPD) and tetanus toxoid (TT), was detected in cell culture supernatants from blood mononuclear cells by ELISA. Preeclamptic women showed reduced numbers of basophil granulocytes in the blood (p = 0.004) and lower spontaneous secretion of IL-5 from blood mononuclear cells (p = 0.016). In addition, paternal antigen-induced secretion of IL-10 was decreased in preeclampsia compared with normal pregnancy (p = 0.012). No further differences between preeclampsia and normal pregnancy were found for any stimuli or cytokines. The present findings of reduced basophil numbers and lower spontaneous in vitro secretion of IL-5 in preeclampsia compared with normal pregnancy indicate a decrease in systemic Th2 immunity in preeclampsia. Furthermore, the decrease in paternal antigen-induced secretion of the immunosuppressive cytokine IL-10 in preeclampsia indicates a fetus-specific decrease in immunosuppression mediated by blood mononuclear cells. Whether these systemic changes are a cause or a consequence of preeclampsia remains to be elucidated.

Keyword
Cytokines; Preeclampsia; In vitro; ELISA; Th1/Th2
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14373 (URN)10.1016/j.jri.2005.02.002 (DOI)
Available from: 2007-03-23 Created: 2007-03-23 Last updated: 2013-08-29
3. Cytokine mapping of sera from women with preeclampsia and from women with normal pregnancies
Open this publication in new window or tab >>Cytokine mapping of sera from women with preeclampsia and from women with normal pregnancies
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2006 (English)In: Journal of Reproductive Immunology, ISSN 0165-0378, Vol. 70, no 1-2, 83-91 p.Article in journal (Refereed) Published
Abstract [en]

Introduction

Preeclampsia is a pregnancy-specific syndrome. The immune system in preeclampsia is changed with an increased innate activity and there is a hypothesis of a shift towards Th1-type immunity. The aim of this study was to determine a spectrum of soluble immunological factors denoting different aspects of immune activation in third trimester sera from women with preeclampsia (N = 15) and compare with levels in sera from normal pregnant women (N = 15).

Material and methods

IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 p40, IL-13, IL-15, IL-17, IFN-α, IFN-γ, TNF-α, GM-CSF, MIP-lα, MIP-1β, MCP-1, eotaxin and RANTES were measured in serum using multiplex bead arrays. The levels of soluble CD14 and soluble IL-4 receptor were measured by enzyme-linked immunoassay (ELISA).

Results

Preeclamptic women had significantly increased levels of circulating IL-6 (p = 0.002), IL-8 (p = 0.003) and soluble IL-4R (p = 0.037), compared to women with normal pregnancies.

Conclusion

This study supports the hypothesis of increased inflammatory responses in preeclampsia, illustrated by the increased levels of IL-6 and IL-8. The finding of increased levels of soluble IL-4 receptor is an intriguing finding with several interpretations, which may partly support the hypothesis of a Th1 shift in preeclampsia.

Keyword
Cytokines; Serum; Multiple bead array; Preeclampsia
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14374 (URN)10.1016/j.jri.2005.10.007 (DOI)
Available from: 2007-03-23 Created: 2007-03-23 Last updated: 2013-08-29
4. Immunohistochemical studies of interleukin-4 (IL-4) and tumor necrosis factor α (TNF-α) in placentas from preeclamptic and normal pregnancies
Open this publication in new window or tab >>Immunohistochemical studies of interleukin-4 (IL-4) and tumor necrosis factor α (TNF-α) in placentas from preeclamptic and normal pregnancies
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Manuscript (Other academic)
Identifiers
urn:nbn:se:liu:diva-14375 (URN)
Available from: 2007-03-23 Created: 2007-03-23 Last updated: 2010-01-13

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