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Local Immune regulation in human pregnancy: with focus on decidual macrophages
Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

During pregnancy, the woman carries a fetus partly foreign to her immune system, because of the expression of paternal antigens. Despite this, the fetus is normally tolerated and not rejected, as is often the case with organs in allogeneic transplantations. Systemic changes in maternal blood occur during pregnancy but, perhaps of greater importance, are changes in tissues locally in the uterus. The pregnant uterine endometrium, the decidua, is infiltrated by large numbers of leukocytes, mainly natural killer (NK) cells but also macrophages and T lymphocytes. Further, various cytokines are known to be secreted at the fetomaternal interface. However, the functions of these cells and the cytokine networks are not fully understood. The aim of this thesis was to investigate the local immune balance in normal human pregnancy decidua, both in the early phase of pregnancy and at parturition.

First trimester decidual mononuclear cells, NK cells and macrophages were all shown to secrete IFN-γ, IL-4 and IL-10, as detected by ELISPOT. The secretion was not mirrored in blood from the same subjects. A significantly larger number of decidual macrophages secreted IL-10 than did their blood counterparts, indicating potential regulatory functions of this cell type.

Further examination of early pregnancy decidual macrophages by microarray revealed 120 genes being differentially regulated at the transcriptional level in decidual compared to blood monocytes/macrophages. Several genes were associated with alternative activation/M2 polarization of macrophages, including CCL-18, CD209, IGF-1, MRC-1 and FN-1. Genes connected to immune regulation and tissue remodelling were common, in line with the potential functions for this cell type in utero. In addition, some molecules not previously connected to decidual macrophages, such as TREM-2, A2M and PGDS, were found to be upregulated, gaining new insights into the regulatory functions of decidual macrophages.

Term decidual mononuclear cells spontaneously secrete IFN-γ, TNF, IL-4, IL-10, and TGF-β. No differences were seen between tissues obtained before and after the onset of labour, indicating that decidual mononuclear cells are not the main cell population responsible for plausible cytokine regulation in the process of labour induction. Placental and fetal membranes as well as cells in the maternal systemic circulation may instead contribute to a possible shift in immune balance prior to pregnancy termination.

In conclusion, decidual leukocytes, including NK cells and macrophages, are potential producers of both Th1-like/pro-inflammatory and Th2-like/anti-inflammatory cytokines in early pregnancy as well as at parturition. Decidual macrophages are of a specialized phenotype with effector functions contributing to a proper invasion of the placenta and to immunological protection of the semi-allogeneic fetus. This thesis adds new knowledge on local immune balance during normal human pregnancy, however, the clinical significance of the presented data needs to be clarified.

Place, publisher, year, edition, pages
Institutionen för klinisk och experimentell medicin , 2007. , 68 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1016
Keyword [en]
reproduction, placenta, leukocyte, ELISPOT
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:liu:diva-9985ISBN: 978-91-85895-85-4 (print)OAI: oai:DiVA.org:liu-9985DiVA: diva2:24262
Public defence
2007-10-19, Berzeliussalen, Hälsouniversitetet, Universitetssjukhuset, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2007-10-10 Created: 2007-10-10 Last updated: 2013-08-29
List of papers
1. Spontaneous secretion of interleukin-4, interleukin-10 and interferon-gamma by first trimester decidual mononuclear cells
Open this publication in new window or tab >>Spontaneous secretion of interleukin-4, interleukin-10 and interferon-gamma by first trimester decidual mononuclear cells
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2002 (English)In: American Journal of reproductive immunology, ISSN 8755-8920, Vol. 47, no 3, 159-166 p.Article in journal (Refereed) Published
Abstract [en]

PROBLEM: A T-helper cell type 2 (Th2) cytokine dominated microenvironment has been predicted to be crucial for successful pregnancy. However, little information is available about local cytokine secretion in the human decidua. We determined the spontaneous secretion of interleukin-4 (IL-4), interferon-γ (IFN-γ) and IL-10 by decidual mononuclear cells at the single cell level and compared it with their secretion by peripheral blood mononuclear cells (PBMC) in the first trimester of pregnancy.

METHODS OF STUDY: The cytokine secretion from decidual and blood cells was detected by a sensitive enzyme-linked immunosorbent spot-forming cell (ELISPOT)-assay.

RESULTS: Cells secreting IL-4 (median 153, range 8–530), IL-10 (median 188, range 32–1600) and IFN-γ (median 123, range 15–1140) were detected in all decidual and blood samples. The cytokine secretion showed a co-linear pattern in both the blood and decidua, i.e. when one cytokine was secreted at high levels, the others followed the trend. No correlation was found between the number of cytokine secreting cells in blood and decidua for any of the cytokines.

CONCLUSIONS: Interleukin-4 and IL-10 are locally secreted in the decidua early during normal pregnancy, probably counteracting the fetal rejecting effects of co-expressed IFN-γ. The cytokine secretion by blood cells does not generally reflect the local secretion pattern during first trimester pregnancy.

Keyword
Decidua, inteferon-γ, interleukin-10, interleukin-4, pregnancy
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14684 (URN)10.1034/j.1600-0897.2002.1o057.x (DOI)
Available from: 2007-10-10 Created: 2007-10-10 Last updated: 2013-08-29
2. Cytokine secretion patterns of NK cells and macrophages in early human pregnancy decidua and blood: Implications for suppressor macrophages in decidua
Open this publication in new window or tab >>Cytokine secretion patterns of NK cells and macrophages in early human pregnancy decidua and blood: Implications for suppressor macrophages in decidua
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2003 (English)In: American Journal of reproductive immunology, ISSN 8755-8920, Vol. 50, no 6, 444-452 p.Article in journal (Refereed) Published
Abstract [en]

Problem: Local immune modulation has been shown to be of considerable importance for the maintenance of successful pregnancy. We have previously reported the secretion of interferon-γ (IFN-γ), interleukin-4 (IL-4) and IL-10 in human decidua from early normal pregnancy. The aim of this study was to investigate the cellular source of cytokine secretion in the decidua, and compare this to secretion patterns in peripheral blood.

Method of study: Decidual tissue and peripheral blood was collected from 20 women undergoing surgical abortion during first trimester pregnancy. Monocytes/macrophages and NK cells were enriched by immunomagnetic cell separation and cytokine secretion was detected by enzyme-linked immunosorbent spot-forming cell assay.

Results: Decidual and peripheral monocytes/macrophages and NK cells spontaneously secrete IFN-γ, IL-4 and IL-10. The number of IL-10 secreting cells was significantly higher in decidual macrophages compared with decidual non-monocytic cells as well as compared with blood monocytes/macrophages. These differences were not seen for IFN-γ or IL-4.

Conclusions: Our results indicate that decidual macrophages subserve important suppressive functions in the pregnant uterus.

Keyword
Decidua, IFN-γ, IL-10, IL-4, macrophages, natural killer cells, pregnancy
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14685 (URN)10.1046/j.8755-8920.2003.00112.x (DOI)
Available from: 2007-10-10 Created: 2007-10-10 Last updated: 2013-08-29
3. Gene expression profiling of human decidual macrophages: Evidence for immunosuppressive phenotype
Open this publication in new window or tab >>Gene expression profiling of human decidual macrophages: Evidence for immunosuppressive phenotype
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2008 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 3, no 4, e2078- p.Article in journal (Refereed) Published
Abstract [en]

Background: Although uterine macrophages are thought to play an important regulatory role at the maternal-fetal interface, their global gene expression profile is not known.

Methodology/Principal Findings: Using micro-array comprising approximately 14,000 genes, the gene expression pattern of human first trimester decidual CD14+ monocytes/macrophages was characterized and compared with the expression profile of the corresponding cells in blood. Some of the key findings were confirmed by real time PCR or by secreted protein. A unique gene expression pattern intrinsic of first trimester decidual CD14+ cells was demonstrated. A large number of regulated genes were functionally related to immunomodulation and tissue remodelling, corroborating polarization patterns of differentiated macrophages mainly of the alternatively activated M2 phenotype. These include known M2 markers such as CCL-18, CD209, insulin-like growth factor (IGF)-1, mannose receptor c type (MRC)-1 and fibronectin-1. Further, the selective up-regulation of triggering receptor expressed on myeloid cells (TREM)-2, alpha-2-macroglobulin (A2M) and prostaglandin D2 synthase (PGDS) provides new insights into the regulatory function of decidual macrophages in pregnancy that may have implications in pregnancy complications.

Conclusions/Significance: The molecular characterization of decidual macrophages presents a unique transcriptional profile replete with important components for fetal immunoprotection and provides several clues for further studies of these cells.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14686 (URN)10.1371/journal.pone.0002078 (DOI)
Note
Original Publication: Charlotte Gustafsson (Lidström), Jenny Mjösberg, Andreas Matussek, Robert Geffers, Leif Matthiesen, Göran Berg, Surendra Sharma, Jan Buer and Jan Ernerudh, Gene expression profiling of human decidual macrophages: Evidence for immunosuppressive phenotype, 2008, PLoS ONE, (3), 4, e2078. http://dx.doi.org/10.1371/journal.pone.0002078 Copyright: Public Library of Science (PLoS) http://www.plos.org/ Available from: 2007-10-10 Created: 2007-10-10 Last updated: 2010-03-19
4. Cytokine secretion in decidual mononuclear cells from term human pregnancy with or without labour: ELISPOT detection of IFN-gamma, IL-4, IL-10, TGF-beta and TNF-alpha
Open this publication in new window or tab >>Cytokine secretion in decidual mononuclear cells from term human pregnancy with or without labour: ELISPOT detection of IFN-gamma, IL-4, IL-10, TGF-beta and TNF-alpha
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2006 (English)In: Journal of reproductive immunology, ISSN 0165-0378, Vol. 71, no 1, 41-56 p.Article in journal (Refereed) Published
Abstract [en]

Cytokines are believed to be important in maintaining pregnancy and in the process of labour induction in humans. The aim of this study was to investigate the secretion of the cytokines interferon-γ (IFN-γ), interleukin-4 (IL-4), IL-10, transforming growth factor-β (TGF-β) and tumour necrosis factor-α (TNF-α) in decidual tissue with or without labour.

Decidual tissue was collected from 32 healthy women undergoing elective caesarean sections before the onset of labour (n = 17) or after normal vaginal delivery (n = 15). Mononuclear cells were analysed for cytokine secretion with ELISPOT. To validate the widely used method of tissue collected at caesarean sections and after vaginal deliveries as a representative of before and after labour, respectively, placenta biopsies were collected from 12 healthy women to study the expression of the prostaglandin pathway enzymes cyclooxygenase-2 (COX-2) and microsomal prostaglandin E2 synthase (mPGES).

Decidual mononuclear cells from term human pregnancy spontaneously secrete IFN-γ, IL-4, IL-10, TGF-β and TNF-α. No difference was seen in cytokine secretion with or without labour, indicating that decidual leukocytes are not the main cell population responsible for plausible cytokine regulation in the process of termination of pregnancy. Placental tissues obtained after vaginal delivery showed a higher mRNA expression of the prostaglandin regulating molecules COX-2 and mPGES than tissues from caesarean sections before the onset of labour, validating that the model can be used as a representative of the state before and after labour.

Keyword
Parturition; Prostaglandins; COX-2; mPGES
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14687 (URN)10.1016/j.jri.2005.12.009 (DOI)
Available from: 2007-10-10 Created: 2007-10-10 Last updated: 2013-08-29

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