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Svensson, Judit
Alternative names
Publications (10 of 13) Show all publications
Svensson Arvelund, J., Söderberg, D., Wendel, C., Freland, S., Geffers, R., Berg, G., . . . Ernerudh, J. (2015). Decidual macrophages contribute to the unique leukocyte composition at the fetal-maternal interface by production of IL-35, induction of Treg cells and production of homeostatic chemokines.
Open this publication in new window or tab >>Decidual macrophages contribute to the unique leukocyte composition at the fetal-maternal interface by production of IL-35, induction of Treg cells and production of homeostatic chemokines
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2015 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Reproductive success depends on the ability of the maternal immune system to adapt in order to tolerate and support the growing semi-allogenic fetus. Macrophages, being a major leukocyte population in the uterine mucosa (decidua), may play a central role in promoting the unique composition and regulatory phenotype of leukocytes that is characteristic for the fetal-maternal interface. We show that decidual macrophages display a predominantly immune regulatory gene profile and produce the immunosuppressive cytokine IL-35 but no other members of the IL-12 family (IL-12, IL-23 and IL-27). Decidual macrophages also promoted the selective expansion of CD25highFoxp3+ Tregs but not of Tbet+ Th1, GATA-3+ Th2 and Rorγt+ Th17 cells. In addition, these macrophages preferentially secreted the monocyte- and Treg-associated chemokines CCL2 and CCL18, while Th1-, Th2- and Th17-related chemokines were produced at low levels. Among in vitro macrophages, distinct chemokine profiles were observed; IL-4/13 upregulated Th2-associated chemokines (CCL17, CCL22, CCL26) while LPS/IFNγ upregulated Th1-associated chemokines (CXCL9, CXCL10, CXCL11, CCL5). M(IL-10) macrophages (induced by M-CSF and IL-10) showed a chemokine profile similar to that of decidual macrophages, as shown by gene expression and protein analysis. By using M(IL-10) macrophages as a model of decidual macrophages, we show that these cells promote the recruitment of CD14+ monocytes, while migration of several lymphocyte populations was unaltered or prevented. These data implicate decidual macrophages as critical regulators of the decidual leukocyte composition and phenotype that is associated with successful reproduction.

National Category
Immunology Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-117182 (URN)
Available from: 2015-04-21 Created: 2015-04-21 Last updated: 2020-01-16Bibliographically approved
Svensson‐Arvelund, J. (2015). Immune regulation at the fetal‐maternal interface with focus on decidual macrophages. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Immune regulation at the fetal‐maternal interface with focus on decidual macrophages
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A successful pregnancy requires that the maternal immune system adapts to tolerate the semi-allogeneic fetal-placental unit. This adaptation mainly occurs locally, i.e. at the fetal-maternal interface, where fetal-derived tissues come into close contact with maternal cells in the uterine endometrium (called decidua during pregnancy). Macrophages and regulatory T (Treg) cells are maternal immune cells that are enriched in the decidua and they likely play a central role in promoting fetal tolerance. However, the precise function of decidual macrophages and the factors regulating both macrophages and Treg cells in humans are unknown. The aim of this thesis was to characterize the phenotype and function of decidual macrophages from first trimester human pregnancy and to identify factors responsible for inducing tolerogenic properties in both decidual macrophages and Treg cells. CD14+ decidual macrophages showed characteristics of immune suppressive or homeostatic macrophages (expression of CD163, CD206 and CD209), mainly produced immunosuppressive cytokines, like IL-10 and IL-35, while levels of inflammatory cytokines, for instance IL-12 and IL-23, were low. Decidual macrophages also induced the expansion of CD25highFoxp3+ Treg cells, but not of Th1, Th2 and Th17 cells, in vitro. In addition, decidual macrophages preferentially secreted the monocyte- and Treg cell-associated chemokines CCL2 and CCL18, while Th1-, Th2- and Th17-related chemokines were produced at low levels. These results suggest that decidual macrophages contribute to create the unique decidual cell composition and a tolerogenic immune environment that is compatible with fetal development. Further, by comparing decidual macrophages with different in vitro macrophage subsets, we showed that M-CSF and IL-10, but not GM-CSF, Th1 or Th2 stimuli, induced macrophages that resemble decidual macrophages in terms of cell surface marker expression, cytokine andchemokine production and gene expression profile. First trimester placental tissue, in particular placental trophoblast cells, was identified as an important source of M-CSF and IL-10. We also demonstrated that human fetal-derived placental tissue can induce the characteristics of decidual macrophages (CD163+CD206+CD209+IL-10+CCL18+) and the selective expansion of functionally suppressive CD25highFoxp3+ Treg cells, the latter partly mediated through IL-10, TGF-β and TRAIL. The placenta also limited activation of Th cells, for instance by generally reduced cytokine production. Our data show that the placenta has a unique ability to induce tolerogenic immune cells with a reduced inflammatory potential, which is essential for maintaining tissue integrity and preventing inflammation-induced fetal loss.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. p. 150
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1448
National Category
Immunology Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-117183 (URN)10.3384/diss.diva-117183 (DOI)978-91-7519-117-1 (ISBN)
Public defence
2015-05-22, Linden, Campus US, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2015-04-21 Created: 2015-04-21 Last updated: 2020-01-16Bibliographically approved
Boij, R., Mjosberg, J., Svensson Arvelund, J., Hjorth, M., Berg, G., Matthiesen, L., . . . Ernerudh, J. (2015). Regulatory T-cell Subpopulations in Severe or Early-onset Preeclampsia. American Journal of Reproductive Immunology, 74(4), 368-378
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, p. 368-378Article 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
Keywords
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: 2020-01-16
Svensson, J., Bhai Mehta, R., Lindau, R., Mirrasekhian, E., Rodriguez-Martinez, H., Berg, G., . . . Ernerudh, J. (2015). The Human Fetal Placenta Promotes Tolerance against the Semiallogeneic Fetus by Inducing Regulatory T Cells and Homeostatic M2 Macrophages. Journal of Immunology, 194(4), 1534-1544
Open this publication in new window or tab >>The Human Fetal Placenta Promotes Tolerance against the Semiallogeneic Fetus by Inducing Regulatory T Cells and Homeostatic M2 Macrophages
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2015 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 194, no 4, p. 1534-1544Article in journal (Refereed) Published
Abstract [en]

A successful pregnancy requires that the maternal immune system is instructed to a state of tolerance to avoid rejection of the semiallogeneic fetal-placental unit. Although increasing evidence supports that decidual (uterine) macrophages and regulatory T cells (Tregs) are key regulators of fetal tolerance, it is not known how these tolerogenic leukocytes are induced. In this article, we show that the human fetal placenta itself, mainly through trophoblast cells, is able to induce homeostatic M2 macrophages and Tregs. Placental-derived M-CSF and IL-10 induced macrophages that shared the CD14(+)CD163(+)CD206(+)CD209(+) phenotype of decidual macrophages and produced IL-10 and CCL18 but not IL-12 or IL-23. Placental tissue also induced the expansion of CD25(high)CD127(low)Foxp3(+) Tregs in parallel with increased IL-10 production, whereas production of IFN-gamma (Th1), IL-13 (Th2), and IL-17 (Th17) was not induced. Tregs expressed the suppressive markers CTLA-4 and CD39, were functionally suppressive, and were induced, in part, by IL-10, TGF-beta, and TRAIL. Placental-derived factors also limited excessive Th cell activation, as shown by decreased HLA-DR expression and reduced secretion of Th1-, Th2-, and Th17-associated cytokines. Thus, our data indicate that the fetal placenta has a central role in promoting the homeostatic environment necessary for successful pregnancy. These findings have implications for immune-mediated pregnancy complications, as well as for our general understanding of tissue-induced tolerance.

Place, publisher, year, edition, pages
American Association of Immunologists, 2015
National Category
Clinical Medicine Immunology in the medical area
Identifiers
urn:nbn:se:liu:diva-115319 (URN)10.4049/jimmunol.1401536 (DOI)000349462000017 ()25560409 (PubMedID)
Note

Funding Agencies|Medical Research Council [K2013-61X-22310-01-4]

Available from: 2015-03-13 Created: 2015-03-13 Last updated: 2020-01-16
Svensson Arvelund, J. & Ernerudh, J. (2015). The Role of Macrophages in Promoting and Maintaining Homeostasis at the Fetal-Maternal Interface. American Journal of Reproductive Immunology, 74(2), 100-109
Open this publication in new window or tab >>The Role of Macrophages in Promoting and Maintaining Homeostasis at the Fetal-Maternal Interface
2015 (English)In: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 74, no 2, p. 100-109Article, review/survey (Refereed) Published
Abstract [en]

A successful pregnancy requires that the maternal immune system adapts properly to avoid rejection of the semi-allogeneic fetus without compromising the ability to protect the mother and the fetus against infections. In this review, we describe the role of decidual macrophages in creating a homeostatic environment at the fetal-maternal interface. We also discuss their role in pregnancy complications as well as future possibilities to modulate macrophage function therapeutically. Decidual macrophages are enriched at the fetal-maternal interface and play a major role in the regulation of inflammatory responses and the maintenance of a tolerant environment. Their function is, however, not restricted to immune tolerance, but extends to include functions such as the recognition and clearance of infections, the clearance of apoptotic debris, and tissue remodeling. Decidual macrophages seem to largely function as tissue-resident macrophages that are crucial for maintaining homeostasis and reproductive success.

Place, publisher, year, edition, pages
Wiley: 12 months, 2015
Keywords
Colony-stimulating factors; decidual macrophages; M2 macrophages; pregnancy; pregnancy complications; tolerance
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-120724 (URN)10.1111/aji.12357 (DOI)000358532800002 ()25582625 (PubMedID)
Note

Funding Agencies|Swedish Research Council [K2013-61X-22310-01-4]; Health Research Council in the South East of Sweden; Ostergotland County Council

Available from: 2015-08-24 Created: 2015-08-24 Last updated: 2020-01-16
Buse, E., Häeger, J.-D., Svensson-Arvelund, J., Markert, U. R., Faas, M. M., Ernerudh, J., . . . Pfarrer, C. (2014). The placenta in toxicology. Part I: Animal models in toxicology. Toxicologic pathology (Print), 42(2), 314-326
Open this publication in new window or tab >>The placenta in toxicology. Part I: Animal models in toxicology
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2014 (English)In: Toxicologic pathology (Print), ISSN 0192-6233, E-ISSN 1533-1601, Vol. 42, no 2, p. 314-326Article, review/survey (Refereed) Published
Abstract [en]

The immune system represents a key defense mechanism against potential pathogens and adverse non-self materials. During pregnancy, the placenta is the point of contact between the maternal organism and non-self proteins of the fetal allograft and hence undoubtedly fulfils immune functions. In the placenta bacteria, foreign (non-self) proteins and proteins that might be introduced in toxicological studies or by medication are barred from reaching the progeny, and the maternal immune system is primed for acceptance of non-maternal fetal protein. Both immunologic protection of the fetus and acceptance of the fetus by the mother require effective mechanisms to prevent an immunologic fetomaternal conflict and to keep both organisms in balance. This is why the placenta requires toxicological consideration in view of its immune organ function. The following articles deal with placenta immune-, control-, and tolerance mechanisms in view of both fetal and maternal aspects. Furthermore, models for experimental access to placental immune function are addressed and the pathological evaluation is elucidated. "The Placenta as an Immune Organ and Its Relevance in Toxicological Studies" was subject of a continuing education course at the 2012 Society of Toxicologic Pathology meeting held in Boston, MA.

Place, publisher, year, edition, pages
Sage Publications, 2014
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-108388 (URN)10.1177/0192623313482208 (DOI)000337625300003 ()23548606 (PubMedID)
Available from: 2014-06-27 Created: 2014-06-27 Last updated: 2020-01-16Bibliographically approved
Svensson-Arvelund, J., Ernerudh, J., Buse, E., Cline, J. M., Haeger, J.-D., Dixon, D., . . . Faas, M. M. (2014). The placenta in toxicology. Part II: Systemic and local immune adaptations in pregnancy. Toxicologic pathology (Print), 42(2), 327-338
Open this publication in new window or tab >>The placenta in toxicology. Part II: Systemic and local immune adaptations in pregnancy
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2014 (English)In: Toxicologic pathology (Print), ISSN 0192-6233, E-ISSN 1533-1601, Vol. 42, no 2, p. 327-338Article in journal (Refereed) Published
Abstract [en]

During pregnancy, the maternal immune system is challenged by the semiallogeneic fetus, which must be tolerated without compromising fetal or maternal health. This review updates the systemic and local immune changes taking place during human pregnancy, including some examples in rodents. Systemic changes are induced by contact of maternal blood with placental factors and include enhanced innate immunity with increased activation of granulocytes and nonclassical monocytes. Although a bias toward T helper (Th2) and regulatory T cell (Treg) immunity has been associated with healthy pregnancy, the relationship between different circulating Th cell subsets is not straightforward. Instead, these adaptations appear most evidently at the fetal-maternal interface, where for instance Tregs are enriched and promote fetal tolerance. Also innate immune cells, that is, natural killer cells and macrophages, are enriched, constituting the majority of decidual leukocytes. These cells not only contribute to immune regulation but also aid in establishing the placenta by promoting trophoblast recruitment and angiogenesis. Thus, proper interaction between leukocytes and placental trophoblasts is necessary for normal placentation and immune adaptation. Consequently, spontaneous maladaptation or interference of the immune system with toxic substances may be important contributing factors for the development of pregnancy complications such as preeclampsia, preterm labor, and recurrent miscarriages.

Place, publisher, year, edition, pages
Sage Publications, 2014
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-108394 (URN)10.1177/0192623313482205 (DOI)000337625300004 ()23531796 (PubMedID)
Available from: 2014-06-27 Created: 2014-06-27 Last updated: 2020-01-16Bibliographically approved
Cline, J. M., Dixon, D., Ernerudh, J., Faas, M. M., Göhner, C., Häger, J.-D., . . . Buse, E. (2014). The placenta in toxicology. Part III: Pathologic assessment of the placenta. Toxicologic pathology (Print), 42(2), 339-344
Open this publication in new window or tab >>The placenta in toxicology. Part III: Pathologic assessment of the placenta
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2014 (English)In: Toxicologic pathology (Print), ISSN 0192-6233, E-ISSN 1533-1601, Vol. 42, no 2, p. 339-344Article in journal (Refereed) Published
Abstract [en]

This short review is derived from the peer-reviewed literature and the experience and case materials of the authors. Brief illustrated summaries are presented on the gross and histologic normal anatomy of rodent and macaque placentas, including typical organ weights, with comments on differences from the human placenta. Common incidental findings, background lesions, and induced toxic lesions are addressed, and a recommended strategy for pathologic evaluation of placentas is provided.

Place, publisher, year, edition, pages
Sage Publications, 2014
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-108396 (URN)10.1177/0192623313482207 (DOI)000337625300005 ()23531795 (PubMedID)
Available from: 2014-06-27 Created: 2014-06-27 Last updated: 2020-01-16
Göhner, C., Svensson-Arvelund, J., Pfarrer, C., Häger, J.-D., Faas, M., Ernerudh, J., . . . Markert, U. R. (2014). The placenta in toxicology. Part IV: Battery of toxicological test systems based on human placenta. Toxicologic pathology (Print), 42(2), 345-351
Open this publication in new window or tab >>The placenta in toxicology. Part IV: Battery of toxicological test systems based on human placenta
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2014 (English)In: Toxicologic pathology (Print), ISSN 0192-6233, E-ISSN 1533-1601, Vol. 42, no 2, p. 345-351Article in journal (Refereed) Published
Abstract [en]

This review summarizes the potential and also some limitations of using human placentas, or placental cells and structures for toxicology testing. The placenta contains a wide spectrum of cell types and tissues, such as trophoblast cells, immune cells, fibroblasts, stem cells, endothelial cells, vessels, glands, membranes, and many others. It may be expected that in many cases the relevance of results obtained from human placenta will be higher than those from animal models due to species specificity of metabolism and placental structure. For practical and economical reasons, we propose to apply a battery of sequential experiments for analysis of potential toxicants. This should start with using cell lines, followed by testing placenta tissue explants and isolated placenta cells, and finally by application of single and dual side ex vivo placenta perfusion. With each of these steps, the relative workload increases while the number of feasible repeats decreases. Simultaneously, the predictive power enhances by increasing similarity with in vivo human conditions. Toxic effects may be detected by performing proliferation, vitality and cell death assays, analysis of protein and hormone expression, immunohistochemistry or testing functionality of signaling pathways, gene expression, transport mechanisms, and so on. When toxic effects appear at any step, the subsequent assays may be cancelled. Such a system may be useful to reduce costs and increase specificity in testing questionable toxicants. Nonetheless, it requires further standardization and end point definitions for better comparability of results from different toxicants and to estimate the respective in vivo translatability and predictive value.

Place, publisher, year, edition, pages
Sage Publications, 2014
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-108390 (URN)10.1177/0192623313482206 (DOI)000337625300006 ()23548605 (PubMedID)
Available from: 2014-06-27 Created: 2014-06-27 Last updated: 2020-01-16
Boij, R., Svensson, J., Nilsson-Ekdahl, K., Sandholm, K., Lindahl, T., Palonek, E., . . . Matthiesen, L. (2012). Biomarkers of Coagulation, Inflammation, and Angiogenesis are Independently Associated with Preeclampsia. AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, 68(3), 258-270
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, p. 258-270Article 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
Keywords
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: 2020-01-16
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