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Circulating CD4dimCD25highFOXP3+ regulatory T cells in severe early-onset preeclampsia
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.
Linköping University, Department of Clinical and Experimental Medicine, Obstetrics and gynecology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Gynecology and Obstetrics in Linköping.
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

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.

National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-53617OAI: oai:DiVA.org:liu-53617DiVA: diva2:290241
Available from: 2010-01-26 Created: 2010-01-26 Last updated: 2010-01-26
In thesis
1. Regulatory T cells in human pregnancy
Open this publication in new window or tab >>Regulatory T cells in human pregnancy
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

During pregnancy, fetal tolerance has to be achieved without compromising the immune integrity of the mother. CD4+CD25highFoxp3+ regulatory cells (Tregs) have received vast attention as key players in immune regulation. However, the identification of human Tregs is complicated by their similarity to activated nonsuppressive T cells. The general aim of this thesis was to determine the antigen specificity, frequency, phenotype and function of Tregs in first to second trimester healthy and severe early-onset preeclamptic human pregnancy. Regarding antigen specificity, we observed that in healthy pregnant women, Tregs suppressed both TH1 and TH2 reactions when stimulated with paternal alloantigens but only TH1, not TH2 reactions when stimulated with unrelated alloantigens. Hence, circulating paternal-specific Tregs seem to be present during pregnancy. Further, by strictly defining typical Tregs (CD4dimCD25high) using flow cytometry, we could show that as a whole, the Treg population was reduced already during first trimester pregnancy as compared with non-pregnant women. This was in contrast to several previous studies and the discrepancy was most likely due to the presence of activated non-suppressive cells in pregnant women, showing similarities to the suppressive Tregs. Although deserving confirmation in a larger sample, severe early-onset preeclampsia did not seem to be associated with alterations in the circulating Treg population. The circulating Treg population was controlled by hormones which, alike pregnancy, reduced the frequency of Foxp3 expressing cells. Yet, in vitro, pregnancy Tregs were highly suppressive of pro-inflammatory cytokine secretion and showed an enhanced capability of secreting immune modulatory cytokines such as IL-4 and IL-10, as well as IL-17, indicating an increased plasticity of pregnancy Tregs. At the fetalmaternal interface during early pregnancy, Tregs, showing an enhanced suppressive and proliferating phenotype, were enriched as compared with blood. Further, CCR6- TH1 cells, with a presumed moderate TH1 activity were enhanced, whereas pro-inflammatory TH17 and CCR6+ TH1 cells were fewer as compared with blood. This thesis adds to and extends the view of Tregs as key players in immune regulation during pregnancy. In decidua, typical Tregs seem to have an important role in immune suppression whereas systemically, Tregs are under hormonal control and are numerically suppressed during pregnancy. Further, circulating pregnancy Tregs show reduced expression of Foxp3 and an increased degree of cytokine secretion and thereby also possibly plasticity. This would ensure systemic defense against infections with simultaneous tolerance at the fetal-maternal interface during pregnancy.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2010. 156 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1163
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-53619 (URN)9789173934602 (ISBN)
Public defence
2010-01-22, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (English)
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Available from: 2010-01-26 Created: 2010-01-26 Last updated: 2017-12-14Bibliographically approved

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Mjösberg, JennyMatthiesen, LeifJenmalm, Maria C.Ernerudh, JanBerg, Göran

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Clinical Immunology Faculty of Health SciencesDepartment of Clinical Immunology and Transfusion MedicineObstetrics and gynecology Department of Gynecology and Obstetrics in LinköpingPediatrics
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