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For a successful pregnancy, the maternal immune system must acquire tolerance towards the paternal antigens present in the semi-allogeneic foetus. This tolerance is mainly established locally at the foetal-maternal interface, where foetally-derived trophoblasts invade the maternal endometrium (called decidua during pregnancy) and come in close proximity to maternal immune cells. The decidua is populated by maternal immune cells of a unique composition, characterised by their suppressive phenotypes that are essential for maintaining tissue homeostasis. Accordingly, failure of immune tolerance can lead to pregnancy complications. Macrophages and regulatory T-cells are enriched in the decidua and are believed to play important roles in the establishment of tolerance. However, there is limited information regarding the factors that regulate their functions and if their function is compromised in pregnancy complications. The aim of this thesis was to further elucidate which factors are responsible for induction of the regulatory phenotypes of macrophages and T-cells found in the decidua, how tissue resident cells in the decidua contribute to this and if this system is compromised during pregnancy complications, such as preeclampsia and recurrent pregnancy loss. Decidual stromal cells (DSCs) constitute the largest population of tissue resident cells in the decidua. In an in vitro system of macrophage differentiation, we found that Isolated peripheral blood monocytes cultured in conditioned medium (CM) from DSCs acquired a high expression of the regulatory M2 markers CD163, CD209 and CD14, and a low expression of CD86, characteristics of decidual macrophages. This induction was in part mediated by macrophage-colony stimulating factor (M-CSF), as neutralising its effects reduced the expression of CD163. However, since only a partial reduction was reached, other factors are involved. Another likely candidate for this polarisation is interleukin (IL)-34, a second ligand for the M-CSF receptor. We showed that IL-34 is expressed by both DSCs and the foetal placenta. Further, in vitro, IL-34 was able to induce macrophages with similar properties as that of M-CSF-induced macrophages, with high expression of CD163, CD209 and CD14. This was also coupled to a cytokine secretion profile similar to M-CSF-induced macrophages, with high production of IL-10, low production of tumour necrosis factor (TNF) and no production of IL-12. We found no evidence of IL-34 being aberrantly expressed in placentas from preeclamptic women. In addition to promoting induction of macrophages with a regulatory phenotype, CM from DSCs promoted expansion of Foxp3+CD25bright regulatory T (Treg) cells in an in vitro polarisation system, in a SMAD3 dependent manner. Protein profiling of DSCs revealed limited production of the Th2 related IL-13, IL-4, IL-33 and thymic stromal lymphopoietin (TSLP), as well as no production of the Th17 related IL-17A and chemokine (C-C motif) ligand (CCL) 20. Instead we found that DSCs were more prone to production of regulatory factors, such as M-CSF, leukaemia inhibitory factor (LIF) and transforming growth factor (TGF)-?, albeit with addition of the more pro-inflammatory IL-6, chemokine (C-X-C motif) ligand (CXCL) 8 and the Th1-related CXCL10. We also investigated if the placenta´s ability to induce Treg cells and regulatory M2 macrophages is compromised in women with a history of unexplained recurrent pregnancy loss (uRPL) and if the placental secreted protein profile is skewed to a pro-inflammatory response in uRPL. Using surplus materials from chorionic villous sampling (CVS), we generated CM from placental tissue taken from healthy and uRPL pregnancies and used this to polarise macrophages and T-cells in vitro. We found no difference in the ability to induce Treg cells and regulatory M2 macrophages between the healthy group and the uRPL group. Likewise, no differences in the protein profile was observed between the two groups. Taken together, our findings imply that DSCs produce a variety of factors promoting foetal tolerance by induction of Treg cells and regulatory M2 macrophages. Furthermore, we also showed that the placenta retained its ability to induce Treg cells and regulatory M2 macrophages in women with a history of uRPL. Graviditet utgör en stor utmaning för mammans immunförsvar eftersom fostret till hälften består av gener från pappan, vilket innebär att fostret bär på gener som är främmande för mammans immunförsvar. Detta betyder att mamman måste utveckla en tolerans för att förhindra en avstötningsreaktion, men samtidigt också bevara skyddet mot potentiellt farliga infektioner. Tolerans skapas främst lokalt i kontakten mellan livmoderslemhinnan (kallad decidua under graviditet) och placentan (moderkakan), där placentaceller från fostret kommer i nära kontakt med mammans immunceller. Således har dessa immunceller en central roll i att skapa tolerans. Två celltyper som är anrikade i deciduan under en graviditet är specialiserade makrofager och regulatoriska T-celler. Dock är det inte fastställt hur dessa celler får sina immundämpande egenskaper. I denna avhandling studeras hur mammans immunceller utvecklar tolerans genom kommunikation med andra celler och genom att interagera med varandra. Fokus i avhandlingen är stödjeceller, stroma-celler, i decidua, som inte bara bygger upp vävnaden utan också deltar genom produktion av tillväxtfaktorer och hormoner som bidrar till skapande av tolerans. De övergripande målen i avhandlingen var att kartlägga faktorer som styr utvecklingen av decidua-makrofager och regulatoriska T-celler, var dessa faktorer produceras och om kvinnor som utvecklat graviditetskomplikationer har en försämrad förmåga att utveckla immundämpande immunceller lokalt. I en delstudie visar vi att de stödjeceller som utgör majoriteten av alla celler i deciduan, deciduala stromaceller, har förmågan att stimulera utvecklingen av makrofager som liknar de som finns i deciduan. För utveckling av immundämpande makrofager visade det sig att tillväxtfaktorn M-CSF var en drivande faktor. Dock dämpades uttrycket endast delvis, vilket tyder på att även andra faktorer är inblandade. En av de mest troliga är IL-34, som binder till och aktiverar samma receptor som M-CSF. I en annan delstudie visade vi att IL-34 bildas både i placentan och av stromaceller i deciduan. IL-34 var, i likhet med M-CSF, också drivande i utvecklingen av makrofager som är mycket lika makrofager i deciduan. Utöver effekten på makrofagerna drev de deciduala stromacellerna även utvecklingen av regulatoriska T-celler, troligen via produktion av en annan tillväxtfaktor, TGF-?. Då IL-34 och M-CSF var involverade i utveckling av tolerans hos makrofager, undersökte vi även om havandeskapsförgiftning (preeklampsi) var associerad med en försämrad förmåga att producera dessa faktorer i placentan. Dock hittade vi inga skillnader i förekomst av IL-34 och M-CSF hos placenta-celler från kvinnor med havandeskapsförgiftning. Sammantaget visar våra studier att deciduala stromaceller är viktiga för att producera en repertoar av faktorer som skapar och bibehåller immundämpande egenskaper hos makrofager och regulatoriska T-celler under en graviditet. Vi visar att M-CSF, IL-34 och TGF-? är centrala för denna toleransutveckling och att de bildas av deciduala stromaceller. Dock verkar dessa faktorer inte vara avvikande vid havandeskapsförgiftning
Detail About Immune regulation at the foetal maternal interface implications for healthy and complicated pregnancies PDF
- Author : Robert Lindau
- Publisher : Linköping University Electronic Press
- Genre :
- Total Pages : 66 pages
- ISBN : 9179297803
- Release Date : 10 November 2020
- PDF File Size : 15,7 Mb
- Language : English
- Rating : 4/5 from 21 reviews
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