Immunological Challenges Around Pregnancy Complications Associated With Failures Of Maternal Tolerance To The Fetus

This book covers in detail contemporary hypotheses and studies related to the immunology of implantation and provides a practical approach for the application of basic reproductive immunology research to pregnancy complications such as preeclampsia, pre-term labor and IUGR. Provides complete and up to date review of current knowledge of the role of the immune system during pregnancy and the interactions between the placenta and the maternal immune system.

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

Recurrent pregnancy loss (RPL) is defined as two or more consecutive pregnancy losses before the 20th week of gestation, occuring in 1%–3% of reproductive women. Unexplained RPL (URPL) is a heterogeneous condition affecting approximately 50% of RPL cases, with one contributing factor thought to be a disruption in maternal immune tolerance. Various immune effectors and molecules in the immune-microenvironment establish specific maternal tolerance toward the semi-allogeneic fetus during pregnancy. Immune cells including innate lymphoid cells (ILCs), myeloid cells, T cells and B cells have been found to contribute to maintaining this maternal immunological tolerance during pregnancy. ILCs have been found to be the most abundant immune cells in the pregnant uterus, with many studies focusing on the relationship between RPL and either T cells or natural killer (NK) cells in peripheral blood and the endometrium/decidua. Despite progress in uncovering the roles of NK, and regulatory T cells and cytokines in pregnancy, the immune heterogeneity in patients with URPL remains elusive.

Reproductive Immunology: Basic Concepts gives a holistic insight into the understanding of the complex interactions between the maternal immune system and the fetal/placental unit necessary for the success of pregnancy. This interaction is critical for the support of the human fetal semiallograft and the protection against infections. The book covers various topics such as B cells, macrophages, T cells, discussion on fetal signals and their impact on maternal reproductive cells such as endometrial cells, mast cells, and the role of fetal Hofbauer cells, the immune regulatory role of glucorticoids, and many other novel topics within the field of reproductive immunology. Edited and written by experts in the field, this book introduces the up-to-date knowledge of the role of the immune system during pregnancy and provides the necessary background to understand pregnancy complications associated with alterations in the functioning of the immune system. The book provides a complete discussion on the immunological aspects of pregnancy and serves as a great tool for research scientists, students, reproductive immunologists and OBGYNs. Shows the detailed evaluation of the knowledge related to each immune cell type in the pregnant and not pregnant uterus Evaluates each immune cell type and its function during specific reproductive events Provides the biological background for understanding the clinical aspects that will be discussed in subsequent volumes in the series

The 29 papers contained in this volume look closely at various aspects of what is termed, "The Maternal-Fetal Interface," as it relates to the latest research in placental science. A substantial section of the book is devoted to the troublesome question of vertical transmission of infectious agents: namely, the HIV-1 virus. However, other sections of the volume examine related issues such as drug and toxin transfer across the term placenta and the diversity of placental types and how this can affect a placenta's effectiveness as a barrier. Anthony Carter is at the University of Odense, Denmark Vibeke Dantzer is at the University of Copenhagen, DenmarkThomas Jansson is at the University of Gothenburg, Sweden

This book presents the discipline of immunology which studies a unique physiological phenomenon contradicting many of the generally established rules in the field: immunology of pregnancy. It provides a wide overview of the current research of this topic. Prominent and leading international groups contributed by reviewing the most significant findings in the field.