Eikmans, Michael

Markert, Udo R.

Morales-Prieto, Diana M.

van der Hoorn, Marie-Louise

English

PubMed

Eikmans, M.

Morales-Prieto, D.M.M.

Hoorn, M.L. van der

Markert, U.R.R.

NARCIS 

Editorial: Immunological challenges around pregnancy complications associated with failures of maternal tolerance to the fetus

Leiden University Scholary Publications

PubMed Central

Digitale Bibliothek Thüringen

Frontiers in ImmunologyOPEN ACCESSEDITED AND REVIEWED BYLucienne Chatenoud,UniversitéParis Descartes,France*CORRESPONDENCEMichael Eikmansm.eikmans@lumc.nlSPECIALTY SECTIONThis article was submitted toImmunological Toleranceand Regulation,a section of the journalFrontiers in ImmunologyRECEIVED 01 July 2022ACCEPTED 12 July 2022PUBLISHED 01 August 2022CITATIONEikmans M, Morales-Prieto DM, vander Hoorn M-L and Markert UR (2022)Editorial: Immunological challengesaround pregnancy complicationsassociated with failures of maternaltolerance to the fetus.Front. Immunol. 13:983739.doi: 10.3389/fimmu.2022.983739COPYRIGHT© 2022 Eikmans, Morales-Prieto, vander Hoorn and Markert. This is an open-access article distributed under theterms of the Creative CommonsAttribution License (CC BY). The use,distribution or reproduction in otherforums is permitted, provided theoriginal author(s) and the copyrightowner(s) are credited and that theoriginal publication in this journal iscited, in accordance with acceptedacademic practice. No use,distribution or reproduction ispermitted which does not comply withthese terms.TYPE EditorialPUBLISHED 01 August 2022DOI 10.3389/fimmu.2022.983739Editorial: Immunologicalchallenges around pregnancycomplications associated withfailures of maternal toleranceto the fetusMichael Eikmans1*, Diana M. Morales-Prieto2,Marie-Louise van der Hoorn1 and Udo R. Markert21Leiden University Medical Center, Leiden, Netherlands, 2Placenta Lab, Department of Obstetrics,Jena University Hospital, Jena, GermanyKEYWORDSpregnancy, trophoblast, immune cells, preeclampsia, recurrent pregnancy loss,chronic histiocytic intervillositisEditorial on the Research TopicImmunological challenges around pregnancy complications associ-ated with failures of maternal tolerance to the fetusSuccessful pregnancy provides an intriguing immunologic paradox. The fetus carriesboth paternal and maternal genes and therefore is 50% foreign to the mother, but istolerized by the maternal immune system. Several immune regulatory mechanisms are atplay at the maternal-fetal interface, which represents the location where fetal trophoblastsin the placenta come into contact with maternal immune cells. In early pregnancy,extravillous trophoblasts are relevant in plugging and remodeling maternal spiral arteriesand thereby are relevant for the proper development of the placenta and the fetus. At thesame time, fetal trophoblasts at the maternal-fetal interface need to be tolerized againstimmune attack by maternal T cells, myeloid cells (macrophages and dendritic cells), anddecidual natural killer (NK) cells. One way of establishing this is the expression of HLA-G on the surface of trophoblasts and the secretion of soluble HLA-G. A second way is thegeneration and development of regulatory immune cells, including regulatory T cells(Tregs) and myeloid-derived suppressor cells (MDSCs). These cell types mediatehomeostasis by dampening effector immune cell mechanisms.This Research Topic focuses on mechanisms that effectuate a tolerogenicmicroenvironment in healthy pregnancy and describes how these features may bedisturbed in various types of pregnancy complications.An experimental study by Dietz et al. uses a murine model lacking the Qa-2 antigen, amurine homologue-candidate for HLA-G, to show the effect of sHLA-G in reducingabortion rates through inducing Tregs and MDSCs. Both cell types are shown to suppressfrontiersin.org01Eikmans et al. 10.3389/fimmu.2022.983739the action of effector T cells. Interaction and cross-talk betweenthe trophoblast and macrophage may lead to direct polarizationof the latter, as reviewed by Ding et al.. Such effects mediatingtolerogenicity can be driven either by direct cell-cell contact,excreted soluble factors or a combination of the two. Next tomacrophages, dendritic cells make part of the myeloid celllineage. These cells are the most efficient type of antigen-presenting cells, and as part of the decidual environment, theyare thought to drive fetus-specific immunity by the maternalimmune system. Zhang et al. show that the female steroidhormone progesterone has major effects on the characteristicsof dendritic cells. Another regulatory mechanism at thematernal-fetal interface may be directed by surface moleculesCD39 and CD73, which promote conversion of adenosine 5′-triphosphate (ATP) to adenosine and thereby change a pro-inflammatory to an anti-inflammatory environment. Zhu et al.demonstrate that trophoblasts express both molecules and alsoshow that a high fraction of decidual NK cells are positive forCD39. Expression of both molecules was found to be decreasedat the maternal-fetal interface in women with pregnancy loss,thereby emphasizing their importance in this disease.The current Research Topic is further directed at pregnancy-related complications with possible involvement of the immunesystem, which are studied here. These include recurrent pregnancyloss (RPL), chronichistiocytic intervillositis (CHI), andpreeclampsia.As the fetal cells are tolerized by thematernal immune system inhealthy pregnancy, immunological mechanisms and disturbancestherein may underlie RPL.Women with RPL have had two or morespontaneous miscarriages. It affects approximately 3% of all fertilecouples and inmore than 50% of couples the underlying cause is notclear: a considerable part of such cases are suspected to have animmunologic nature. Li et al. outline how big data analysis of thematernal-fetal interface, as well as placenta and blood, from womenwith RPL may help elucidating the pathogenesis.CHI is a poorly understood histopathological lesion of theplacenta. CHI is significantly associated with miscarriage, fetalgrowth restriction, and intrauterine fetal death. In this disease, anintervillous infiltrate, which is of maternal origin, can be seen inevery trimester throughout gestation. The interplay betweenmaternal immune cells and fetal trophoblasts in CHI might pointtoward a breach in immune tolerance and is a topic for ongoingresearch. Cornish et al. present a detailed overview of prevalence,pathology, and clinical consequences of different gestationalsyndromes, including CHI, which are associated with adversepregnancy outcomes. Brady et al. describe how application ofimmune modulatory medication in women with CHI mayimprove placental lesions and higher the chance of livebirth.Frontiers in Immunology 02The third type of pregnancy-related complication discussedin this Research Topic is preeclampsia, which is a seriouscomplication endangering the mother and the fetus. Highblood pressure is an important indicator for diagnosingpreeclampsia. Gan et al. found that systolic blood pressure ofthe mother at 12 weeks of gestation predicts the development ofsevere preeclampsia and of low birth weight of the baby. Greenet al. present a systematic review concerning the role of Tregs inadverse pregnancy outcome. They show that decreased Tregnumbers in the peripheral blood of pregnant women issignificantly associated with the occurrence of pre-eclampsia.Acute atherosis is a lesion which can be present at the maternalspiral arteries, and which may be encountered in preeclampsia.Jacobsen et al. provide an extensive overview and discussion onacute atherosis, including its definition, underlying mechanism,and possible clinical consequences.In summary, this Research Topic provides insights in theimmunological challenges around pregnancy complicationsassociated with failures of maternal tolerance to the fetus.The collection of articles highlights the function of specificimmune cell populations and describes new mechanisms ofpregnancy monitoring that can contribute to advanced basicresearch and clinical translation for various types ofpregnancy complications.Author contributionsME, M-LH, DM-P, and UM composed the text, revised it,and approved the final draft.Conflict of interestThe authors declare that the research was conducted in theabsence of any commercial or financial relationships that couldbe construed as a potential conflict of interest.Publisher’s noteAll claims expressed in this article are solely those of theauthors and do not necessarily represent those of their affiliatedorganizations, or those of the publisher, the editors and thereviewers. Any product that may be evaluated in this article, orclaim that may be made by its manufacturer, is not guaranteedor endorsed by the publisher.frontiersin.org

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Editorial: Immunological challenges around pregnancy complications associated with failures of maternal tolerance to the fetus

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