bims-reprim 2021-04-18 papers

Issue of 2021–04–18
four papers selected by
Iva Filipovic, Karolinska Institutet

J Reprod Immunol. 2021 Apr 08. pii: S0165-0378(21)00049-8. [Epub ahead of print]145 103319

Imbalance between inflammatory and regulatory cord blood B cells following pre-term birth.

Mandy Busse, Anke Redlich, Roland Hartig, Serban-Dan Costa, Henning Rathert, Stefan Fest, Ana Claudia Zenclussen.

Preterm birth (PTB) is one of the most frequent pregnancy complications. It affects millions of babies each year worldwide and is associated with increased morbidity and mortality. PTB-associated alterations in the maternal immune response may have a direct effect on the developing fetal immune system. Having recently shown that B regulatory (Breg) cells are decreased in number and functionally impaired in maternal blood from women delivering preterm, we now addressed the question whether the adaptive immune system is also altered in cord blood (CB) after the onset of PTB. PTB was associated with increased concentrations of IL-6, TNF-α and IL-21 in CB and enhanced IL-6, but decreased IFN-γ and IL-4 in amniotic fluid (AF) samples compared to term delivery (TD). We found no differences in the frequency of CD19 + B cells, CD4 + T cells or CD4+Foxp3+CD25+ T regulatory (Treg) cells in CB cells in PTB vs TD. The frequency of CD86 + B cells was increased, while the percentage of CD24hiCD38hiCD19 + Breg and CD1dhiCD5+ Breg cells and the ability of B cells to convert into Breg cells was diminished in PTB compared to TD. CB B cells from PTB secreted more IL-6, TNF-α, IL-9 and IL-2 compared to B cells obtained from term samples. We conclude that, after PTB onset, a shift from immunoregulation towards inflammation takes place in CB cells that are reportedly representative of the fetal compartment. B cells have a substantial contribution herein. This phenomenon might account for the observed enhanced mortality and morbidity in prematurely born infants. Further studies will clarify how to employ this easy-to-obtain information for closely monitoring newborns at risk.

Keywords: B cells; B regulatory cells; Interleukin-6; Pregnancy; Preterm birth

DOI: https://doi.org/10.1016/j.jri.2021.103319

J Leukoc Biol. 2021 Apr 13.

Cellular immune responses in the pathophysiology of preeclampsia.

Derek Miller, Kenichiro Motomura, Jose Galaz, Meyer Gershater, Eun D Lee, Roberto Romero, Nardhy Gomez-Lopez.

Preeclampsia, defined as new-onset hypertension accompanied by proteinuria occurring at 20 weeks of gestation or later, is a leading cause of perinatal morbidity and mortality worldwide. The pathophysiology of this major multi-systemic syndrome includes defective deep placentation, oxidative stress, endothelial dysfunction, the presence of an anti-angiogenic state, and intravascular inflammation, among others. In this review, we provide a comprehensive overview of the cellular immune responses involved in the pathogenesis of preeclampsia. Specifically, we summarize the role of innate and adaptive immune cells in the maternal circulation, reproductive tissues, and at the maternal-fetal interface of women affected by this pregnancy complication. The major cellular subsets involved in the pathogenesis of preeclampsia are regulatory T cells, effector T cells, NK cells, monocytes, macrophages, and neutrophils. We also summarize the literature on those immune cells that have been less characterized in this clinical condition, such as γδ T cells, invariant natural killer T cells, dendritic cells, mast cells, and B cells. Moreover, we discuss in vivo studies utilizing a variety of animal models of preeclampsia to further support the role of immune cells in this disease. Finally, we highlight the existing gaps in knowledge of the immunobiology of preeclampsia that require further investigation. The goal of this review is to promote translational research leading to clinically relevant strategies that can improve adverse perinatal outcomes resulting from the obstetrical syndrome of preeclampsia.

Keywords: NK cell; T cell; gestational hypertension; hypertensive disorders of pregnancy (HDP); immune cell; macrophage; monocyte; natural killer cell; neutrophil; pregnancy; regulatory T cell

DOI: https://doi.org/10.1002/JLB.5RU1120-787RR

bioRxiv. 2021 Apr 05. pii: 2021.04.04.438404. [Epub ahead of print]

COVID-19 mRNA vaccines drive differential Fc-functional profiles in pregnant, lactating, and non-pregnant women.

Caroline Atyeo, Elizabeth A DeRiso, Christine Davis, Evan A Bordt, Rose M DeGuzman, Lydia L Shook, Lael M Yonker, Alessio Fasano, Babatunde Akinwunmi, Douglas A Lauffenburger, Michal A Elovitz, Kathryn J Gray, Andrea G Edlow, Galit Alter.

Significant immunological changes occur throughout pregnancy to tolerize the mother and allow growth of the fetal graft. However, additional local and systemic immunological adaptations also occur, allowing the maternal immune system to continue to protect the dyad against foreign invaders both during pregnancy and after birth through lactation. This fine balance of tolerance and immunity, along with physiological and hormonal changes, contribute to increased susceptibility to particular infections in pregnancy, including more severe COVID-19 disease. Whether these changes also make pregnant women less responsive to vaccination or induce altered immune responses to vaccination remains incompletely understood. To holistically define potential changes in vaccine response during pregnancy and lactation, we deeply profiled the humoral vaccine response in a group of pregnant and lactating women and non-pregnant age-matched controls. Vaccine-specific titers were comparable, albeit slightly lower, between pregnant and lactating women, compared to non-pregnant controls. Among pregnant women, we found higher antibody titers and functions in those vaccinated with the Moderna vaccine. FcR-binding and antibody effector functions were induced with delayed kinetics in both pregnant and lactating women compared to non-pregnant women. Antibody boosting resulted in high FcR-binding titers in breastmilk. These data point to an immune resistance to generate highly inflammatory antibodies during pregnancy and lactation, and a critical need to follow prime/boost timelines in this vulnerable population to ensure full immunity is attained.

DOI: https://doi.org/10.1101/2021.04.04.438404

Front Immunol. 2021 ;12 656701

The Endometrial Immune Profiling May Positively Affect the Management of Recurrent Pregnancy Loss.

Meryam Cheloufi, Alaa Kazhalawi, Anne Pinton, Mona Rahmati, Lucie Chevrier, Laura Prat-Ellenberg, Anne-Sophie Michel, Geraldine Dray, Arsène Mekinian, Gilles Kayem, Nathalie Lédée.

Introduction: The endometrial immune profiling is an innovative approach based on the analysis of the local immune reaction occurring in the endometrium at the time of the embryo implantation. By documenting the local immune activation during the period of uterine receptivity, we aim to detect and correct potential imbalances before and at the very beginning of placentation. The main objective of the study was to analyze in women with a history of repeated pregnancy loss (RPL) the association of personalized strategies based on immune dysregulations with live birth rates. The secondary objective was to highlight the main prognostic factors for live births.
Methods: This is an observational retrospective analysis of 104 patients with RPL, included between January 2012 and December 2019. Inclusion criteria included a spontaneous fertility with at least three miscarriages, an assessment including a three-dimension ultrasound scan, an endometrial biopsy for uterine immune profiling and a follow-up over at least 6 months with personalized care if indicated after the complete assessment. We defined as a success if the patients had a live birth after the suggested plan, as a failure if the patient either did not get pregnant or experienced a new miscarriage after the targeted therapies.
Results: Uterine immune profiling was the only exploration to be significantly associated with a higher live birth rate (LBR) if a dysregulation was identified and treated accordingly (55% vs 45%, p=0.01). On the contrary, an absence of local dysregulation (resulting in an apparently balanced immune environment) was associated with a higher risk of a new miscarriage, suggesting that the cause inducing RPL still needed to be identified. Independently of age and AMH level, dysregulated immune profile is significatively associated with 3 times higher LBR than a non-deregulated profile (OR=3.4 CI 95%1.27-9.84) or five times in case of an overactive profile treated by immunotherapy (OR=5 CI 95% 1.65-16.5). The usage of ART was significantly associated with lower LBR regardless of the presence of a subfertility factor (p=0.012). Personalization of medical care using natural cycle or simple hormonal stimulation is associated with a significantly higher LBR than personalization including ART treatments regardless of maternal age and AMH level (OR= 2.9 CI 95% 1.03-8.88).
Conclusion: Our study suggests that some endometrial immune profiles with targeted management of RPL are associated with a higher rate of LBR. ART may be negatively associated with LBR.

Keywords: Assisted Reproductive Technology (ART); embryo implantation; endometrium; recurrent pregnancy loss (RPL); uterine immune profile

DOI: https://doi.org/10.3389/fimmu.2021.656701