bims-reprim 2021-04-04 papers

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

Sci Rep. 2021 Mar 31. 11(1): 7281

Hypoxia and oxidative stress induce sterile placental inflammation in vitro.

Bernadette C Baker, Alexander E P Heazell, Colin Sibley, Rachael Wright, Helen Bischof, Frances Beards, Tatiana Guevara, Sylvie Girard, Rebecca L Jones.

Fetal growth restriction (FGR) and stillbirth are associated with placental dysfunction and inflammation and hypoxia, oxidative and nitrative stress are implicated in placental damage. Damage-associated molecular patterns (DAMPs) are elevated in pregnancies at increased risk of FGR and stillbirth and are associated with increase in pro-inflammatory placental cytokines. We hypothesised that placental insults lead to release of DAMPs, promoting placental inflammation. Placental tissue from uncomplicated pregnancies was exposed in vitro to hypoxia, oxidative or nitrative stress. Tissue production and release of DAMPs and cytokines was determined. Oxidative stress and hypoxia caused differential release of DAMPs including uric acid, HMGB1, S100A8, cell-free fetal DNA, S100A12 and HSP70. After oxidative stress pro-inflammatory cytokines (IL-1α, IL-1β, IL-6, IL-8, TNFα, CCL2) were increased both within explants and in conditioned culture medium. Hypoxia increased tissue IL-1α/β, IL-6, IL-8 and TNFα levels, and release of IL-1α, IL-6 and IL-8, whereas CCL2 and IL-10 were reduced. IL1 receptor antagonist (IL1Ra) treatment prevented hypoxia- and oxidative stress-induced IL-6 and IL-8 release. These findings provide evidence that relevant stressors induce a sterile inflammatory profile in placental tissue which can be partially blocked by IL1Ra suggesting this agent has translational potential to prevent placental inflammation evident in FGR and stillbirth.

DOI: https://doi.org/10.1038/s41598-021-86268-1

Am J Obstet Gynecol. 2021 Mar 30. pii: S0002-9378(21)00208-8. [Epub ahead of print]

Pregnancy alters IL-1β expression and anti-viral antibody responses during SARS-CoV-2 infection.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the disease-causing pathogen of the COVID-19 pandemic, has resulted in morbidity and mortality worldwide. Pregnant women are more susceptible to severe COVID-19 disease and are at higher risk for preterm birth compared to uninfected pregnant women. Despite this evidence, the immunological effects of SARS-CoV-2 infection during pregnancy remain understudied.
OBJECTIVE: To assess the impact of SARS-CoV-2 infection during pregnancy on inflammatory and humoral responses in maternal and fetal samples and compare antibody responses to SARS-CoV-2 among pregnant and non-pregnant women.
STUDY DESIGN: Immune responses to SARS-CoV-2 were analyzed using samples from pregnant (n=33) and non-pregnant (n=17) women who had either tested positive (pregnant n=22; non-pregnant n=17) or negative for SARS-CoV-2 (pregnant n=11) at Johns Hopkins Hospital. We measured proinflammatory and placental cytokine mRNAs, neonatal Fc receptor (FcRn) expression, and tetanus antibody transfer in maternal and cord blood samples. Additionally, we evaluated anti-spike (S) IgG, anti-S-receptor binding domain (RBD) IgG, and neutralizing antibody (nAb) responses to SARS-CoV-2 in serum or plasma collected from non-pregnant women, pregnant women, and cord blood.
RESULTS: SARS-COV-2 positive pregnant women expressed more IL1β, but not IL6, in blood samples collected within 14 days versus > 14 days after a confirmed SARS-CoV-2 test. Pregnant women with confirmed SARS-CoV-2 infection also had reduced anti-S-RBD IgG titers and were less likely to have detectable nAb as compared with non-pregnant women. Although SARS-CoV-2 infection did not disrupt FcRn expression in the placenta, maternal transfer of SARS-CoV-2 nAb was inhibited by infection during pregnancy.
CONCLUSIONS: SARS-CoV-2 infection during pregnancy was characterized by placental inflammation and reduced antiviral antibody responses, which may impact the efficacy of COVID-19 therapeutics in pregnancy. The long-term implications of placental inflammation for neonatal health also requires greater consideration.

Keywords: COVID-19; SARS-CoV-2; antibody; cytokine; maternal infection; pregnancy

DOI: https://doi.org/10.1016/j.ajog.2021.03.028

J Reprod Immunol. 2021 Mar 09. pii: S0165-0378(21)00039-5. [Epub ahead of print]145 103309

Epithelial membrane protein 2 (Emp2) modulates innate immune cell population recruitment at the maternal-fetal interface.

Alison Chu, Su-Yin Kok, Jessica Tsui, Meng-Chin Lin, Brian Aguirre, Madhuri Wadehra.

Epithelial membrane protein 2 (EMP2) is a tetraspan membrane protein that has been revealed in cancer and placental models to mediate a number of vascular responses. Recently, Emp2 modulation has been shown to have an immunologic effect on uterine NK cell recruitment in the mouse placenta. Given the importance of immune cell populations on both placental vascularization and maternal immune tolerance of the developing fetus, we wanted to better characterize the immunologic effects of Emp2 at the placental-fetal interface. We performed flow cytometry of WT and Emp2 KO C57Bl/6 mouse uterine horns at GD12.5 to characterize immune cell populations localized to the various components of the maternal-fetal interface. We found that Emp2 KO decidua and placenta showed an elevated overall percentage of CD45+ cells compared to WT. Characterization of CD45+ cells in the decidua of Emp2 KO dams revealed an increase in NK cells, whereas in the placenta, Emp2 KO dams showed an increased percentage of M1 macrophages (with an increased ratio of M1/M2 macrophages). Given the differences detected in uNK cell populations in the decidua, we further characterized the interaction between Emp2 genetic KO and NK cell deletion via anti-asialo GM1 antibody injections. While the double knock-out of Emp2 and NK cells did not alter individual pup birthweight, it significantly reduced total litter weight and size by ∼50 %. In conclusion, Emp2 appears to regulate uNK and macrophage cell populations in pregnancy.

Keywords: Epithelial membrane protein 2; Macrophages; Placenta; Uterine natural killer cells

DOI: https://doi.org/10.1016/j.jri.2021.103309

Am J Obstet Gynecol. 2021 Mar 24. pii: S0002-9378(21)00187-3. [Epub ahead of print]

COVID-19 vaccine response in pregnant and lactating women: a cohort study.

BACKGROUND: Pregnant and lactating women were excluded from initial COVID-19 vaccine trials; thus, data to guide vaccine decision-making are lacking.
OBJECTIVES: To evaluate the immunogenicity and reactogenicity of COVID-19 mRNA vaccination in pregnant and lactating women compared to: (1) non-pregnant controls and (2) natural COVID-19 infection in pregnancy.
STUDY DESIGN: 131 reproductive-age vaccine recipients (84 pregnant, 31 lactating, and 16 non-pregnant) were enrolled in a prospective cohort study at two academic medical centers. Titers of SARS-CoV-2 Spike and RBD IgG, IgA and IgM were quantified in participant sera (N=131) and breastmilk (N=31) at baseline, second vaccine dose, 2-6 weeks post second vaccine, and at delivery by Luminex. Umbilical cord sera (N=10) titers were assessed at delivery. Titers were compared to those of pregnant women 4-12 weeks from natural infection (N=37) by ELISA. A pseudovirus neutralization assay was used to quantify neutralizing antibody titers for the subset of women who delivered during the study period. Post-vaccination symptoms were assessed via questionnaire. Kruskal-Wallis tests and a mixed effects model, with correction for multiple comparisons, were used to assess differences between groups.
RESULTS: Vaccine-induced antibody titers were equivalent in pregnant and lactating compared to non-pregnant women (median [IQR] 5.59 [4.68-5.89] pregnant, 5.74 [5.06-6.22] lactating, 5.62 [4.77-5.98] non-pregnant, p = 0.24). All titers were significantly higher than those induced by SARS-CoV-2 infection during pregnancy (p < 0.0001). Vaccine-generated antibodies were present in all umbilical cord blood and breastmilk samples. Neutralizing antibody titers were lower in umbilical cord compared to maternal sera, although this finding did not achieve statistical significance (median [IQR] 104.7 [61.2-188.2] maternal sera, 52.3 [11.7-69.6] cord sera, p=0.05). The second vaccine dose (boost dose) increased SARS-CoV-2-specific IgG, but not IgA, in maternal blood and breastmilk. No differences were noted in reactogenicity across the groups.
CONCLUSIONS: COVID-19 mRNA vaccines generated robust humoral immunity in pregnant and lactating women, with immunogenicity and reactogenicity similar to that observed in non-pregnant women. Vaccine-induced immune responses were significantly greater than the response to natural infection. Immune transfer to neonates occurred via placenta and breastmilk.

Keywords: Antibodies; COVID-19 vaccine; breastfeeding; breastmilk; cord blood; mRNA; maternal immunity; neonatal immunity; pregnancy

DOI: https://doi.org/10.1016/j.ajog.2021.03.023