bims-reprim 2021-07-18 papers

Issue of 2021–07–18
six papers selected by
Iva Filipovic, Karolinska Institutet

Sci Immunol. 2021 Jul 16. pii: eabf1968. [Epub ahead of print]6(61):

Extrathymic Aire-expressing cells support maternal-fetal tolerance.

Eva Gillis-Buck, Haleigh Miller, Marina Sirota, Stephan J Sanders, Vasilis Ntranos, Mark S Anderson, James M Gardner, Tippi C MacKenzie.

Healthy pregnancy requires tolerance to fetal alloantigens as well as syngeneic embryonic and placental antigens. Given the importance of the autoimmune regulator (Aire) gene in self-tolerance, we investigated the role of Aire-expressing cells in maternal-fetal tolerance. We report that maternal ablation of Aire-expressing (Aire +) cells during early mouse pregnancy caused intrauterine growth restriction (IUGR) in both allogeneic and syngeneic pregnancies. This phenotype is immune mediated, as IUGR was rescued in Rag1-deficient mice, and involved a memory response, demonstrated by recurrence of severe IUGR in second pregnancies. Single-cell RNA sequencing demonstrated that Aire + cell depletion in pregnancy results in expansion of activated T cells, particularly T follicular helper cells. Unexpectedly, selective ablation of either Aire-expressing medullary thymic epithelial cells or extrathymic Aire-expressing cells (eTACs) mapped the IUGR phenotype exclusively to eTACs. Thus, we report a previously undescribed mechanism for the maintenance of maternal-fetal immune homeostasis and demonstrate that eTACs protect the conceptus from immune-mediated IUGR.

DOI: https://doi.org/10.1126/sciimmunol.abf1968

Clin Infect Dis. 2021 Jul 14. pii: ciab627. [Epub ahead of print]

Congenital human cytomegalovirus infection is associated with decreased transplacental IgG transfer efficiency due to maternal hypergammaglobulinemia.

Eleanor C Semmes, Shuk Hang Li, Jillian H Hurst, Zidanyue Yang, Donna Niedzwiecki, Genevieve G Fouda, Joanne Kurtzberg, Kyle M Walsh, Sallie R Permar.

BACKGROUND: Placentally-transferred maternal IgG protects against pathogens in early life, yet vertically-transmitted infections can interfere with transplacental IgG transfer. Although human cytomegalovirus (HCMV) is the most common placentally-transmitted viral infection worldwide, the impact of congenital HCMV (cCMV) infection on transplacental IgG transfer has been underexplored.
METHODS: We evaluated total and antigen-specific maternal and cord blood IgG levels and transplacental IgG transfer efficiency in a U.S-based cohort of 93 mother-infant pairs including 27 cCMV-infected and 66 cCMV-uninfected pairs, of which 29 infants were born to HCMV-seropositive non-transmitting mothers and 37 to HCMV-seronegative mothers. Controls were matched on sex, race/ethnicity, maternal age, and delivery year.
RESULTS: Transplacental IgG transfer efficiency was decreased by 23% (95% CI 10-36%, p=0.0079) in cCMV-infected pairs and 75% of this effect (95% CI 28-174%, p=0.0085) was mediated by elevated maternal IgG levels (i.e., hypergammaglobulinemia) in HCMV-transmitting women. Despite reduced transfer efficiency, IgG levels were similar in cord blood from infants with and without cCMV infection.
CONCLUSIONS: Our results indicate that cCMV infection moderately reduces transplacental IgG transfer efficiency due to maternal hypergammaglobulinemia; however, infants with and without cCMV infection had similar antigen-specific IgG levels, suggesting comparable protection from maternal IgG acquired via transplacental transfer.

Keywords: congenital CMV infection; human cytomegalovirus; maternal hypergammaglobulinemia; maternal-fetal vaccination; transplacental IgG transfer

DOI: https://doi.org/10.1093/cid/ciab627

Endocrinology. 2021 Jul 16. pii: bqab143. [Epub ahead of print]

Paternal high fat diet impairs maternal adaptations essential for normal pregnancy.

Hannah L Morgan, Adam J Watkins.

Keywords: Maternal adaptations; Paternal diet; Seminal plasma; Uterine immune cells

DOI: https://doi.org/10.1210/endocr/bqab143

Sci Rep. 2021 07 13. 11(1): 14390

Placental response to maternal SARS-CoV-2 infection.

Mirella Mourad, Taylor Jacob, Elena Sadovsky, Shai Bejerano, Glicella Salazar-De Simone, Tarique Rajasaheb Bagalkot, Jason Zucker, Michael T Yin, Jennifer Y Chang, Lihong Liu, Larisa Debelenko, Carrie J Shawber, Morgan Firestein, Yingshi Ouyang, Cynthia Gyamfi-Bannerman, Anna Penn, Alexander Sorkin, Ronald Wapner, Yoel Sadovsky.

The coronavirus disease 2019 (COVID-19) pandemic affected people at all ages. Whereas pregnant women seemed to have a worse course of disease than age-matched non-pregnant women, the risk of feto-placental infection is low. Using a cohort of 66 COVID-19-positive women in late pregnancy, we correlated clinical parameters with disease severity, placental histopathology, and the expression of viral entry and Interferon-induced transmembrane (IFITM) antiviral transcripts. All newborns were negative for SARS-CoV-2. None of the demographic parameters or placental histopathological characteristics were associated with disease severity. The fetal-maternal transfer ratio for IgG against the N or S viral proteins was commonly less than one, as recently reported. We found that the expression level of placental ACE2, but not TMPRSS2 or Furin, was higher in women with severe COVID-19. Placental expression of IFITM1 and IFITM3, which have been implicated in antiviral response, was higher in participants with severe disease. We also showed that IFITM3 protein expression, which localized to early and late endosomes, was enhanced in severe COVID-19. Our data suggest an association between disease severity and placental SARS-CoV-2 processing and antiviral pathways, implying a role for these proteins in placental response to SARS-CoV-2.

DOI: https://doi.org/10.1038/s41598-021-93931-0

Bio Protoc. 2021 Jun 05. 11(11): e4044

Isolation of First-Trimester and Full-term Human Placental Hofbauer Cells.

Anna Appios, Jake R Thomas, Naomi McGovern.

The placenta is the crucial organ that regulates the health of both mother and fetus during pregnancy. The human placenta is composed of villous tree-like structures that embed into the maternal decidua. Within the stroma of the villi resides a population of fetally-derived macrophages, the Hofbauer cells (HBC). HBC are the only fetal immune cells found within the placenta in the steady-state and are thought to play a crucial role in placental function. From the 10th week of gestation, maternal blood flow into the intervillous space begins, resulting in the placental villi becoming bathed in maternal blood. To study HBC it is necessary to develop techniques that allow for their specific isolation and distinction from maternal blood monocytes and decidual macrophages. Here, we describe a protocol that explains step-by-step the strategy we have developed that allows the specific isolation of HBC.

Keywords: Hofbauer cells; Macrophages; Placenta; Tissue processing

DOI: https://doi.org/10.21769/BioProtoc.4044

Front Immunol. 2021 ;12 693189

Epidemiology of Pregnancy Complications Through the Lens of Immunological Memory.

Emily J Gregory, James Liu, Hilary Miller-Handley, Jeremy M Kinder, Sing Sing Way.

In the fifteen minutes it takes to read this short commentary, more than 400 babies will have been born too early, another 300 expecting mothers will develop preeclampsia, and 75 unborn third trimester fetuses will have died in utero (stillbirth). Given the lack of meaningful progress in understanding the physiological changes that occur to allow a healthy, full term pregnancy, it is perhaps not surprising that effective therapies against these great obstetrical syndromes that include prematurity, preeclampsia, and stillbirth remain elusive. Meanwhile, pregnancy complications remain the leading cause of infant and childhood mortality under age five. Does it have to be this way? What more can we collectively, as a biomedical community, or individually, as clinicians who care for women and newborn babies at high risk for pregnancy complications, do to protect individuals in these extremely vulnerable developmental windows? The problem of pregnancy complications and neonatal mortality is extraordinarily complex, with multiple unique, but complementary perspectives from scientific, epidemiological and public health viewpoints. Herein, we discuss the epidemiology of pregnancy complications, focusing on how the outcome of prior pregnancy impacts the risk of complication in the next pregnancy - and how the fundamental immunological principle of memory may promote this adaptive response.

Keywords: immunological memory; parity; preeclampsia; prematurity; stillbirth

DOI: https://doi.org/10.3389/fimmu.2021.693189