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Insights in Pregnancy Immunobiology and the Maternal–Placental–Fetal Interaction in Health and Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (15 October 2023) | Viewed by 15745

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Dr. Lorenza Díaz

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Departamento de Biología de la Reproducción, Instituto Nacional de la Nutrición Salvador Zubiran, Tlalpan 14080, Ciudad de Mexico, México
Interests: breast cancer; calcitriol; curcumin; resveratrol; antibiotics

Special Issue Information

Dear Colleagues,

During pregnancy, maternal physiology undergoes profound changes to tolerate and nourish an antigenically foreign body for several months. These changes include cardiovascular modifications, vessel remodeling, shifts in the immunoendocrine profile, and the activation of signaling pathways that maintain myometrium quiescence. Likewise, at the feto-maternal interface, adaptations to pregnancy include the regulation of the immune-cell population as well as immunoendocrine activity by placenta and fetal membranes. All these adjustments can be significantly affected by pregnancy complications, resulting in deleterious effects for both the mother and her baby, increasing perinatal morbidity and mortality.

Supervised by Dr. Lorenza Díaz Nieto and assisted by Dr. Andrea Olmos-Ortiz, this Special Issue aims to include the latest research and state-of-the-art reviews on the maternal–placental–fetal interaction, both under physiological conditions as well as under infectious and inflammatory settings (e.g., obesity, hyperglycemia, preeclampsia, pregnancy-induced hypertension). This Issue will also include papers addressing the underlying mechanisms of how the maternal organism and the placenta cope with invading pathogens while avoiding detrimental immune responses against the fetus. In addition, manuscripts related to sex-specific differences in the fetal–placental response to complications of pregnancy and sexually dimorphic placental characteristics will also be considered.

Dr. Lorenza Díaz
Guest Editor

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Keywords

pregnancy
inflammation
placenta
perinatal infections
gestational diabetes mellitus
gestational hypertension
preeclampsia
fetal growth restriction
preterm birth
antimicrobial peptides

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Published Papers (7 papers)

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Research

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11 pages, 1140 KiB

Open AccessArticle

A Novel Predictive Machine Learning Model Integrating Cytokines in Cervical-Vaginal Mucus Increases the Prediction Rate for Preterm Birth

by Hector Borboa-Olivares, Maria Jose Rodríguez-Sibaja, Aurora Espejel-Nuñez, Arturo Flores-Pliego, Jonatan Mendoza-Ortega, Ignacio Camacho-Arroyo, Ramón González-Camarena, Juan Carlos Echeverría-Arjonilla and Guadalupe Estrada-Gutierrez

Int. J. Mol. Sci. 2023, 24(18), 13851; https://doi.org/10.3390/ijms241813851 - 8 Sep 2023

Cited by 2 | Viewed by 1714

Abstract

Preterm birth (PB) is a leading cause of perinatal morbidity and mortality. PB prediction is performed by measuring cervical length, with a detection rate of around 70%. Although it is known that a cytokine-mediated inflammatory process is involved in the pathophysiology of PB, none screening method implemented in clinical practice includes cytokine levels as a predictor variable. Here, we quantified cytokines in cervical-vaginal mucus of pregnant women (18–23.6 weeks of gestation) with high or low risk for PB determined by cervical length, also collecting relevant obstetric information. IL-2, IL-6, IFN-γ, IL-4, and IL-10 were significantly higher in the high-risk group, while IL-1ra was lower. Two different models for PB prediction were created using the Random Forest machine-learning algorithm: a full model with 12 clinical variables and cytokine values and the adjusted model, including the most relevant variables-maternal age, IL-2, and cervical length- (detection rate 66 vs. 87%, false positive rate 12 vs. 3.33%, false negative rate 28 vs. 6.66%, and area under the curve 0.722 vs. 0.875, respectively). The adjusted model that incorporate cytokines showed a detection rate eight points higher than the gold standard calculator, which may allow us to identify the risk PB risk more accurately and implement strategies for preventive interventions. Full article

(This article belongs to the Special Issue Insights in Pregnancy Immunobiology and the Maternal–Placental–Fetal Interaction in Health and Disease)

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13 pages, 1446 KiB

Open AccessArticle

Placental AA/EPA Ratio Is Associated with Obesity Risk Parameters in the Offspring at 6 Years of Age

by Ariadna Gómez-Vilarrubla, Berta Mas-Parés, Gemma Carreras-Badosa, Mariona Jové, Rebeca Berdún, Alexandra Bonmatí-Santané, Francis de Zegher, Lourdes Ibañez, Abel López-Bermejo and Judit Bassols

Int. J. Mol. Sci. 2023, 24(12), 10087; https://doi.org/10.3390/ijms241210087 - 13 Jun 2023

Viewed by 1489

Abstract

During pregnancy, maternal polyunsaturated fatty acids (PUFA) are transferred to the fetus through the placenta by specific FA transporters (FATP). A higher perinatal exposure to n-6 over n-3 PUFA could be linked to excess fat mass and obesity development later in life. In this context, we aimed to assess the associations between long chain PUFAs (LC-PUFAs) (n-6, n-3, and n-6/n-3 ratios) measured in the placenta at term birth with obesity-related parameters in the offspring at 6 years of age and assess whether these associations are dependent on the placental relative expression of fatty acid transporters. As results, the PUFAn-6/PUFAn-3 ratio was 4/1, which scaled up to 15/1 when considering only the arachidonic acid/eicosapentaenoic acid ratio (AA/EPA ratio). Positive associations between the AA/EPA ratio and offspring’s obesity risk parameters were found with weight-SDS, BMI-SDS, percent fat mass-SDS, visceral fat, and HOMA-IR (r from 0.204 to 0.375; all p < 0.05). These associations were more noticeable in those subjects with higher expression of fatty acid transporters. Therefore, in conclusion, a higher placental AA/EPA ratio is positively associated with offspring’s visceral adiposity and obesity risk parameters, which become more apparent in subjects with higher expressions of placental FATPs. Our results support the potential role of n-6 and n-3 LC-PUFA in the fetal programming of obesity risk in childhood. For the present study, 113 healthy pregnant women were recruited during the first trimester of pregnancy and their offspring were followed up at 6 years of age. The fatty acid profiles and the expression of fatty acid transporters (FATP1 and FATP4) were analyzed from placental samples at birth. Associations between LC-PUFA (n-6, n-3, and n-6/n-3 ratios) and obesity risk parameters (weight, body mass index (BMI), percent fat mass, visceral fat, and homeostatic model assessment of insulin resistance (HOMA-IR)) in the offspring at 6 years of age were examined. Full article

(This article belongs to the Special Issue Insights in Pregnancy Immunobiology and the Maternal–Placental–Fetal Interaction in Health and Disease)

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23 pages, 5477 KiB

Open AccessArticle

High Glucose Promotes Inflammation and Weakens Placental Defenses against E. coli and S. agalactiae Infection: Protective Role of Insulin and Metformin

by Rodrigo Jiménez-Escutia, Donovan Vargas-Alcantar, Pilar Flores-Espinosa, Addy Cecilia Helguera-Repetto, Oscar Villavicencio-Carrisoza, Ismael Mancilla-Herrera, Claudine Irles, Yessica Dorin Torres-Ramos, María Yolotzin Valdespino-Vazquez, Pilar Velázquez-Sánchez, Rodrigo Zamora-Escudero, Marcela Islas-López, Caridad Carranco-Salinas, Lorenza Díaz, Verónica Zaga-Clavellina and Andrea Olmos-Ortiz

Int. J. Mol. Sci. 2023, 24(6), 5243; https://doi.org/10.3390/ijms24065243 - 9 Mar 2023

Cited by 2 | Viewed by 2950

Abstract

Placentas from gestational diabetes mellitus (GDM) patients undergo significant metabolic and immunologic adaptations due to hyperglycemia, which results in an exacerbated synthesis of proinflammatory cytokines and an increased risk for infections. Insulin or metformin are clinically indicated for the treatment of GDM; however, there is limited information about the immunomodulatory activity of these drugs in the human placenta, especially in the context of maternal infections. Our objective was to study the role of insulin and metformin in the placental inflammatory response and innate defense against common etiopathological agents of pregnancy bacterial infections, such as E. coli and S. agalactiae, in a hyperglycemic environment. Term placental explants were cultivated with glucose (10 and 50 mM), insulin (50–500 nM) or metformin (125–500 µM) for 48 h, and then they were challenged with live bacteria (1 × 10⁵ CFU/mL). We evaluated the inflammatory cytokine secretion, beta defensins production, bacterial count and bacterial tissue invasiveness after 4–8 h of infection. Our results showed that a GDM-associated hyperglycemic environment induced an inflammatory response and a decreased beta defensins synthesis unable to restrain bacterial infection. Notably, both insulin and metformin exerted anti-inflammatory effects under hyperglycemic infectious and non-infectious scenarios. Moreover, both drugs fortified placental barrier defenses, resulting in reduced E. coli counts, as well as decreased S. agalactiae and E. coli invasiveness of placental villous trees. Remarkably, the double challenge of high glucose and infection provoked a pathogen-specific attenuated placental inflammatory response in the hyperglycemic condition, mainly denoted by reduced TNF-α and IL-6 secretion after S. agalactiae infection and by IL-1β after E. coli infection. Altogether, these results suggest that metabolically uncontrolled GDM mothers develop diverse immune placental alterations, which may help to explain their increased vulnerability to bacterial pathogens. Full article

(This article belongs to the Special Issue Insights in Pregnancy Immunobiology and the Maternal–Placental–Fetal Interaction in Health and Disease)

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17 pages, 2984 KiB

Open AccessArticle

Infection and Persistence of Coxiella burnetii Clinical Isolate in the Placental Environment

by Sandra Madariaga Zarza, Muriel Militello, Laetitia Gay, Anthony Levasseur, Hubert Lepidi, Yassina Bechah, Soraya Mezouar and Jean-Louis Mege

Int. J. Mol. Sci. 2023, 24(2), 1209; https://doi.org/10.3390/ijms24021209 - 7 Jan 2023

Viewed by 2054

Abstract

Infection by Coxiella burnetii, the etiological agent of Q fever, poses the risk of causing severe obstetrical complications in pregnant women. C. burnetii is known for its placental tropism based on animal models of infection. The Nine Mile strain has been mostly used to study C. burnetii pathogenicity but the contribution of human isolates to C. burnetii pathogenicity is poorly understood. In this study, we compared five C. burnetii isolates from human placentas with C. burnetii strains including Nine Mile (NM) as reference. Comparative genomic analysis revealed that the Cb122 isolate was distinct from other placental isolates and the C. burnetii NM strain with a set of unique genes involved in energy generation and a type 1 secretion system. The infection of Balb/C mice with the Cb122 isolate showed higher virulence than that of NM or other placental isolates. We evaluated the pathogenicity of the Cb122 isolate by in vitro and ex vivo experiments. As C. burnetii is known to infect and survive within macrophages, we isolated monocytes and placental macrophages from healthy donors and infected them with the Cb122 isolate and the reference strain. We showed that bacteria from the Cb122 isolate were less internalized by monocyte-derived macrophages (MDM) than NM bacteria but the reference strain and the Cb122 isolate were similarly internalized by placental macrophages. The Cb122 isolate and the reference strain survived similarly in the two macrophage types. While the Cb122 isolate and the NM strain stimulated a poorly inflammatory program in MDM, they elicited an inflammatory program in placenta macrophages. We also reported that the Cb122 isolate and NM strain were internalized by trophoblastic cell lines and primary trophoblasts without specific replicative profiles. Placental explants were then infected with the Cb122 isolate and the NM strain. The bacteria from the Cb122 isolate were enriched in the chorionic villous foetal side. It is likely that the Cb122 isolate exhibited increased virulence in the multicellular environment provided by explants. Taken together, these results showed that the placental isolate of C. burnetii exhibits a specific infectious profile but its pathogenic role is not as high as the host immune response in pregnant women. Full article

(This article belongs to the Special Issue Insights in Pregnancy Immunobiology and the Maternal–Placental–Fetal Interaction in Health and Disease)

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Review

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17 pages, 1042 KiB

Open AccessReview

Immunomodulation of Antibody Glycosylation through the Placental Transfer

by Chang Gao, Qingyan Chen, Xinxin Hao and Qiushi Wang

Int. J. Mol. Sci. 2023, 24(23), 16772; https://doi.org/10.3390/ijms242316772 - 26 Nov 2023

Viewed by 2218

Abstract

Establishing an immune balance between the mother and fetus during gestation is crucial, with the placenta acting as the epicenter of immune tolerance. The placental transfer of antibodies, mainly immunoglobulin G (IgG), is critical in protecting the developing fetus from infections. This review looks at how immunomodulation of antibody glycosylation occurs during placental transfer and how it affects fetal health. The passage of maternal IgG antibodies through the placental layers, including the syncytiotrophoblast, stroma, and fetal endothelium, is discussed. The effect of IgG subclass, glycosylation, concentration, maternal infections, and antigen specificity on antibody transfer efficiency is investigated. FcRn-mediated IgG transport, influenced by pH-dependent binding, is essential for placental transfer. Additionally, this review delves into the impact of glycosylation patterns on antibody functionality, considering both protective and pathological effects. Factors affecting the transfer of protective antibodies, such as maternal vaccination, are discussed along with reducing harmful antibodies. This in-depth examination of placental antibody transfer and glycosylation provides insights into improving neonatal immunity and mitigating the effects of maternal autoimmune and alloimmune conditions. Full article

(This article belongs to the Special Issue Insights in Pregnancy Immunobiology and the Maternal–Placental–Fetal Interaction in Health and Disease)

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13 pages, 588 KiB

Open AccessReview

Sex-Specific Dysconnective Brain Injuries and Neuropsychiatric Conditions such as Autism Spectrum Disorder Caused by Group B Streptococcus-Induced Chorioamnionitis

by Seline Vancolen, Taghreed Ayash, Marie-Julie Allard and Guillaume Sébire

Int. J. Mol. Sci. 2023, 24(18), 14090; https://doi.org/10.3390/ijms241814090 - 14 Sep 2023

Cited by 3 | Viewed by 2306

Abstract

Global health efforts have increased against infectious diseases, but issues persist with pathogens like Group B Streptococcus (GBS). Preclinical studies have elaborated on the mechanistic process of GBS-induced chorioamnionitis and its impact on the fetal programming of chronic neuropsychiatric diseases. GBS inoculation in rodents demonstrated the following: (i) silent and self-limited placental infection, similar to human chorioamnionitis; (ii) placental expression of chemokines attracting polymorphonuclear (PMN) cells; (iii) in vitro cytokine production; (iv) PMN infiltration in the placenta (histologic hallmark of human chorioamnionitis), linked to neurobehavioral impairments like cerebral palsy and autism spectrum disorders (ASD); (v) upregulation of interleukin-1β (IL-1β) in the placenta and fetal blood, associated with higher ASD risk in humans; (vi) sex-specific effects, with higher IL-1β release and PMN recruitment in male placenta; (vii) male offspring exhibiting ASD-like traits, while female offspring displayed attention deficit and hyperactivity disorder (ADHD)-like traits; (viii) IL-1 and/or NF-kB blockade alleviate placental and fetal inflammation, as well as subsequent neurobehavioral impairments. These findings offer potential therapeutic avenues, including sex-adapted anti-inflammatory treatment (e.g., blocking IL-1; repurposing of FDA-approved IL-1 receptor antagonist (IL-1Ra) treatment). Blocking the IL-1 pathway offers therapeutic potential to alleviate chorioamnionitis-related disabilities, presenting an opportunity for a human phase II RCT that uses IL-1 blockade added to the classic antibiotic treatment of chorioamnionitis. Full article

(This article belongs to the Special Issue Insights in Pregnancy Immunobiology and the Maternal–Placental–Fetal Interaction in Health and Disease)

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Other

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16 pages, 2448 KiB

Open AccessPerspective

Molecular and Cellular Insights: A Focus on Glycans and the HNK1 Epitope in Autism Spectrum Disorder

by Camille M. Hours, Sophie Gil and Pierre Gressens

Int. J. Mol. Sci. 2023, 24(20), 15139; https://doi.org/10.3390/ijms242015139 - 13 Oct 2023

Cited by 2 | Viewed by 2208

Abstract

Autism Spectrum Disorder (ASD) is a synaptic disorder with a GABA/glutamate imbalance in the perineuronal nets and structural abnormalities such as increased dendritic spines and decreased long distance connections. Specific pregnancy disorders significantly increase the risk for an ASD phenotype such as preeclampsia, preterm birth, hypoxia phenomena, and spontaneous miscarriages. They are associated with defects in the glycosylation-immune placental processes implicated in neurogenesis. Some glycans epitopes expressed in the placenta, and specifically in the extra-villous trophoblast also have predominant functions in dendritic process and synapse function. Among these, the most important are CD57 or HNK1, CD22, CD24, CD33 and CD45. They modulate the innate immune cells at the maternal–fetal interface and they promote foeto-maternal tolerance. There are many glycan-based pathways of immunosuppression. N-glycosylation pathway dysregulation has been found to be associated with autoimmune-like phenotypes and maternal-autoantibody-related (MAR) autism have been found to be associated with central, systemic and peripheric autoimmune processes. Essential molecular pathways associated with the glycan-epitopes expression have been found to be specifically dysregulated in ASD, notably the Slit/Robo, Wnt, and mTOR/RAGE signaling pathways. These modifications have important effects on major transcriptional pathways with important genetic expression consequences. These modifications lead to defects in neuronal progenitors and in the nervous system’s implementation specifically, with further molecular defects in the GABA/glutamate system. Glycosylation placental processes are crucial effectors for proper maternofetal immunity and endocrine/paracrine pathways formation. Glycans/ galectins expression regulate immunity and neurulation processes with a direct link with gene expression. These need to be clearly elucidated in ASD pathophysiology. Full article

(This article belongs to the Special Issue Insights in Pregnancy Immunobiology and the Maternal–Placental–Fetal Interaction in Health and Disease)

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