Role of Human Leukocyte Antigens at the Feto-Maternal Interface in Normal and Pathological Pregnancy: An Update

Tersigni, Chiara; Meli, Federica; Neri, Caterina; IACOANGELI, Azzurra; Franco, Rita; Lanzone, Antonio; Scambia, Giovanni; Simone, Nicoletta Di

doi:10.3390/ijms21134756

Cited by 47 publications

(46 citation statements)

References 57 publications

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“…A third type of trophoblasts, the endovascular trophoblasts, which differentiate from extravillous trophoblasts, remodel the maternal spiral arteries that provide the placenta with maternal blood (12). Due to their location at the interface with maternal cells, trophoblasts play critical roles in promoting immune tolerance of the semi-allogeneic fetal cells via controlling expression of immune modulatory surface receptors and releasing tolerogenic mediators (19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

Human Placental Trophoblasts Infected by Listeria monocytogenes Undergo a Pro-Inflammatory Switch Associated With Poor Pregnancy Outcomes

et al. 2021

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The placenta controls the growth of the fetus and ensures its immune protection. Key to these functions, the syncytiotrophoblast (SYN) is a syncytium formed by fusion of underlying mononuclear trophoblasts. The SYN covers the placental surface and is bathed in maternal blood to mediate nutritional and waste exchanges between the mother and fetus. The bacterial pathogen Listeria monocytogenes breaches the trophoblast barrier and infects the placental/fetal unit resulting in poor pregnancy outcomes. In this work, we analyzed the L. monocytogenes intracellular lifecycle in primary human trophoblasts. In accordance with previous studies, we found that the SYN is 20-fold more resistant to infection compared to mononuclear trophoblasts, forming a protective barrier to infection at the maternal interface. We show for the first time that this is due to a significant reduction in L. monocytogenes uptake by the SYN rather than inhibition of the bacterial intracellular division or motility. We here report the first transcriptomic analysis of L. monocytogenes-infected trophoblasts (RNA sequencing). Pathway analysis showed that infection upregulated TLR2, NOD-like, and cytosolic DNA sensing pathways, as well as downstream pro-inflammatory circuitry (NF-κB, AP-1, IRF4, IRF7) leading to the production of mediators known to elicit the recruitment and activation of maternal leukocytes (IL8, IL6, TNFα, MIP-1). Signature genes associated with poor pregnancy outcomes were also upregulated upon infection. Measuring the release of 54 inflammatory mediators confirmed the transcriptomic data and revealed sustained production of tolerogenic factors (IL-27, IL-10, IL-1RA, TSLP) despite infection. Both the SYN and mononuclear trophoblasts produced cytokines, but surprisingly, some cytokines were predominantly produced by the SYN (IL-8, IL-6) or by non-fused trophoblasts (TNFα). Collectively, our data support that trophoblasts act as placental gatekeepers that limit and detect L. monocytogenes infection resulting in a pro-inflammatory response, which may contribute to the poor pregnancy outcomes if the pathogen persists.

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Section: Introductionmentioning

confidence: 99%

Human Placental Trophoblasts Infected by Listeria monocytogenes Undergo a Pro-Inflammatory Switch Associated With Poor Pregnancy Outcomes

et al. 2021

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“…Tight control of HLA class I and class II expression in villous and extra-villous trophoblast (VT and EVT, respectively) is essential for successful pregnancy outcome (6). In particular, the lack of HLA class II (-DP, -DQ and -DR) molecule expression on trophoblasts prevents maternal T cell alloimmune responses against paternal-derived antigens.…”

Section: Introductionmentioning

confidence: 99%

Circulating Placental Vesicles Carry HLA-DR in Pre-Eclampsia: A New Potential Marker of the Syndrome

Tersigni¹,

Lucchetti

Franco

et al. 2021

Front. Immunol.

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BackgroundPre-eclampsia (PE) is a common disorder of pregnancy that usually presents with hypertension and proteinuria. The clinical presentation arises from soluble factors released into the maternal circulation from the placenta owing to the stress of syncytiotrophoblast, consequence of defective placentation occurring in the first half of pregnancy. Reduced tolerance of the semiallogeneic fetus by the maternal immune system has been proposed as first trigger leading to poor placentation. We previously observed aberrant expression of human leukocyte antigen (HLA)-DR molecules in the syncytiotrophoblast of a subset of women with PE. Aim of this study was to investigate abnormal expression of circulating HLA-DR in syncytiotrophoblast-derived extracellular vesicles (STBEVs) in women with PE compared to normal pregnant women.Methodsperipheral venous blood was collected from 22 women with PE and 22 normal pregnant women. Circulating STBEVs were collected by ultra-centrifugation (120000 g) and analyzed for the expression of HLA-DR and placental alkaline phosphatase (PLAP), a specific marker of the placenta, by Western blot analysis and flow cytometry.Resultscirculating STBEVs positive for HLA-DR were observed in 64% of PE women while no HLA-DR positivity was detected in any of the controls (P<0.01).ConclusionsAberrant expression of HLA-DR in circulating STBEVs is specifically associated to PE. Further studies are required: a) to define the role of aberrant placental expression of HLA-DR molecules in the pathogenesis of PE; b) evaluate a possible application of detecting circulating HLA-DR positive STBEVs in the diagnosis and prediction of PE in the first and second trimester of pregnancy.

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“…While the lateral edges of the anchoring villi are similarly covered by outer STB and inner CTB layers, the tips of the anchoring villi are populated by villous cytotrophoblast progenitors that transform into invasive extravillous trophoblast cells (EVT). EVT move through and along the maternal decidua to become: (1) endovascular trophoblast cells that transform their invasive capacity and adopt a vascular phenotype as they remodel maternal spiral arteries [ 4 , 5 ], (2) interstitial EVT that populate the maternal decidua and invade into the maternal myometrium without significant fusion and (3) fusion-mediated multinucleated trophoblast giant cells (TGC) that can be found mostly near the maternal decidual/myometrial border. While most believe end differentiated interstitial EVT fusion to be the origin of TGC, other cellular origins for this giant cell type have been posited.…”

Section: The Hemochorial Placenta Poses Unique Immune Challengesmentioning

confidence: 99%

“…Over the time course of human pregnancy, placental trophoblast cells and maternal immune mediators interact at a minimum of eight major sites ( Figure 1 ), (also reviewed elsewhere in this issue [ 5 ]). Four of these sites involve interactions with specialized [ 6 , 7 ] immune cells populating the maternal decidua, many of which are already present in the post-ovulatory decidua just prior to blastocyst attachment ( Figure 1 , panels 1–4).…”

Section: The Hemochorial Placenta Poses Unique Immune Challengesmentioning

confidence: 99%

The Immunology of Syncytialized Trophoblast

Schust

Bonney

Sugimoto

et al. 2021

IJMS

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Multinucleate syncytialized trophoblast is found in three forms in the human placenta. In the earliest stages of pregnancy, it is seen at the invasive leading edge of the implanting embryo and has been called primitive trophoblast. In later pregnancy, it is represented by the immense, multinucleated layer covering the surface of placental villi and by the trophoblast giant cells found deep within the uterine decidua and myometrium. These syncytia interact with local and/or systemic maternal immune effector cells in a fine balance that allows for invasion and persistence of allogeneic cells in a mother who must retain immunocompetence for 40 weeks of pregnancy. Maternal immune interactions with syncytialized trophoblast require tightly regulated mechanisms that may differ depending on the location of fetal cells and their invasiveness, the nature of the surrounding immune effector cells and the gestational age of the pregnancy. Some specifically reflect the unique mechanisms involved in trophoblast cell–cell fusion (aka syncytialization). Here we will review and summarize several of the mechanisms that support healthy maternal–fetal immune interactions specifically at syncytiotrophoblast interfaces.

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Role of Human Leukocyte Antigens at the Feto-Maternal Interface in Normal and Pathological Pregnancy: An Update

Cited by 47 publications

References 57 publications

Human Placental Trophoblasts Infected by Listeria monocytogenes Undergo a Pro-Inflammatory Switch Associated With Poor Pregnancy Outcomes

Human Placental Trophoblasts Infected by Listeria monocytogenes Undergo a Pro-Inflammatory Switch Associated With Poor Pregnancy Outcomes

Circulating Placental Vesicles Carry HLA-DR in Pre-Eclampsia: A New Potential Marker of the Syndrome

The Immunology of Syncytialized Trophoblast

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