Human leukocyte antigens: the unique expression in trophoblasts and their crosstalk with local immune cells

Lin, Xinxiu; Xie, Yingming; Zhao, Sijia; Liu, Chunyan; Mor, Gil; Liao, Aihua

doi:10.7150/ijbs.73616

Cited by 10 publications

(7 citation statements)

References 110 publications

(150 reference statements)

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“…We found HLA-G was increased in placenta increta regions (Figure 3a), suggesting local immune suppression in these regions. Furthermore, HLA-C is expressed on trophoblast cells in the Beta-2-microglobulin (B2M) form, and is the only HLA on EVT cells which can present paternal antigens and therefore plays an important role in preventing fetal rejection by the maternal immune system (36). We found B2M was increased in PAS regions in our study (see below), similar to previous studies (8, 24).…”

Section: Resultsmentioning

confidence: 99%

Spatial proteomics and transcriptomics of placenta accreta spectrum

Bartels,

Hameed,

Young

et al. 2024

Preprint

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In severe Placenta Accreta Spectrum (PAS), trophoblasts gain deep access in the myometrium (placenta increta). This study investigated alterations at the fetal-maternal interface in PAS cases using a systems biology approach consisting of immunohistochemistry, spatial transcriptomics and proteomics. We identified spatial variation in the distribution of CD4+, CD3+and CD8+T-cells at the maternal-interface in placenta increta cases. Spatial transcriptomics identified transcription factors involved in promotion of trophoblast invasion such as AP-1 subunits ATF-3 and JUN, and NFKB were upregulated in regions with deep myometrial invasion. Pathway analysis of differentially expressed genes demonstrated that degradation of extracellular matrix (ECM) and class 1 MHC protein were increased in increta regions, suggesting local tissue injury and immune suppression. Spatial proteomics demonstrated that increta regions were characterised by excessive trophoblastic proliferation in an immunosuppressive environment. Expression of inhibitors of apoptosis such as BCL-2 and fibronectin were increased, while CTLA-4 was decreased and increased expression of PD-L1, PD-L2 and CD14 macrophages. Additionally, CD44, which is a ligand of fibronectin that promotes trophoblast invasion and cell adhesion was also increased in increta regions. We subsequently examined ligand receptor interactions enriched in increta regions, with interactions with ITGβ1, including with fibronectin and ADAMS, emerging as central in increta. These ITGβ1 ligand interactions are involved in activation of epithelial–mesenchymal transition and remodelling of ECM suggesting a more invasive trophoblast phenotype. In PAS, we suggest this is driven by fibronectin via AP-1 signalling, likely as a secondary response to myometrial scarring. Overall, this study suggests the biological processes leading to deep trophoblast invasion in the myometrium in placenta increta are as a result of upregulation of transcription factors and subsequent genes and proteins which promote trophoblast invasion. This occurs in a locally immune suppressed environment, with increased ECM degradation suggesting these findings are secondary to iatrogenic uterine injury.Significance statementPlacenta Accreta Spectrum (PAS) is a rare pregnancy complication, where the placenta fails to separate from the womb resulting in severe bleeding, which is associated with significant maternal morbidity and mortality. As Caesarean section rates increase, the incidence of PAS is increasing. The underlying pathophysiology of PAS is poorly understood. Here, we apply a spatial multi-omic approach to explore the biologic changes at the maternal-fetal interface in severe PAS (placenta increta). Using spatial transcriptomics and proteomics, we identified genes and proteins that are dysregulated in severe PAS involving processes such as extracellular matrix degradation, local immune suppression and promotion of epithelial–mesenchymal transition. This study provides new insights into the biological changes and underlying pathophysiology leading to placenta increta.

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Section: Resultsmentioning

confidence: 99%

Spatial proteomics and transcriptomics of placenta accreta spectrum

Bartels,

Hameed,

Young

et al. 2024

Preprint

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“…HLA-G has been well-studied due to its role in maternal and infant immune tolerance [51,52]. During pregnancy, HLA-G mediates immune tolerance and supports fetal growth by binding to immune cells and exerting its immunosuppressive effects [53].…”

Section: Hla-gmentioning

confidence: 99%

Dimerization of Transmembrane Proteins in Cancer Immunotherapy

2023

Membranes

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Transmembrane proteins (TMEMs) are integrated membrane proteins that span the entire lipid bilayer and are permanently anchored to it. TMEMs participate in various cellular processes. Some TMEMs usually exist and perform their physiological functions as dimers rather than monomers. TMEM dimerization is associated with various physiological functions, such as the regulation of enzyme activity, signal transduction, and cancer immunotherapy. In this review, we focus on the dimerization of transmembrane proteins in cancer immunotherapy. This review is divided into three parts. First, the structures and functions of several TMEMs related to tumor immunity are introduced. Second, the characteristics and functions of several typical TMEM dimerization processes are analyzed. Finally, the application of the regulation of TMEM dimerization in cancer immunotherapy is introduced.

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“…The expression of HLA-E on the cell surface is regulated by the acquisition of peptides derived from the leader sequences of HLA-C and HLA-G molecules ( 12 ), and can be discovered in all stages of pregnancy. HLA-E was found to be expressed on the surface of EVTs ( 13 ), and it was weakly expressed in CTBs and STBs at 5 weeks of gestation ( 14 ).…”

Section: The Hla Class Ib Complexmentioning

confidence: 99%

“…HLA-E was found to be expressed on the surface of EVTs ( 13 ), and it was weakly expressed in CTBs and STBs at 5 weeks of gestation ( 14 ). The expressions of HLA-F are less well understood, based on existing research results, it is still controversial whether HLA-F is expressed in cells or on the surface of cells ( 12 ). In fact, studies have shown that HLA-F was observed to be expressed on the surface of EVTs ( 14 ), and in the cytoplasm of CTBs, STBs and EVTs ( 15 , 16 ).…”

Section: The Hla Class Ib Complexmentioning

confidence: 99%

“…In fact, studies have shown that HLA-F was observed to be expressed on the surface of EVTs ( 14 ), and in the cytoplasm of CTBs, STBs and EVTs ( 15 , 16 ). HLA-G is most abundantly expressed at immune-privileged sites ( 2 ), it can be found extensively expressed on the surface of EVTs during the entire pregnancy ( 12 ), and its soluble isoforms can be secreted by CTBs and STBs ( Figure 1 ) ( 15 , 17 ).…”

Section: The Hla Class Ib Complexmentioning

confidence: 99%

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Advances in the study of HLA class Ib in maternal-fetal immune tolerance

et al. 2022

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The HLA class Ib molecule is an alloantigen that causes transplant rejection on behalf of individual human and plays an important role in maternal-fetal immune tolerance. Early studies on HLA class Ib focused on the mechanism of HLA-G-induced immune escape, but in recent years, studies on the mechanism of HLA-G have deepened and gradually explored the mechanism of HLA-E and HLA-F, which are also HLA class Ib molecules. In the maternal-fetal interface, trophoblast cells express HLA class Ib molecules to protect the fetus from maternal immune cells by binding to inhibitory receptors of decidual immune cells (DICs) and shifting Th1/Th2 balance toward Th2 bias. Further studies on the molecular mechanism of HLA class Ib molecules provide a reference for its application in the field of clinical assisted reproduction.

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Human leukocyte antigens: the unique expression in trophoblasts and their crosstalk with local immune cells

Cited by 10 publications

References 110 publications

Spatial proteomics and transcriptomics of placenta accreta spectrum

Spatial proteomics and transcriptomics of placenta accreta spectrum

Dimerization of Transmembrane Proteins in Cancer Immunotherapy

Advances in the study of HLA class Ib in maternal-fetal immune tolerance

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