Bronchial Epithelial Cells from Asthmatic Patients Display Less Functional HLA-G Isoform Expression

Carlini, Federico; Picard, Christophe; Garulli, Céline; Piquemal, David; Roubertoux, Pierre L.; Chiaroni, Jacques; Chanez, Pascal; Gras, Delphine; Cristofaro, Julie Di

doi:10.3389/fimmu.2017.00006

Cited by 18 publications

(20 citation statements)

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“…Furthermore, cytokines such as IFN-γ and/or TNF-α differentially regulated HLA-G isoform expression in a retinal pigment epithelial cell line ( 80 ). In pathological settings, fewer functional HLA-G molecules and differential expression of HLA-G isoforms were observed in asthma and prostatic adenocarcinoma patients, respectively ( 81 , 82 ). All these mechanisms of regulation and disease status alone or in combination can contribute to the heterogeneity of HLA-G expression.…”

Section: Hla-g Heterogeneity In Cancersmentioning

confidence: 99%

Heterogeneity of HLA-G Expression in Cancers: Facing the Challenges

2018

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Phenotypic heterogeneity has been observed in most malignancies, which represents a considerable challenge for tumor therapy. In recent decades, the biological function and clinical significance of the human leukocyte antigen (HLA)-G have been intensively explored. It is now widely accepted that HLA-G is a critical marker of immunotolerance in cancer cell immune evasion and is strongly associated with disease progress and prognosis for cancer patients. Moreover, it has recently been emphasized that the signaling pathway linking HLA-G and immunoglobulin-like transcripts (ILTs) is considered an immune checkpoint. In addition, HLA-G itself can generate at least seven distinct isoforms, and intertumor and intratumor heterogeneity of HLA-G expression is common across different tumor types. Furthermore, HLA-G heterogeneity in cancers has been related to disease stage and outcomes, metastatic status and response to different therapies. This review focuses on the heterogeneity of HLA-G expression in malignant lesions, and clinical implications of this heterogeneity that might be relevant to personalized treatments are also discussed.

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Section: Hla-g Heterogeneity In Cancersmentioning

confidence: 99%

Heterogeneity of HLA-G Expression in Cancers: Facing the Challenges

2018

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“…These sequences differ at position 1827G>A in the last positions of exon 4 which, according to in silico predictive analysis, creates an exonic cryptic acceptor site. We previously reported alternatively spliced isoform expression of HLA-G in HBEC from asthmatic patients as compared to HI forms ( 10 ). These results support the hypothesis that the mRNA transcript of these HLA-G *01:04 alleles might be processed differently leading to varied protein expression but could also explain discrepancies of clinical studies with HLA-G typing at a four-digit level.…”

Section: Discussionmentioning

confidence: 99%

“…In BAL from asthmatic patients, however, sHLA-G expression was reported to be inversely correlated with markers of asthma inflammation ( 9 ). Our group reported an impairment of full-length protein HLA-G expression in HBEC from asthmatic patients and abnormal expression of alternatively spliced membrane-bound (HLA-G1 to 4) and soluble (HLA-G5 to 7) forms ( 10 ). Both HLA-G1 and -G5 isoforms reduced NK cell cytotoxicity with an additive effect, and HLA-G2, -G4, and -G6 were described as functional, whereas conflicting results were published concerning HLA-G3 ( 11 – 14 ).…”

Section: Introductionmentioning

confidence: 99%

HLA-G Haplotypes Are Differentially Associated with Asthmatic Features

et al. 2018

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Human leukocyte antigen (HLA)-G, a HLA class Ib molecule, interacts with receptors on lymphocytes such as T cells, B cells, and natural killer cells to influence immune responses. Unlike classical HLA molecules, HLA-G expression is not found on all somatic cells, but restricted to tissue sites, including human bronchial epithelium cells (HBEC). Individual variation in HLA-G expression is linked to its genetic polymorphism and has been associated with many pathological situations such as asthma, which is characterized by epithelium abnormalities and inflammatory cell activation. Studies reported both higher and equivalent soluble HLA-G (sHLA-G) expression in different cohorts of asthmatic patients. In particular, we recently described impaired local expression of HLA-G and abnormal profiles for alternatively spliced isoforms in HBEC from asthmatic patients. sHLA-G dosage is challenging because of its many levels of polymorphism (dimerization, association with β2-microglobulin, and alternative splicing), thus many clinical studies focused on HLA-G single-nucleotide polymorphisms as predictive biomarkers, but few analyzed HLA-G haplotypes. Here, we aimed to characterize HLA-G haplotypes and describe their association with asthmatic clinical features and sHLA-G peripheral expression and to describe variations in transcription factor (TF) binding sites and alternative splicing sites. HLA-G haplotypes were differentially distributed in 330 healthy and 580 asthmatic individuals. Furthermore, HLA-G haplotypes were associated with asthmatic clinical features showed. However, we did not confirm an association between sHLA-G and genetic, biological, or clinical parameters. HLA-G haplotypes were phylogenetically split into distinct groups, with each group displaying particular variations in TF binding or RNA splicing sites that could reflect differential HLA-G qualitative or quantitative expression, with tissue-dependent specificities. Our results, based on a multicenter cohort, thus support the pertinence of HLA-G haplotypes as predictive genetic markers for asthma.

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“…Total RNA was isolated using the RNeasy kit (Qiagen, France). cDNA was reverse transcribed using Superscript III Reverse Transcriptase (Invitrogen), and Real-time PCR analyses were performed using TaqMan technology (Life Technologies) as previously described (28). The primers/probes were designed using the Primer 3 v.0.4.0 program (http://bioinfo.ut.ee/primer3-0.4.0/primer3/) to specifically target HLA-H as checked with the Human Genome Browser (http://genome.ucsc.edu/) (29) and IPD-IMGT/HLA database 3.37.0 (30) ( Supplementary Table 1).…”

Section: Hla-h Transcriptional Expression In Pbmc and Bronchial Epithmentioning

confidence: 99%

“…The primers/probes were designed using the Primer 3 v.0.4.0 program (http://bioinfo.ut.ee/primer3-0.4.0/primer3/) to specifically target HLA-H as checked with the Human Genome Browser (http://genome.ucsc.edu/) (29) and IPD-IMGT/HLA database 3.37.0 (30) ( Supplementary Table 1). HLA-G and HLA-E were investigated as previously described (28), and ACTB (actinβ) was used as an endogenous control (ACTB Hs99999903_m1, Invitrogen).…”

Section: Hla-h Transcriptional Expression In Pbmc and Bronchial Epithmentioning

confidence: 99%

HLA-H: Transcriptional Activity and HLA-E Mobilization

et al. 2020

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Little attention is paid to pseudogenes from the highly polymorphic HLA genetic region. The pseudogene HLA-H is defined as a non-functional gene because it is deleted at different frequencies in humans and because it encodes a potentially non-functional truncated protein. However, different studies have shown HLA-H transcriptional activity. We formerly identified 13 novel HLA-H alleles, including the H * 02:07 allele, which reaches 19.6% in East Asian populations and encodes a full-length HLA protein. The aims of this study were to explore the expression and possible function of the HLA-H molecule. HLA-H may act as a transmembrane molecule and/or indirectly via its signal peptide by mobilizing HLA-E to the cell surface. We analyzed HLA-H RNA expression in Peripheral Blood Mononuclear Cells (PBMC), Human Bronchial Epithelial Cells (HBEC), and available RNA sequencing data from lymphoblastoid cell lines, and we looked to see whether HLA-E was mobilized at the cell surface by the HLA-H signal peptide. Our data confirmed that HLA-H is transcribed at similar levels to HLA-G. We characterized a hemizygous effect in HLA-H expression, and expression differed according to HLA-H alleles; most interestingly, the HLA-H * 02:07 allele had the highest level of mRNA expression. We showed that HLA-H signal peptide incubation mobilized HLA-E molecules at the cell surface of T-Lymphocytes, monocytes, B-Lymphocytes, and primary epithelial cells. Our results suggest that HLA-H may be functional but raises many biological issues that need to be addressed.

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Bronchial Epithelial Cells from Asthmatic Patients Display Less Functional HLA-G Isoform Expression

Cited by 18 publications

References 50 publications

Heterogeneity of HLA-G Expression in Cancers: Facing the Challenges

Heterogeneity of HLA-G Expression in Cancers: Facing the Challenges

HLA-G Haplotypes Are Differentially Associated with Asthmatic Features

HLA-H: Transcriptional Activity and HLA-E Mobilization

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