HLA-F displays highly divergent and frequent haplotype lineages associated with different mRNA expression levels

Buttura, Renato V.; Ramalho, Jaqueline; Donadi, Eduardo Antônio; Veiga‐Castelli, Luciana C.; Mendes-Junior, Celso Teixeira; Castelli, Erick C.

doi:10.1016/j.humimm.2018.10.016

Cited by 10 publications

(18 citation statements)

References 40 publications

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“…Little data are available concerning associations between specific HLA-F alleles and the expression of HLA-F or clinical outcome. HLA-F*01:01:02 was associated with higher mRNA expression ( 40 ), and HLA-F*01:03 was associated with lower Hepatitis B virus DNA level in Tunisian patients with hepatitis B virus chronic infection ( 41 ).…”

Section: Introductionmentioning

confidence: 99%

Maternal HLA Ib Polymorphisms in Pregnancy Allo-Immunization

Persson

Picard

Marin³

et al. 2021

Front. Immunol.

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During pregnancy the formation of alloreactive anti-human leukocyte antigen (HLA) antibodies are a major cause of acute rejection in organ transplantation and of adverse effects in blood transfusion. The purpose of the study was to identify maternal HLA class Ib genetic factors associated with anti-HLA allo-immunization in pregnancy and the degree of tolerance estimated by IgG4 expression. In total, 86 primiparous women with singleton pregnancies were included in the study. Maternal blood samples and umbilical cord samples were collected at delivery. Clinical data were obtained. Maternal blood serum was screened for HLA class I and II antibodies, identification of Donor Specific Antibody (DSA), activation of complement measured by C1q and IgG4 concentrations. Mothers were genotyped for HLA class Ib (HLA-E, -F and -G). Anti-HLA class I and II antibodies were identified in 24% of the women. The maternal HLA-E*01:06 allele was significantly associated with a higher fraction of anti-HLA I immunization (20.0% vs. 4.8%, p = 0.048). The maternal HLA-G 3’-untranslated region UTR4-HLA-G*01:01:01:05 haplotype and the HLA-F*01:03:01 allele were significantly associated with a low anti-HLA I C1q activation (16.7% vs. 57.1%, p = 0.028; 16.7% vs. 50.0%, p = 0.046; respectively). Both HLA‑G and HLA-F*01:03:01 showed significantly higher levels of IgG4 compared with the other haplotypes. The results support an association of certain HLA class Ib alleles with allo-immunization during pregnancy. Further studies are needed to elucidate the roles of HLA-E*01:06, HLA-F*01:03 and HLA‑G UTR4 in reducing the risk for allo-immunization.

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Section: Introductionmentioning

confidence: 99%

Maternal HLA Ib Polymorphisms in Pregnancy Allo-Immunization

Persson

Picard

Marin³

et al. 2021

Front. Immunol.

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“…In HBEC, its expression is similar to that of HLA-G. RNAsequencing data from lymphoblastoid cell lines from the 1000 Genomes Project allowed us to show a hemizygous effect in the expression of HLA-H and to characterize different levels of expression according to HLA-H alleles; most interestingly, the HLA-H * 02:07 allele, which potentially encodes a full-length protein, presents the highest level of mRNA expression. HLA-H expression results from RNA-sequencing data, but this should, however, be taken with precaution and needs further confirmation; a part of the reported expression level, notably in the low-expression alleles, may be due to mismapped reads, as observed in the HLA-A * 23 and/or * 24 samples and as reported in different studies dealing with HLA NGS mapping (34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

“…RNA sequencing data were analyzed using PolyPheMe software specially designed for HLA NGS data analysis (Xegen, France) for which accuracy was assessed at 99.3% (10,32,33). This software is based on a specific strategy to avoid bias raised by the use of a unique genome as a reference for HLA NGS data mapping (34)(35)(36). First, RNAseq reads were selected for their specificity for HLA class I alleles.…”

Section: Hla-h Transcriptional Expression In Cell Line From the 1000mentioning

confidence: 99%

“…As HLA-H is deleted from chromosomes bearing HLA-A * 23/ * 24 alleles, two samples bearing HLA-A * 24:02/24:02 and HLA-A * 23:01/24:02 showed 22 and 203 HLA-H reads, respectively, representing background noise. No attempt was made to correct this mismapping bias that is inherent to HLA NGS data mapping (34)(35)(36).…”

Section: Hla-h Mrna Expression Is Lower In Hemizygous Hla-h Samplesmentioning

confidence: 99%

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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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“…All investigations to elucidate the function of HLA-F concentrate on the most frequent allelic variant HLA-F*01:01 (Table 1) [3,4,19,20,21]. A recent study on the haplotype lineages of HLA-F describes the relation between haplotypes and RNA expression levels [22]; moreover, recently a significant association of HLA-F polymorphism on genomic level with chronic HBV infection has been suggested [23]. However, the functional impact of allelic mismatches on the protein and peptidome has not yet been comprehensively described.…”

Section: Introductionmentioning

confidence: 99%

HLA-F Allele-Specific Peptide Restriction Represents an Exceptional Proteomic Footprint

Hò

Heinen

Blasczyk

et al. 2019

IJMS

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Peptide-dependent engagement between human leucocyte antigens class I (HLA-I) molecules and their cognate receptors has been extensively analyzed. HLA-F belongs to the non-classical HLA-Ib molecules with marginal polymorphic nature and tissue restricted distribution. The three common allelic variants HLA-F*01:01/01:03/01:04 are distinguished by polymorphism outside the peptide binding pockets (residue 50, α1 or residue 251, α3) and are therefore not considered relevant for attention. However, peptide selection and presentation undergoes a most elaborated extraction from the whole available proteome. It is known that HLA-F confers a beneficial effect on disease outcome during HIV-1 infections. The interaction with the NK cell receptor initiates an antiviral downstream immune response and lead to delayed disease progression. During the time of HIV infection, HLA-F expression is upregulated, while its interaction with KIR3DS1 is diminished. The non-polymorphic nature of HLA-F facilitates the conclusion that understanding HLA-F peptide selection and presentation is essential to a comprehensive understanding of this dynamic immune response. Utilizing soluble HLA technology we recovered stable pHLA-F*01:01, 01:03 and 01:04 complexes from K562 cells and analyzed the peptides presented. Utilizing a sophisticated LC-MS-method, we analyzed the complete K562 proteome and matched the peptides presented by the respective HLA-F subtypes with detected proteins. All peptides featured a length of 8 to 24 amino acids and are not N-terminally anchored; the C-terminus is preferably anchored by Lys. To comprehend the alteration of the pHLA-F surface we structurally compared HLA-F variants bound to selected peptides. The peptides were selected from the same cellular content; however, no overlap between the proteomic source of F*01:01, 01:03 or 01:04 selected peptides could be observed. Recognizing the balance between HLA-F expression, HLA-F polymorphism and peptide selection will support to understand the role of HLA-F in viral pathogenesis.

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HLA-F displays highly divergent and frequent haplotype lineages associated with different mRNA expression levels

Cited by 10 publications

References 40 publications

Maternal HLA Ib Polymorphisms in Pregnancy Allo-Immunization

Maternal HLA Ib Polymorphisms in Pregnancy Allo-Immunization

HLA-H: Transcriptional Activity and HLA-E Mobilization

HLA-F Allele-Specific Peptide Restriction Represents an Exceptional Proteomic Footprint

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