Abstract
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.
Highlights
Human leukocyte antigen-G (HLA-G), a member of the human leukocyte antigen (HLA) class Ib family, modulates natural killer (NK) cells and cytotoxic T-lymphocyte-mediated activity as well as B-lymphocyte proliferation
Associations between patients’ asthmatic features, soluble HLA-G (sHLA-G) expression, and genetic polymorphism were tested with logistic regressions when the predicted variable was categorical and general linear regression when the predicted variable was quantitative
HLA-G alleles were typed at maximum resolution and regulatory regions (UTR1–8) were typed at low resolution according to eight single-nucleotide polymorphism (SNP) in 5′upstream regulatory region (URR) and at high resolution based on all 28 polymorphisms in the 5′URR and 12 polymorphisms in the 3′untranslated region (UTR)
Summary
Human leukocyte antigen-G (HLA-G), a member of the HLA class Ib (non-classical) family, modulates natural killer (NK) cells and cytotoxic T-lymphocyte-mediated activity as well as B-lymphocyte proliferation. Human leukocyte antigen-G is expressed by a restricted pattern of cells including human bronchial epithelium cells (HBEC) and displays interindividual variation expression in physiological conditions. 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 HLAG3 [11,12,13,14]
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