Abstract
Not all asthmatic patients adequately respond to current available treatments, such as inhaled corticosteroids or omalizumab®. New treatments will aim to target the bronchial epithelium–immune response interaction using different pathways. HLA-G is involved in immunomodulation and may promote epithelial cell differentiation and proliferation. HLA-G protein has several isoforms generated by alternative splicing that might have differential functionalities. HLA-G protein expression and genetic polymorphisms have been reported to be associated with asthma. Our hypothesis is that bronchial epithelium from asthmatic patients displays less functional HLA-G isoforms. HLA-G transcriptional isoforms were quantified by real-time PCR in human bronchial epithelium cells (HBEC) grown in air–liquid interface culture obtained from five healthy controls (HC), seven patients with mild asthma (MA), and seven patients with severe asthma (SA). They were re-differentiated, and IL-13 exposure was used as a proxy for a pro-inflammatory cytokine. HLA-G protein expression was assessed by western blot analysis. HLA-G allele was typed by direct sequencing. Our results showed that both MA and SA display less functional HLA-G isoforms than HC (p < 0.05); in vitro HBEC re-differentiation from SA displays a particular isoform expression profile compared to MA and HC (p = 0.03); HLA-G*01:06 frequency in MA and SA was significantly higher than in the healthy population (p = 0.03 and p < 0.001, respectively); and IL-13 exposure had no impact on HLA-G expression. Our results support that an impaired expression of HLA-G isoforms in asthmatic patients could contribute to the loss of inflammation control and epithelium structural remodeling. Therefore, HLA-G might be an interesting alternative target for asthmatic patients not adequately responding to current drugs.
Highlights
Asthma affects almost 300 million people worldwide and is related to a chronic inflammation of the airways
This study, performed on a rarely accessible method of Human bronchial epithelium cells (HBEC) derived from endobronchial biopsies fully re-differentiated into bronchial epithelium tissue using an air–liquid interface (ALI) culture, is the first to have investigated into the expression of all of the HLA-G mRNA isoforms
Given that the immunotolerant HLA-G molecule is well-known for its implication in various inflammatory conditions, a more comprehensive analysis of its local bronchial expression in asthmatic patients could bring this molecule into the limelight as a new therapeutical strategy
Summary
Asthma affects almost 300 million people worldwide and is related to a chronic inflammation of the airways. It groups various phenotypes which can be classified according to clinical severity, age of onset, and different immune responses, i.e., T2-associated and non-T2 asthma [1]. The bronchial epithelium is abnormal in asthma, with structural changes and thickening of the sub-epithelial layer [3], and its function is characterized by an exaggerated release of various cytokines, including TSLP, IL-33, and IL-25, as well as impaired inflammation resolution [4]. HBEC from severe asthma patients secrete higher levels of IL-8, a chemoattractant for neutrophils, and reduced levels of lipoxins, mediators which normally resolve inflammation [6]
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