DNA methylation down-regulates integrin ß4 expression in asthmatic airway epithelial cells.

BACKGROUND: Integrin ß4 (ITGB4) is a hemi-desmosome protein which is downregulated in the airway epithelial cells of asthma patients. The proximal promoters and exons of ITGB4 contain CpG islands or multiple CpG sites both in human and mice, which indicated the possible methylation regulation of ITGB4 in airway epithelial cells. OBJECTIVE: We sought to unveil that DNA methylation regulates the decreased ITGB4 during the pathogenesis of asthma. METHODS: Mice were exposed to house dust mite (HDM) extracts to construct an asthma model. 5-Aza-2'-deoxycytidine (5-AZA) or dexamethasone (DEX) were added in the last two weeks. Besides, the primary human bronchial epithelial (HBE) cells were incubated for the detection of ITGB4 expression and methylation status after HDM stress. Furthermore, DNA methylation of ITGB4 in peripheral blood was measured in asthma patients. Logistic regression was employed to evaluate the association between methylation sites and asthma patients' ages in the control of potential confounders. Moreover, the correlations between differentially methylated sites (DMSs) and clinical parameters in asthma patients were assessed. Finally, the ability of candidate DMSs to predict asthma was evaluated by receiver operating characteristic (ROC) analysis and principal component analysis (PCA). RESULTS: We found that in HDM-stressed asthma model, DNA methylation regulated the reduced ITGB4 expression in airway epithelial cells. Moreover, alteration in the specific CpG sites (chr17:73717720 and chr17:73717636) of ITGB4 may regulate ITGB4 expression and further may be associated with the clinically phenotypic of asthma. The specific DMSs of ITGB4 in peripheral blood can distinguish asthma patients from healthy controls (HCs) effectively. CONCLUSIONS AND CLINICAL RELEVANCE: This study confirmed that DNA methylation regulates the decreased expression of ITGB4 in the airway epithelial cells of asthma patients. These results supply some useful insights to the mechanism of the decreased ITGB4 in asthmatic airway epithelial and provide possible targets for early prediction and screening of asthma.

Profile of autoantibody to basement membrane zone proteins in patients with mucous membrane pemphigoid: long-term follow up and influence of therapy.

Mucous membrane pemphigoid (MMP) is an autoimmune mucocutaneous blistering disease characterized by autoantibodies to components within the basement membrane zone. In this study, we report the titers of autoantibodies to antigens in the BMZ, in the sera of 13 patients, treated with intravenous immunoglobulin as monotherapy over a consecutive 18-month period. Using bovine gingiva lysate as substrate in an immunoblot assay, autoantibodies to human bullous pemphigoid antigens (BPAg1 and BPAg2), human beta4 integrin, and laminin 5 were measured. A statistically significant (P < 0.05) decline in the autoantibody titers to beta4-integrin was observed after 3.42 months of initiating the IVIg therapy. These titers were undetectable after 13 months of therapy. The titers of antibodies to BPAg1 and BPAg2 did not correlate with disease activity or response to therapy. Antibodies to laminins were not detected. In patients with MMP, autoantibody titers to beta4-integrin correlate with disease activity and response to therapy.