Clinical and Biological Features of a Thickened Basement Membrane Zone in Asthma

Rationale: A subset of patients with asthma have airway pathology characterized by a thickened subepithelial basement membrane zone ("BMZ-thick asthma"). Objectives: To characterize the clinical features of BMZ-thick asthma and to determine if BMZ thickness accompanies specific patterns of inflammation in the airway epithelium. Methods: Design-based stereology was used to quantify BMZ thickness in endobronchial biopsy tissue sections from 109 patients with asthma and 41 healthy control subjects from SARP (Severe Asthma Research Program)-3, whose participants had undergone spirometry and gene expression profiling in airway epithelial brushings. Measurements and Main Results: The upper 90th-percentile value for BMZ thickness in the healthy cohort was 2.9 μM, and 35% of the asthma cohort had values above this upper limit. Compared with patients with BMZ-thin asthma, patients with BMZ-thick asthma were younger and had higher blood eosinophil numbers and serum immunoglobulin E concentrations that were specific to animal proteins. Mean prebronchodilator FEV₁ was significantly lower in patients with BMZ-thick asthma than in those with BMZ-thin asthma, but postbronchodilator FEV₁ was not. Upregulation of genes signifying IL-13 activation and the presence of mast cells were evident in epithelial brushings in patients with BMZ-thick asthma, but gene signatures for activation by IFN-γ or IL-17 were not. Conclusions: A thickened BMZ marks a subset of younger patients with asthma characterized by higher immunoglobulin E concentrations to animal aeroallergens and by increased bronchomotor tone occurring in the context of airway epithelial cells activated by IL-13 and infiltrated by mast cells.