Alveolar T-helper type-2 immunity in atopic asthma is associated with poor clinical control

Abstract

Real-world evaluation studies have shown that many patients with asthma remain symptomatic despite treatment with inhaled corticosteroids (ICSs). As conventional ICSs have poor access to the peripheral airways, the aim of the present paper was to study the relationship between peripheral airway inflammation and clinical control in allergic asthma. Consequently, bronchial and transbronchial biopsies were obtained from patients with poorly controlled asthma [n=12, asthma control test (ACT) score<20], patients with well-controlled asthma (n=12, ACT score≥20) and healthy controls (n=8). Tissue sections were immunostained to assess multiple leucocyte populations. To determine the degree of T-helper type-2 (Th2) immunity, the logarithmic value of the ratio between Th2 cells/mm2 and Th1 cells/mm2 was used as a surrogate score for Th2-skewed immunity. In the bronchi, the leucocyte infiltration pattern and the Th2-score were similar between patients with well-controlled asthma and those with poorly controlled asthma. In contrast, in the alveolar parenchyma, the expression of T-helper cells was significantly higher in patients with poorly controlled asthma than in patients with well-controlled asthma (P<0.01). Furthermore, the alveolar Th2-score was significantly higher in patients with poorly controlled asthma (median 0.4) than in the controlled patients (median -0.10, P<0.05). In addition, in contrast with bronchial Th2-score, the alveolar Th2-score correlated significantly with ACT score (rs=-0.62, P<0.01) in the pooled asthma group. Collectively, our data reveal an alveolar Th2-skewed inflammation, specifically in asthmatic patients who are poorly controlled with ICSs, and suggest that pharmacological targeting of the peripheral airways may be beneficial in this large patient category.

Inducible nitric oxide synthase expression is increased in the alveolar compartment of asthmatic patients

“…Uncontrolled asthmatics, but also controlled asthmatics, showed higher levels of iNOS compared to healthy controls, which suggest an increased peripheral airway inflammation. This is in line with the alveolar Th2‐skewed inflammation in uncontrolled asthmatics that we have previously shown in these patients .…”

Uncontrolled asthmatics have increased FceRI+ and TGF‐β–positive MCTC mast cells and collagen VI in the alveolar parenchyma

“…The pathological differences between well‐controlled and uncontrolled asthmatic patients are not fully understood, particularly regarding tissue changes and inflammatory patterns in the alveolar parenchyma. An increasing body of evidence suggests that inflammatory processes in the distal airways contribute to asthma pathogenesis . For example, several studies have shown infiltration of leucocytes and fibroblasts in the alveolar parenchymal tissue .…”

“…An increasing body of evidence suggests that inflammatory processes in the distal airways contribute to asthma pathogenesis . For example, several studies have shown infiltration of leucocytes and fibroblasts in the alveolar parenchymal tissue . Inflammatory cells implicated in asthma, such as eosinophils, Th2 lymphocytes and mast cells, have also been shown to increase in distal airways compared to healthy controls …”

“…3,[5][6][7] For example, several studies have shown infiltration of leucocytes and fibroblasts in the alveolar parenchymal tissue. 6,[8][9][10] Inflammatory cells implicated in asthma, such as eosinophils, Th2 lymphocytes and mast cells, have also been shown to increase in distal airways compared to healthy controls. 11 In human lungs, mast cells (MCs) are abundant throughout the airways and gradually increase towards and within the alveolar parenchyma.…”

Interaction between allergic asthma and atherosclerosis

“…Furthermore, the alveolar Th2-score (calculated as the logarithmic value of the ratio between Th2 cells/mm 2 and Th1 cells/mm 2 ) was significantly higher in patients with poorly controlled asthma than in the well-controlled patients and correlated significantly with ACT score, revealing an alveolar Th2-skewed inflammation specifically in asthmatic patients poorly controlled with inhaled corticorsteroids. 71 By mapping genome-wide histone modification profiles for subsets of T cells isolated from peripheral blood of healthy and asthmatic individuals, evidence revealed that enhancers in T cells that gained the histone H3 Lys4 dimethyl (H3K4me2) mark during Th2 cell development showed the highest enrichment for asthma-associated single nucleotide polymorphisms (SNPs), supporting a predominant role for Th2 cells in the pathogenesis of asthma. 72 In a randomized, double-blind, placebo-controlled, multicenter clinical trial of SB010, a novel DNA enzyme that can cleave and inactivate GATA3 (an important transcription factor of the Th2 pathway) messenger RNA, patients with allergic asthma showed significantly attenuated both late and early asthmatic responses and an attenuation of Th2-regulated inflammatory responses in a biomarker analysis of SB010 treatment.…”