Dataset Information

Mechanism of T_H2/T_H17-predominant and neutrophilic T_H2/T_H17-low subtypes of asthma.

ABSTRACT:

Background

The mechanism of T_H2/T_H17-predominant and T_H2/T_H17-low asthma is unknown.

Objective

We sought to study the immune mechanism of T_H2/T_H17-predominant and T_H2/T_H17-low asthma.

Methods

In a previously reported cohort of 60 asthmatic patients, 16 patients were immunophenotyped with T_H2/T_H17-predominant asthma and 22 patients with T_H2/T_H17-low asthma. We examined bronchoalveolar lavage (BAL) fluid leukocytes, cytokines, mediators, and epithelial cell function for these asthma subgroups.

Results

Patients with T_H2/T_H17-predominant asthma had increased IL-1β, IL-6, IL-23, C3a, and serum amyloid A levels in BAL fluid, and these correlated with IL-1β and C3a levels. T_H2/T_H17 cells expressed higher levels of the IL-1 receptor and phospho-p38 mitogen-activated protein kinase. Anakinra, an IL-1 receptor antagonist protein, inhibited BAL T_H2/T_H17 cell counts. T_H2/T_H17-low asthma had 2 distinct subgroups: neutrophilic asthma (45%) and pauci-inflammatory asthma (55%). This contrasted with patients with T_H2/T_H17-predominant and T_H2-predominant asthma, which included neutrophilic asthma in 6% and 0% of patients, respectively. BAL fluid neutrophils strongly correlated with BAL fluid myeloperoxidase, IL-8, IL-1α, IL-6, granulocyte colony-stimulating factor, and GM-CSF levels. Sixty percent of the patients with neutrophilic asthma had a pathogenic microorganism in BAL culture, which suggested a subclinical infection.

Conclusion

We uncovered a critical role for the IL-1β pathway in patients with T_H2/T_H17-predminant asthma. A subgroup of patients with T_H2/T_H17-low asthma had neutrophilic asthma and increased BAL fluid IL-1α, IL-6, IL-8, granulocyte colony-stimulating factor, and GM-CSF levels. IL-1α was directly involved in IL-8 production and likely contributed to neutrophilic asthma. Sixty percent of neutrophilic patients had a subclinical infection.

SUBMITTER: Liu W

PROVIDER: S-EPMC5376378 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mechanism of TH2/TH17-predominant and neutrophilic TH2/TH17-low subtypes of asthma.

Liu Weimin W Liu Sucai S Verma Mukesh M Zafar Iram I Good James T JT Rollins Donald D Groshong Stephen S Gorska Magdalena M MM Martin Richard J RJ Alam Rafeul R

The Journal of allergy and clinical immunology 20161001 5

<h4>Background</h4>The mechanism of TH2/TH17-predominant and TH2/TH17-low asthma is unknown.<h4>Objective</h4>We sought to study the immune mechanism of TH2/TH17-predominant and TH2/TH17-low asthma.<h4>Methods</h4>In a previously reported cohort of 60 asthmatic patients, 16 patients were immunophenotyped with TH2/TH17-predominant asthma and 22 patients with TH2/TH17 ...[more]

PMID: 27702673

Similar Datasets

Project description:Th17 (T-helper 17) cells subtype of non-T2 (non-type 2) asthma is related to neutrophilic infiltration and resistance to inhaled corticosteroids (ICS), so is also known as severe asthma. Methyl-CpG binding domain protein 2 (MBD2) regulates the differentiation of the Th17 cells, tending to show a therapeutic target in severe asthma. miR-146a-3p is associated with anti-inflammatory characteristics and immunity. Moreover, bioinformatic analysis showed that MBD2 may be a target gene of miR-146a-3p. However, the role of miR-146a-3p in the differentiation of Th17 cells via MBD2 in severe asthma remains unknown. Here, we aimed to explore how miR-146a-3p interacts with MBD2 and affects the differentiation of Th17 cells in severe asthma. First, we recruited 30 eligible healthy people and 30 patients with severe asthma to detect the expression of miR-146a-3p in peripheral blood mononuclear cells (PBMCs) by qRT-PCR. Then, we established a HDM/LPS (house dust mite/lipopolysaccharide) exposure model of bronchial epithelial cells (BECs) to evaluate the expression of miR-146a-3p, the interaction between miR-146a-3p and MBD2 using western blot and luciferase reporter analysis and the effect of miR-146a-3p regulated Th17 cells differentiation by flow cytometry in BECs in vitro. Finally, we constructed a mouse model of Th17 predominant neutrophilic severe asthma to assess the therapeutic potential of miR-146a-3p in severe asthma and the effect of miR-146a-3p regulated Th17 cells differentiation via MBD2 in vivo. Decreased miR-146a-3p expression was noted in severe asthma patients, in the BECs and in the animal severe asthma models. Moreover, we demonstrated that miR-146a-3p suppressed Th17 cells differentiation by targeting the MBD2. miR-146a-3p overexpression significantly reduced airway hyperresponsiveness, airway inflammation and airway mucus secretion, while also inhibiting Th17 cells response in vivo, which relieved severe asthma. By targeting MBD2 to suppress Th17 cells differentiation, miR-146a-3p provides a potential novel therapeutic for Th17 predominant neutrophilic severe asthma.

Project description:Asthma is a heterogeneous chronic disorder of the airways, with inflammation and bronchial hyperresponsiveness as its major underlying phenomena. Asthmatics vary in terms of inflammation pattern, concomitant pathologies, and factors aggravating the course of the disease. As a result, there is a need for sensitive and specific biomarkers that could facilitate diagnosing asthma as well as phenotyping in everyday practice. Chitinases and chitinase-like proteins (CLPs) seem promising in this field. Chitinases are evolutionarily conserved hydrolases that degrade chitin. In contrast, CLPs bind chitin but do not have degrading activity. Mammalian chitinases and CLPs are produced by neutrophils, monocytes, and macrophages in response to parasitic or fungal infections. Recently, several questions have been raised about their role in chronic airway inflammation. Several studies demonstrated that overexpression of CLP YKL-40 was associated with asthma. Moreover, it correlated with exacerbation rate, therapy resistance, poor control of symptoms, and, inversely, with FEV1. YKL-40 facilitated allergen sensitization and IgE production. Its concentration was elevated in bronchoalveolar lavage fluid after an allergen challenge. It was also found to promote the proliferation of bronchial smooth muscle cells and correlate with subepithelial membrane thickness. Thus, it may be involved in bronchial remodeling. Associations between YKL-40 and particular asthma phenotypes remain unclear. Some studies showed that YKL-40 correlates with blood eosinophilia and FeNO, suggesting a role in T2-high inflammation. Quite the opposite, cluster analyses revealed the highest upregulation in severe neutrophilic asthma and obesity-associated asthma. The main limitation in the practical application of YKL-40 as a biomarker is its low specificity. High serum levels of YKL-40 were also found in COPD and several malignancies, in addition to infectious and autoimmune diseases. To conclude, the level of YKL-40 correlates with asthma and some clinical features in the whole asthmatic population. The highest levels are found in neutrophilic and obesity-related phenotypes. However, due to its low specificity, the practical application of YKL-40 remains uncertain but could be useful in phenotyping, especially when combined with other biomarkers.