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

Abstract

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