Weimin Liu1, Sucai Liu1, Mukesh Verma1, Iram Zafar1, James T Good2, Donald Rollins2, Stephen Groshong2, Magdalena M Gorska2, Richard J Martin2, Rafeul Alam3. 1. Department of Medicine, Division of Allergy & Immunology, and Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colo. 2. Department of Medicine, Division of Allergy & Immunology, and Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colo; School of Medicine, University of Colorado Denver, Denver, Colo. 3. Department of Medicine, Division of Allergy & Immunology, and Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colo; School of Medicine, University of Colorado Denver, Denver, Colo. Electronic address: alamr@njhealth.org.
Abstract
BACKGROUND: The mechanism of TH2/TH17-predominant and TH2/TH17-low asthma is unknown. OBJECTIVE: We sought to study the immune mechanism of TH2/TH17-predominant and TH2/TH17-low asthma. METHODS: In a previously reported cohort of 60 asthmatic patients, 16 patients were immunophenotyped with TH2/TH17-predominant asthma and 22 patients with TH2/TH17-low asthma. We examined bronchoalveolar lavage (BAL) fluid leukocytes, cytokines, mediators, and epithelial cell function for these asthma subgroups. RESULTS: Patients with TH2/TH17-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. TH2/TH17 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 TH2/TH17 cell counts. TH2/TH17-low asthma had 2 distinct subgroups: neutrophilic asthma (45%) and pauci-inflammatory asthma (55%). This contrasted with patients with TH2/TH17-predominant and TH2-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 TH2/TH17-predminant asthma. A subgroup of patients with TH2/TH17-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.
BACKGROUND: The mechanism of TH2/TH17-predominant and TH2/TH17-low asthma is unknown. OBJECTIVE: We sought to study the immune mechanism of TH2/TH17-predominant and TH2/TH17-low asthma. METHODS: In a previously reported cohort of 60 asthmatic patients, 16 patients were immunophenotyped with TH2/TH17-predominant asthma and 22 patients with TH2/TH17-low asthma. We examined bronchoalveolar lavage (BAL) fluid leukocytes, cytokines, mediators, and epithelial cell function for these asthma subgroups. RESULTS:Patients with TH2/TH17-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. TH2/TH17 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 TH2/TH17 cell counts. TH2/TH17-low asthma had 2 distinct subgroups: neutrophilic asthma (45%) and pauci-inflammatory asthma (55%). This contrasted with patients with TH2/TH17-predominant and TH2-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 TH2/TH17-predminant asthma. A subgroup of patients with TH2/TH17-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.
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