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

• Published in: Journal of allergy and clinical immunology Vol. 139; no. 5; pp. 1548 - 1558.e4
• Main Authors: Liu, Weimin, Liu, Sucai, Verma, Mukesh, Zafar, Iram, Good, James T., Rollins, Donald, Groshong, Stephen, Gorska, Magdalena M., Martin, Richard J., Alam, Rafeul
• Format: Journal Article
• Language: English
• Published: St. Louis Elsevier Inc 01.05.2017; Elsevier Limited
• Subjects: Allergy and Immunology; Alveoli; Asthma; Asthma endotype; Bronchus; C3a; Cell culture; Colonies; Colony-stimulating factor; Cytokines; Flow cytometry; Gene expression; Genotype & phenotype; Granulocyte colony-stimulating factor; Granulocyte-macrophage colony-stimulating factor; Growth factors; Helper cells; Human subjects; IL-1; infection; Inflammation; Interleukin 1; Interleukin 1 receptor antagonist; Interleukin 23; Interleukin 6; Interleukin 8; Kinases; Leukocytes (granulocytic); Leukocytes (neutrophilic); Lymphocytes; Lymphocytes T; MAP kinase; neutrophilic asthma; Peroxidase; Protein kinase; Smooth muscle; Subclinical infection; TH2/TH17-predominant asthma; Uric acid; β-Amyloid; C3a; infection; STAT; IL-1; TH2/TH17-predominant asthma; neutrophilic asthma; Asthma endotype; IL-1R; MAPK; BAL; G-CSF; DAMP; SAA; serum amyloid A; Th2/Th17-predominant asthma; IL1; danger-associated molecular pattern
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2016.08.032

The mechanism of TH2/TH17-predominant and TH2/TH17-low asthma is unknown. We sought to study the immune mechanism of TH2/TH17-predominant and TH2/TH17-low asthma. 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. 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. 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. [Display omitted]