Mechanism of Th2/Th17-predominant and Neutrophilic, Th2/Th17-low Subtypes of Asthma

Publication date: Available online 1 October 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Weimin Liu, Sucai Liu, Mukesh Verma, Iram Zafar, James T. Good, Donald Rollins, Stephen Groshong, Magdalena M. Gorska, Richard J. Martin, Rafeul Alam
BackgroundThe mechanism of Th2/Th17-predominant and Th2/Th17-low asthma is unknown.ObjectiveTo study the immune mechanism of Th2/Th17-predominant and Th2/Th17-low asthma.MethodsIn 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 BAL leukocytes, cytokines, mediators, and epithelial cell function for these asthma subgroups.ResultsTh2/Th17-predominant asthma had elevated IL1β, IL6, IL23, C3a and serum amyloid A (SAA) in BAL, and correlated with IL1β and C3a. Th2/Th17 cells expressed higher levels of the IL1 receptor and p-p38 MAPK. Anakinra, an IL1 receptor antagonist protein, inhibited BAL Th2/Th17 cells. Th2/Th17-low asthma had two distinct subgroups—neutrophilic asthma (45%) and pauci-inflammatory asthma (55%). This contrasted with Th2/Th17-predominant and Th2-predominant asthma, which had neutrophilic asthma in 6% and 0% of patients, respectively. BAL neutrophils strongly correlated with BAL myeloperoxidase, IL8, IL1α, IL6, G-CSF, and GM-CSF.. Sixty percent of the patients with neutrophilic asthma had a pathogenic microorganism in BAL culture, which suggested a subclinical infection.ConclusionWe uncovered a critical role for the IL1β pathway in Th2/Th17-predminant asthma. A subgroup of Th2/Th17-low patients had neutrophilic asthma and elevated BAL IL1α, IL6, IL8, G-CSF, and GM-CSF. IL1α was directly involved in IL8 production and likely contributed to neutrophilic asthma. Sixty percent of neutrophilic patients had a subclinical infection.

Teaser

This paper defines the molecular mechanisms of two subtypes of asthma—Th2/Th17-predominant asthma and Th2/Th17-low, neutrophilic asthma. The paper also delineates phenotype-specific therapeutic agents that are likely benefit these two subtypes of asthma.


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