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

Liu, Weimin; Liu, Sucai; Verma, Mukesh; Zafar, Iram; Good, James T.; Rollins, Donald; Groshong, Stephen; Górska, M.; Martin, Richard J.; Alam, Rafeul

doi:10.1016/j.jaci.2016.08.032

Cited by 119 publications

(81 citation statements)

References 48 publications

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“…We observed little evidence of increased basophils in NA, with a significant negative correlation observed between sputum basophils and neutrophils and only 1/5 NA having more than 0.01% sputum basophils. Our data therefore support previous reports suggesting that there is little or no involvement of TH2‐mediated processes in NA, which is more likely to involve innate cytokine‐driven responses (involving IL‐1α and IL‐8) to epithelial cell‐derived alarmins or subclinical infection …”

Section: Clinical Characteristics Of Participants At Baseline Visit (supporting

confidence: 91%

Sputum basophils are increased in eosinophilic asthma compared with non‐eosinophilic asthma phenotypes

Brooks

Dalen

Hermans

et al. 2017

Allergy

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Sputum basophil numbers are increased in allergic asthmatics, but it is unclear what role airway basophils play in "TH2-low" asthma phenotypes. Using flow cytometry, we found that basophils were significantly increased in all asthmatics (n=26) compared with healthy controls (n=8) (P=0.007) with highest levels observed in eosinophilic asthma (EA); median 0.22%, IQR 0.11%-0.47%; n=14) compared with non-EA (NEA) (0.06%, 0.00%-0.20%; n=12; P<0.05). In asthmatics, basophils were positively correlated with sputum eosinophils (r=0.54; P<0.005) and inversely with sputum neutrophils (r=-0.46: P<0.05), but not with FEV (% predicted), FEV /FVC or bronchodilator reversibility. In a subgroup initially identified as inadequately controlled asthma (n=7), there was a trend (P=0.08) towards a reduction in sputum basophils following increased inhaled corticosteroid (ICS) treatment. Our findings suggest that basophils may be particularly important in eosinophilic asthma and that sputum basophil assessment could be a useful additional indicator of "TH2-high" asthma.

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Section: Clinical Characteristics Of Participants At Baseline Visit (supporting

confidence: 91%

Sputum basophils are increased in eosinophilic asthma compared with non‐eosinophilic asthma phenotypes

Brooks

Dalen

Hermans

et al. 2017

Allergy

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show abstract

“…51 lating barrier function and mucin production. 20,[52][53][54] While we suspect that the IL-1RA affects IL-1β signaling through the IL-1 receptor, we acknowledge that these data do not definitively prove this connection; future studies are needed to understand this mechanism fully. Like allopurinol, there are established safety and dosing profiles for IL-1RAs in children.…”

Section: Discussionmentioning

confidence: 90%

Inhibition of uric acid or IL‐1β ameliorates respiratory syncytial virus immunopathology and development of asthma

Schuler

Malinczak

Best

et al. 2020

Allergy

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Background Respiratory syncytial virus (RSV) affects most infants early in life and is associated with increased asthma risk. The specific mechanism remains unknown. Objective To investigate the role of uric acid (UA) and IL‐1β in RSV immunopathology and asthma predisposition. Methods Tracheal aspirates from human infants with and without RSV were collected and analyzed for pro‐IL‐1β mRNA and protein to establish a correlation in human disease. Neonatal mouse models of RSV were employed, wherein mice infected at 6‐7 days of life were analyzed at 8 days postinfection, 5 weeks postinfection, or after a chronic cockroach allergen asthma model. A xanthine oxidase inhibitor or IL‐1 receptor antagonist was administered during RSV infection. Results Human tracheal aspirates from RSV‐infected infants showed elevated pro‐IL‐1β mRNA and protein. Inhibition of UA or IL‐1β during neonatal murine RSV infection decreased mucus production, reduced cellular infiltrates to the lung (especially ILC2s), and decreased type 2 immune responses. Inhibition of either UA or IL‐1β during RSV infection led to chronic reductions in pulmonary immune cell composition and reduced type 2 immune responses and reduced similar responses after challenge with cockroach antigen. Conclusions Inhibiting UA and IL‐1β during RSV infection ameliorates RSV immunopathology, reduces the consequences of allergen‐induced asthma, and presents new therapeutic targets to reduce early‐life viral‐induced asthma development.

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“…69 However, GM-CSF has also been linked to neutrophilic asthma, which lacks a prominent T H 2 signature, thereby questioning its role in T H 2-driven disease in human subjects. 70 …”

Section: Tslpmentioning

confidence: 99%

Pathogenic CD4 + T cells in patients with asthma

Muehling

Lawrence

Woodfolk

2017

Journal of Allergy and Clinical Immunology

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Asthma encompasses a variety of clinical phenotypes that involve distinct T cell–driven inflammatory processes. Improved understanding of human T-cell biology and the influence of innate cytokines on T-cell responses at the epithelial barrier has led to new asthma paradigms. This review captures recent knowledge on pathogenic CD4+ T cells in asthmatic patients by drawing on observations in mouse models and human disease. In patients with allergic asthma, TH2 cells promote IgE-mediated sensitization, airway hyperreactivity, and eosinophilia. Here we discuss recent discoveries in the myriad molecular pathways that govern the induction of TH2 differentiation and the critical role of GATA-3 in this process. We elaborate on how cross-talk between epithelial cells, dendritic cells, and innate lymphoid cells translates to T-cell outcomes, with an emphasis on the actions of thymic stromal lymphopoietin, IL-25, and IL-33 at the epithelial barrier. New concepts on how T-cell skewing and epitope specificity are shaped by multiple environmental cues integrated by dendritic cell “hubs” are discussed. We also describe advances in understanding the origins of atypical TH2 cells in asthmatic patients, the role of TH1 cells and other non-TH2 types in asthmatic patients, and the features of T-cell pathogenicity at the single-cell level. Progress in technologies that enable highly multiplexed profiling of markers within a single cell promise to overcome barriers to T-cell discovery in human asthmatic patients that could transform our understanding of disease. These developments, along with novel T cell–based therapies, position us to expand the assortment of molecular targets that could facilitate personalized treatments.

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

Cited by 119 publications

References 48 publications

Sputum basophils are increased in eosinophilic asthma compared with non‐eosinophilic asthma phenotypes

Sputum basophils are increased in eosinophilic asthma compared with non‐eosinophilic asthma phenotypes

Inhibition of uric acid or IL‐1β ameliorates respiratory syncytial virus immunopathology and development of asthma

Pathogenic CD4 + T cells in patients with asthma

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