Elsevier

Current Opinion in Immunology

Volume 66, October 2020, Pages 123-128
Current Opinion in Immunology

Mechanisms of non-type 2 asthma

https://doi.org/10.1016/j.coi.2020.10.002Get rights and content

Non-type 2 inflammation (Non-T2)-mediated asthma is difficult to define due to lack of signature biomarkers. It exists in the absence of T2-high or eosinophilic inflammation and includes neutrophilic and paucigranulocytic subtypes. Several cell types and cytokines, including Th1, Th17, IL-6, and IL-17, contribute to mechanisms of non-T2 asthma. Neutrophil extracellular traps (NETs) and inflammasome activation likely play a role in severe neutrophilic asthma. Several mechanisms lead to uncoupling of airway hyperresponsiveness and remodeling from airway inflammation in paucigranulocytic asthma. Recent research on transcriptomics and proteomics in non-T2 asthma is discussed in this review. Investigations of specific drug therapies for non-T2 asthma have been disappointing, and remain an important area for future clinical studies.

Introduction

Asthma is a heterogeneous chronic obstructive airway disease characterized by multiple distinct endotypes. Asthma is commonly categorized by the type of inflammation associated with its pathobiology. The majority of asthma shows evidence of cytokines associated with T-helper 2 cell (T2)-mediated inflammation and is termed T2-high. The pathogenesis of T2-high asthma is chiefly orchestrated by interleukins (IL)-4, IL-5 and IL-13 and is usually accompanied by eosinophil infiltration. T2-high disease is clinically determined by elevated peripheral blood or sputum eosinophil levels using consensus-derived, numerical cutoffs. Conversely, there is currently no agreed upon definition or signature biomarker for T2-low or non-T2 asthma other than absence of T2-high inflammation. In this review, we will discuss several proposed mechanisms underlying non-T2 asthma and potential research directions (Table 1).

Section snippets

Clinical identification of non-T2 asthma

Sputum cytology can be used to categorize airway inflammation as eosinophilic, neutrophilic, mixed granulocytic, or paucigranulocytic. Non-T2 asthma encompasses the neutrophilic and paucigranulocytic categories; whether similar mechanisms drive neutrophilic inflammation in the mixed granulocytic and neutrophilic-only categories is unknown, as is the longitudinal stability of these categories. Although there is no agreed upon numerical criterion, neutrophilic asthma (NA) has been defined as ≥50%

Induction of neutrophilic airway inflammation in asthma

Multiple cytokines are implicated in the development of neutrophilic airway inflammation in asthma. IL-17 levels in bronchial biopsies correlate with airway neutrophil infiltration and are increased in patients with severe and exacerbation-prone asthma relative to those with milder disease [4]. Th17 cells secrete IL-17 cytokines, including IL-17A, which promote neutrophil recruitment in the airways by acting on airway epithelial cells (AEC) to secrete neutrophil chemokines such as CXCL1 and

Pathologic role of NETs in asthma

The major roles of neutrophils include phagocytosis of pathogens, antimicrobial enzyme degranulation, and generation of neutrophil extracellular traps (NETs) from ejected nuclear contents [16]. NET dysregulation may result in asthmatic pathobiology. A recent SARP3 study found that patients with more severe asthma exhibit higher airway neutrophil-derived sputum extracellular DNA levels which correlated with NET formation and inflammasome activation [17]. These processes may result in asthma

Airway dysbiosis in neutrophilic asthma

Airway dysbiosis refers to alterations in normal airway microbiome composition. Multiple investigators have documented dysbiosis in association with NA. In a study including >150 asthmatic participants, the sputum microbiome of those with NA had less bacterial species diversity compared with those with eosinophilic disease [19]. Two groups identified sputum Proteobacteria as overrepresented in NA [20, 21]. Recently, a U-BIOPRED study showed the relative stability of individual subject sputum

Paucigranulocytic asthma

As the name implies, this phenotype involves asthma without an increased granulocytic presence in the airways, described as an ‘uncoupling’ of airway obstruction from airway inflammation [23]. There are several proposed mechanisms for paucigranulocytic asthma, including modulation of neural mediators, sphingolipid synthesis, and regulators of bronchoconstrictive signaling.

Efferent nerves in the airways are controlled by postganglionic, parasympathetic cholinergic neurons and elicit ASM

Obesity and metabolism in non-T2 asthma

Obese asthma is recognized as a distinct phenotype typically seen in women with late-onset symptoms, corticosteroid resistance and non-T2 disease. When accompanied by the metabolic syndrome, asthma severity associates with systemic IL-6-mediated inflammation. A SARP3 study observed that exacerbation-prone asthma (defined as having ≥2 asthma exacerbations per year) is a persistent feature in severe asthmatic patients at 3 years of follow-up that associates with obesity and elevated plasma IL-6

Transcriptomics and proteomics in non-T2 asthma

A deeper mechanistic understanding of asthma phenotypes can be explored through cluster analysis and transcriptomics. Cluster analysis involves mathematically grouping heterogeneous cohorts through specific characteristics. Transcriptomics analyzes RNA transcripts from cells or tissues. Sputum transcriptomics in U-BIOPRED study participants identified three clusters based on differential gene expression [39]. One transcriptome-associated cluster was characterized by elevated sputum neutrophil

Management and potential therapeutic options

There are currently few effective treatment options for non-T2 asthma, and available ones (i.e. trigger avoidance, vaccination against respiratory pathogens, smoking cessation, and weight reduction in obese asthmatics) are not mechanism-based. Corticosteroids are the cornerstone of asthma controller therapy but non-T2 asthma is typically corticosteroid-resistant. Long-acting muscarinic antagonists, beta-2 adrenergic agonists and oral macrolide therapy may improve non-T2 asthma but are not

Conclusion

Despite exciting advances in treatments for T2-high asthma, treatments for non-T2 asthma are limited and specific therapies have largely been disappointing. Future research endeavors should focus on defining practical clinical biomarkers, along with developing more effective therapies.

Sources of funding

This work was conducted with the support of grants K23AI125785 to JCC, and by generous contributions by the James A. Haley Veterans’ Affairs Hospital in Tampa and the Culverhouse family fund to all authors.

Conflicts of interest statement

DKL reports receiving research support (paid to university) from AstraZeneca and Genentech/Roche; is a consultant of AstraZeneca; is a speaker of AstraZeneca, Genentech/Roche, Meda, Novartis, and Teva; and receives fees for legal opinions regarding drug allergy, metal allergy, radiocontrast reaction, and asthma death.

JCC and SH have nothing to disclose.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

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