Increased expression of immunoreactive thymic stromal lymphopoietin in patients with severe asthma

doi:10.1016/j.jaci.2011.08.031

Journal of Allergy and Clinical Immunology

Volume 129, Issue 1, January 2012, Pages 104-111.e9

https://doi.org/10.1016/j.jaci.2011.08.031 Get rights and content

Background

Thymic stromal lymphopoietin (TSLP) is a cytokine implicated in the pathophysiology of asthma through 2 distinct pathways: a TSLP–OX40 ligand (OX40L)–T cell axis and a TSLP–mast cell axis. Whether these pathways are active in human asthma is unknown.

Objective

We sought to investigate whether mucosal TSLP protein expression relates to asthma severity and distinct immunologic pathways.

Methods

In healthy subjects and patients with mild-to-severe asthma, we immunostained bronchial biopsy specimens for TSLP, OX40, OX40L, T_H2 cytokines, and inflammatory cell markers. We examined gene expression using RNA microarrays and quantitative RT-PCR.

Results

There was considerable heterogeneity in the levels of TSLP, IL-13, and IL-4 immunostaining across the cohort of asthmatic patients examined. Overall, TSLP protein expression was significantly increased in airway epithelium and lamina propria of asthmatic patients, particularly in patients with severe asthma. TSLP immunostaining in both compartments correlated with the severity of airflow obstruction. The majority of leukocytes expressing IL-13 were possibly nuocytes. Accounting for intersubject variability, the 55% of asthmatic patients with increased IL-13 immunostaining in the lamina propria also had increased IL-4 and TSLP expression. This was further substantiated by significant correlations between TSLP gene expression, a T_H2 gene expression signature, and eosinophilic inflammation in bronchial biopsy specimens. Immunostaining for OX40, OX40L, and CD83 was sparse, with no difference between asthmatic patients and healthy subjects.

Conclusion

TSLP expression is increased in a subset of patients with severe asthma in spite of high-dose inhaled or oral corticosteroid therapy. Targeting TSLP might only be efficacious in the subset of asthma characterized by increased TSLP expression and T_H2 inflammation.

Section snippets

Leicester cohort

Asthmatic patients (n = 36) and healthy volunteers (n = 12) were recruited for the study of both gene expression and immunohistochemistry. Full details and the assessments undertaken are described in the Methods section in this article’s Online Repository at www.jacionline.org. Asthma severity was defined by the “British guideline on the management of asthma” treatment steps (see the Methods section in this article’s Online Repository).¹⁶ Of the 16 patients with severe asthma at steps 4 and 5,

Demographic data

The demographic data of the asthmatic patients from the Leicester and Belfast cohorts are shown in Tables E1 and E2.

Inflammatory cell infiltration (Leicester cohort)

Numbers of epithelial and lamina propria mast cells, macrophages, eosinophils, neutrophils, and T cells are shown in Table E3 and discussed further in the Results section in this article’s Online Repository at www.jacionline.org.

TSLP immunoreactivity is increased in both the airway epithelium and lamina propria in patients with severe asthma

Epithelial tissue for analysis was available from 11 healthy subjects and 5 patients with mild, 8 patients with moderate, and 14 patients with severe

Discussion

We have shown that expression of TSLP protein is upregulated in the airways of patients with asthma and that this persists in a cohort of patients with severe asthma despite high-dose corticosteroid treatment at steps 4 and 5 of the British asthma treatment guidelines. TSLP expression in the airway epithelium was increased across the spectrum of disease severity, although to a lesser extent in patients with relatively well-controlled moderate asthma. However, in the airway lamina propria,

References (33)

G.P. Anderson
Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease
Lancet
(2008)
Y.H. Wang et al.
Maintenance and polarization of human TH2 central memory T cells by thymic stromal lymphopoietin-activated dendritic cells
Immunity
(2006)
Y. Rochman et al.
Thymic stromal lymphopoietin: a new cytokine in asthma
Curr Opin Pharmacol
(2008)
S. Siddiqui et al.
Airway wall expression of OX40/OX40L and interleukin-4 in asthma
Chest
(2010)
M.A. Berry et al.
Sputum and bronchial submucosal IL-13 expression in asthma and eosinophilic bronchitis
J Allergy Clin Immunol
(2004)
S.K. Saha et al.
Increased sputum and bronchial biopsy IL-13 expression in severe asthma
J Allergy Clin Immunol
(2008)
A. Semlali et al.
Thymic stromal lymphopoietin-induced human asthmatic airway epithelial cell proliferation through an IL-13-dependent pathway
J Allergy Clin Immunol
(2010)
S. Wenzel
Severe asthma in adults
Am J Respir Crit Care Med
(2005)
P. Haldar et al.
Cluster analysis and clinical asthma phenotypes
Am J Respir Crit Care Med
(2008)
P.G. Woodruff et al.
T-helper type 2-driven inflammation defines major subphenotypes of asthma
Am J Respir Crit Care Med
(2009)

A. Kato et al.

TLR3- and Th2 cytokine-dependent production of thymic stromal lymphopoietin in human airway epithelial cells

J Immunol

(2007)

Z. Allakhverdi et al.

Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells

J Exp Med

(2007)

B. Zhou et al.

Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice

Nat Immunol

(2005)

P.A. Reche et al.

Human thymic stromal lymphopoietin preferentially stimulates myeloid cells

J Immunol

(2001)

T. Ito et al.

TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand

J Exp Med

(2005)

D. Seshasayee et al.

In vivo blockade of OX40 ligand inhibits thymic stromal lymphopoietin driven atopic inflammation

J Clin Invest

(2007)

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: The Institute for Lung Health, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom, and the Centre for Infection and Immunity, Health Sciences Building, Queens University Belfast, were supported by grants from Genentech, Inc, South San Francisco, Calif. Research at the Institute for Lung Health, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom, was conducted in laboratories partially funded by ERDF no. 05567.

: Disclosure of potential conflict of interest: D. F. Choy, A. R. Abbas, C. D. Austin, J. Jackman, L. C. Wu, and J. R. Arron are employees of Genentech, Inc. L. G. Heaney has received travel and accommodation support to attend meetings from AstraZeneca, Chiesi, Novartis, GlaxoSmithKline, and Teva UK; has received research support from GlaxoSmithKline, Genentech, Inc, MedImmune, and Novartis UK; and has served on advisory boards for or received speakers’ honoraria from GlaxoSmithKline, Merck Sharpe & Dohme, Nycomed, Novartis, and AstraZeneca. P. Bradding has received research support from Genentech, Inc. The rest of the authors declare that they have no relevant conflicts of interest.

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Asthma and lower airway diseaseIncreased expression of immunoreactive thymic stromal lymphopoietin in patients with severe asthma

Background

Objective

Methods

Results

Conclusion

Section snippets

Leicester cohort

Demographic data

Inflammatory cell infiltration (Leicester cohort)

TSLP immunoreactivity is increased in both the airway epithelium and lamina propria in patients with severe asthma

Discussion

Lancet

Immunity

Curr Opin Pharmacol

Chest

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Severe asthma in adults

Am J Respir Crit Care Med

Cluster analysis and clinical asthma phenotypes

Am J Respir Crit Care Med

T-helper type 2-driven inflammation defines major subphenotypes of asthma

Am J Respir Crit Care Med

TLR3- and Th2 cytokine-dependent production of thymic stromal lymphopoietin in human airway epithelial cells

J Immunol

Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells

J Exp Med

Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice

Nat Immunol

Human thymic stromal lymphopoietin preferentially stimulates myeloid cells

J Immunol

TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand

J Exp Med

In vivo blockade of OX40 ligand inhibits thymic stromal lymphopoietin driven atopic inflammation

J Clin Invest

Asthma and lower airway disease
Increased expression of immunoreactive thymic stromal lymphopoietin in patients with severe asthma