Thymic stromal lymphopoietin activation of basophils in patients with allergic asthma is IL-3 dependent

doi:10.1016/j.jaci.2015.03.039

Journal of Allergy and Clinical Immunology

Volume 136, Issue 6, December 2015, Pages 1636-1644

https://doi.org/10.1016/j.jaci.2015.03.039 Get rights and content

Background

Thymic stromal lymphopoietin (TSLP) released after antigenic stimulation of allergic asthmatic airways is a key initiator of type 2 inflammation. Basophils are important effectors of allergic inflammation in the airways. Murine basophils have been shown to respond to TSLP independently of IL-3 by increasing functional thymic stromal lymphopoietin receptor (TSLPR) expression.

Objective

The purpose of this study was to investigate the effect of TSLP stimulation on human basophil function.

Methods

Ten patients with mild allergic asthma underwent diluent and allergen inhalation challenges. Peripheral blood and sputum samples were collected at baseline and 7 and 24 hours after challenge, and bone marrow samples were collected at baseline and 24 hours after challenge to measure basophil TSLPR expression. In vitro experiments were conducted on purified human basophils to measure the effect of TSLP on degranulation, expression of activation markers and T_H2 cytokines, and eotaxin-induced shape change.

Results

Allergen inhalation increased basophil numbers in the airways and significantly upregulated the expression of activation markers, T_H2 intracellular cytokines, and receptors for TSLP, IL-3, and eotaxin in blood, bone marrow, and sputum basophils. In vitro stimulation with TSLP primed basophil migration to eotaxin and induced rapid and sustained basophil activation mediated directly through TSLPR and indirectly through an IL-3–mediated basophil autocrine loop. Basophils responded to TSLP at a similar magnitude and potency as the well-described basophil-activating stimuli IL-3 and anti-IgE.

Conclusion

Our findings indicate that basophil activation during early- and late-phase responses to inhaled allergen might be driven at least in part by TSLP.

Section snippets

Subjects

Ten patients with mild allergic asthma were enrolled in a diluent-controlled allergen bronchoprovocation study (see Table E1 in this article's Online Repository at www.jacionline.org). Subjects were required to have a positive skin test response to common aeroallergens, a methacholine PC₂₀ value of 16 mg/mL or less, FEV₁ of 70% of predicted value or greater, and a dual-phase response to allergen (≥20% decrease in FEV₁ within 2 hours after allergen and ≥15% decrease in FEV₁ between 3 and 7 hours

Allergen inhalation induces airway bronchoconstriction, hyperresponsiveness, and inflammation in patients with mild allergic asthma

Inhalation of allergen induced a 20.1% ± 5.5% decrease in FEV₁ during the EAR (10-120 minutes) and a 20.8% ± 5.2% decrease in FEV₁ during the LAR (3-7 hours) compared with no change after diluent inhalation (Fig 1, A). The methacholine PC₂₀ value decreased by 1 doubling dose after allergen challenge compared with no change after diluent (Fig 1, B).

Compared with diluent, allergen inhalation significantly increased total cell, eosinophil, neutrophil (Fig 1, C), and basophil (metachromatic cell;

Discussion

TSLP has been proposed to be a master switch for allergic inflammation by activating an array of inflammatory cells that drive type 2 inflammatory responses.1, 2 Gauvreau et al⁶ have recently shown that TSLP blockade significantly attenuated airway functional and inflammatory responses to inhaled allergen in allergic asthmatic patients. In the current study we have extended these findings to show that basophils directly respond to TSLP by producing mediators that can contribute to the

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: Disclosure of potential conflict of interest: G. M. Gauvreau has received research support from Genentech, Sanofi, and CSL Pharma. The rest of the authors declare that they have no relevant conflicts of interest.

View full text

Mechanisms of allergy and clinical immunologyThymic stromal lymphopoietin activation of basophils in patients with allergic asthma is IL-3 dependent

Background

Objective

Methods

Results

Conclusion

Section snippets

Subjects

Allergen inhalation induces airway bronchoconstriction, hyperresponsiveness, and inflammation in patients with mild allergic asthma

Discussion

Cytokine

J Allergy Clin Immunol

Thymical stromal lymphopoietin and the pathophysiology of atopic disease

Expert Rev Clin Immunol

Thymic stromal lymphopoietin: a central regulator of allergic asthma

Expert Opin Ther Targets

Expression and cellular provenance of thymic stromal lymphopoietin and chemokines in patients with severe asthma and chronic obstructive pulmonary disease

J Immunol

Thymic stromal lymphopoietin is increased in asthmatic airways and correlates with expression of Th2 attracting chemokines and disease severity

J Immunol

Constitutive and inducible thymic stromal lymphopoietin expression in human airway smooth muscle cells: role in chronic obstructive pulmonary disease

Am J Physiol Lung Cell Mol Physiol

Effects of an anti-TSLP antibody on allergen-induced asthmatic responses

N Engl J Med

TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation

Nature

The effects of thymic stromal lymphopoietin and IL-3 on human eosinophil–basophil lineage commitment: relevance to atopic sensitization

Immun Inflamm Dis

Mast cell-activated bone marrow mesenchymal stromal cells regulate proliferation and lineage commitment of CD34+ progenitor cells

Front Immunol

A mechanism for the initiation of allergen-induced T helper-type 2 responses

Nat Immunol

Thymic stromal lymphopoietin-dependent basophils promote Th2 cytokine responses following intestinal helminth infection

J Immunol

Mechanisms of allergy and clinical immunology
Thymic stromal lymphopoietin activation of basophils in patients with allergic asthma is IL-3 dependent