Basic and Clinical Immunology
T cells and eosinophils cooperate in the induction of bronchial epithelial cell apoptosis in asthma,☆☆

https://doi.org/10.1067/mai.2002.121460Get rights and content

Abstract

Background: Asthma is an inflammatory airway disease associated with an infiltration of T cells and eosinophils, increased levels of pro-inflammatory cytokines, and shedding of bronchial epithelial cells (ECs). Objective: Shedding of bronchial ECs is characterized by loss of the normal bronchial pseudostratified epithelium and the maintenance of a few basal cells on a thickened basement membrane. The aim of this study was to investigate whether, and by which mechanism, T cells and eosinophils can cause damage to airway ECs. Methods: Bronchial ECs, cultured and exposed to cytokines, eosinophil cationic protein, activated T cells, and eosinophils were studied for the expression of apoptosis receptors (flow cytometry, immunoblotting, and RNA expression) and for the susceptibility for undergoing apoptosis. In addition, bronchial biopsy specimens from patients with asthma were evaluated for EC apoptosis. Results: We demonstrate herein that the respiratory epithelium is an essential target of the inflammatory attack by T cells and eosinophils. Bronchial ECs underwent cytokine-induced cell death with DNA fragmentation and morphologic characteristics of apoptosis mediated by activated T cells and eosinophils. T cell- and eosinophil-induced EC apoptosis was blocked by inhibition of IFN-γ and TNF-α; the Fas ligand-Fas pathway appears to be less important. Recombinant eosinophil cationic protein induced mainly necrosis of ECs. Furthermore, we demonstrated in situ apoptotic features of ECs in bronchial biopsy specimens of asthmatic patients. Conclusion: T cell- and eosinophil-induced apoptosis represents a key pathogenic event leading to EC shedding in asthma. (J Allergy Clin Immunol 2002;109:329-37.)

Section snippets

Subjects

Approval for the use of human tissues was granted by the ethics committee of Davos. The fiberoptic bronchial biopsy specimens of 7 asthma patients (mild persistent asthma according to the Global Initiative for Asthma guidelines) were fixed in 4% paraformaldehyde and embedded in paraffin. Control bronchial mucosa was obtained from 3 patients with malignant lung tumors. T cells and eosinophils were purified from 11 atopic and 6 healthy donors.

Reagents

Human recombinant IFN-γ was a gift from Novartis

Apoptosis receptor expression and induction of apoptosis in bronchial ECs

To assess EC surface molecules, we examined ECs by using flow cytometry (Fig 1, A ).

. A , Death receptor expression on ECs. ECs were cultured in the absence (Control) or presence of IFN-γ, TNF-α, or both cytokines. The percentage of stained ECs after 1 day is indicated. B , Immunoprecipitation and immunoblotting with EC lysates were performed with the same mAb. β-Catenin is a control for equivalent gel loading. C , Gene expression array. cDNA probes of EC stimulated with 10 ng/mL IFN-γ and 10

Discussion

The present study demonstrates that ECs are targets of activated T cells and eosinophils that invade the bronchial wall in asthma. Among the growing complexity in the pathogenic mechanisms of asthma, the potential role of T cells and eosinophils is suggested. It is proposed that ECs can be the target of the immunologic injury in certain inflammatory disorders, such as eczematous dermatitis and asthma.8, 9, 18 A morphologic study of the bronchial mucosa from patients with asthma demonstrated

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    Supported by the Swiss National Foundation (32-65661-01 and 31-63381-00) and the Saurer Foundation. A.T. is a recipient of a grant from the Deutsche Forschungsgemeinschaft (TR460/1-1), P.S.-G. is a recipient of a grant for the promotion of academic young people of the University of Zurich.

    ☆☆

    Reprint requests: A. Trautmann, MD, Swiss Institute of Allergy and Asthma Research (SIAF), Obere Strasse 22, CH-7270 Davos, Switzerland.

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