Mechanisms of allergy and clinical immunology
Allergen-enhanced thrombomodulin (blood dendritic cell antigen 3, CD141) expression on dendritic cells is associated with a TH2-skewed immune response

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Background

Dendritic cells (DCs) are important in allergic diseases such as asthma, although little is known regarding the mechanisms by which DCs induce TH2-polarized responses in atopic individuals. It has been suggested that intrinsic properties of allergens can directly stimulate TH2 polarizing functions of DCs, but little is known of the underlying mechanisms.

Objective

To identify novel genes expressed by house dust mite (HDM) allergen–exposed DCs.

Methods

We screened for allergen-induced gene expression by microarray, and validated differentially expressed genes at the mRNA and protein levels.

Results

Thrombomodulin (CD141, blood dendritic cell antigen 3) expression by microarray was higher on HDM-stimulated DCs from atopic (relative to nonatopic) individuals. These findings were confirmed at both the mRNA and protein levels in an independent group. Purified thrombomodulin+ DCs induced a strongly TH2-polarized cytokine response by allergen-specific T cells compared with DCs lacking thrombomodulin. In vivo, thrombomodulin+ circulating DCs were significantly more frequent in subjects with HDM allergy and asthma, compared with control subjects. Furthermore, thrombomodulin expression in blood leukocytes was higher in children with acute asthma than at convalescence 6 weeks later.

Conclusion

Thrombomodulin expression on DCs may be involved in the pathogenesis of atopy and asthma.

Section snippets

Adult volunteers

Adult volunteers (age range, 21-65 years) were recruited into the study and underwent blood sampling and skin prick testing to common allergens including HDM (D pteronyssinus), perennial ryegrass, southern grass mix, mold mix, feather (chicken, duck, and goose), cat pelt, dog hair dander, peanut, egg, and milk (Hollister-Stier Laboratories). All subjects also completed a questionnaire detailing symptoms of asthma, allergic rhinitis, and eczema. Adult subjects were classified as atopic if they

Differential expression gene expression by allergen-exposed DCs

Initially we used a microarray approach to screen for genes that were differentially expressed by DCs from atopic versus nonatopic adults. Monocyte-derived DCs were stimulated with HDM, and pooled RNA from HDM-atopic individuals was compared with pooled RNA from nonatopic individuals (randomly selected from the adult volunteer population). A pooling strategy was adopted to reduce variance caused by intersubject variation in gene expression.26 Using a threshold of 2-fold difference in gene

Discussion

Although it is well recognized that DCs are important in human allergic diseases such as asthma, little is known regarding the phenotypic features that distinguish DCs from atopic versus nonatopic individuals, nor the mechanisms by which DCs induce or reinforce TH2 polarization in response to common aeroallergens. Moreover, DCs are exquisitely sensitive to environmental stimuli including aeroallergens themselves, some of which can modulate DC phenotype and function.12, 13, 21 Little is known

References (47)

  • J.M. Herbert et al.

    IL-4 and IL-13 exhibit comparable abilities to reduce pyrogen-induced expression of procoagulant activity in endothelial cells and monocytes

    FEBS Lett

    (1993)
  • I.K. Mullarky et al.

    In situ assays demonstrate that interferon-gamma suppresses infection-stimulated hepatic fibrin deposition by promoting fibrinolysis

    J Thromb Haemost

    (2006)
  • J.E. Gereda et al.

    Relation between house-dust endotoxin exposure, type 1 T-cell development, and allergen sensitisation in infants at high risk of asthma

    Lancet

    (2000)
  • S.L. Constant et al.

    Resident lung antigen-presenting cells have the capacity to promote Th2 T cell differentiation in situ

    J Clin Invest

    (2002)
  • B.N. Lambrecht et al.

    Dendritic cells are required for the development of chronic eosinophilic airway inflammation in response to inhaled antigen in sensitized mice

    J Immunol

    (1998)
  • D.H. Strickland et al.

    Reversal of airway hyperresponsiveness by induction of airway mucosal CD4+CD25+ regulatory T cells

    J Exp Med

    (2006)
  • L.S. van Rijt et al.

    In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma

    J Exp Med

    (2005)
  • G.M. Moller et al.

    Increased numbers of dendritic cells in the bronchial mucosa of atopic asthmatic patients: downregulation by inhaled corticosteroids

    Clin Exp Allergy

    (1996)
  • J.W. Upham et al.

    Rapid response of circulating myeloid dendritic cells to inhaled allergen in asthmatic subjects

    Clin Exp Allergy

    (2002)
  • F.L. Jahnsen et al.

    Rapid dendritic cell recruitment to the bronchial mucosa of patients with atopic asthma in response to local allergen challenge

    Thorax

    (2001)
  • A.S. Charbonnier et al.

    Der p 1-pulsed myeloid and plasmacytoid dendritic cells from house dust mite-sensitized allergic patients dysregulate the T cell response

    J Leukoc Biol

    (2003)
  • X.Q. Chen et al.

    Increased expression of CD86 and reduced production of IL-12 and IL-10 by monocyte-derived dendritic cells from allergic asthmatics and their effects on Th1- and Th2-type cytokine balance

    Respiration

    (2006)
  • H. Hammad et al.

    Monocyte-derived dendritic cells exposed to Der p 1 allergen enhance the recruitment of Th2 cells: major involvement of the chemokines TARC/CCL17 and MDC/CCL22

    Eur Cytokine Netw

    (2003)

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    Supported by the National Health and Medical Research Council, Australia.

    Disclosure of potential conflict of interest: J. W. Upham has received an honorarium from AstraZeneca and has received research support from the National Health and Medical Research Council of Australia. The rest of the authors have declared that they have no conflict of interest.

    ∗

    These authors contributed equally to this work.

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    Copyright © 2009 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.