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Spontaneous atopic dermatitis is mediated by innate immunity, with the secondary lung inflammation of the atopic march requiring adaptive immunity - 05/02/16

Doi : 10.1016/j.jaci.2015.06.045 
Sean P. Saunders, PhD a, b, Tara Moran, BSc a, b, Achilleas Floudas, PhD a, b, Felicity Wurlod, MSc a, b, Agnieszka Kaszlikowska, BSc a, b, Maryam Salimi, PhD c, Emma M. Quinn, PhD d, Christopher J. Oliphant, PhD e, f, Gabriel Núñez, MD g, Ross McManus, PhD d, Emily Hams, PhD a, b, Alan D. Irvine, MD b, h, Andrew N.J. McKenzie, PhD e, Graham S. Ogg, MD c, Padraic G. Fallon, PhD a, b, d,
a Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland 
b National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland 
h Department of Paediatric Dermatology, Our Lady's Children's Hospital, Dublin, Ireland 
c MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom 
d Institute of Molecular Medicine, St James's Hospital, Dublin, Ireland 
e MRC Laboratory of Molecular Biology, Cambridge, United Kingdom 
f Biosceptre, Babraham Research Campus, Babraham, Cambridge, United Kingdom 
g Department of Pathology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, Mich 

Corresponding author: Padraic G. Fallon, PhD, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.

Abstract

Background

Atopic dermatitis (AD) is an inflammatory skin condition that can occur in early life, predisposing to asthma development in a phenomenon known as the atopic march. Although genetic and environmental factors are known to contribute to AD and asthma, the mechanisms underlying the atopic march remain poorly understood. Filaggrin loss-of-function mutations are a major genetic predisposer for the development of AD and progression to AD-associated asthma.

Objective

We sought to experimentally address whether filaggrin mutations in mice lead to the development of spontaneous eczematous inflammation and address the aberrant immunologic milieu arising in a mouse model of filaggrin deficiency.

Methods

Filaggrin mutant mice were generated on the proallergic BALB/c background, creating a novel model for the assessment of spontaneous AD-like inflammation. Independently recruited AD case collections were analyzed to define associations between filaggrin mutations and immunologic phenotypes.

Results

Filaggrin-deficient mice on a BALB/c background had profound spontaneous AD-like inflammation with progression to compromised pulmonary function with age, reflecting the atopic march in patients with AD. Strikingly, skin inflammation occurs independently of adaptive immunity and is associated with cutaneous expansion of IL-5–producing type 2 innate lymphoid cells. Furthermore, subjects with filaggrin mutations have an increased frequency of type 2 innate lymphoid cells in the skin in comparison with control subjects.

Conclusion

This study provides new insights into our understanding of the atopic march, with innate immunity initiating dermatitis and the adaptive immunity required for subsequent development of compromised lung function.

Le texte complet de cet article est disponible en PDF.

Key words : Allergy, asthma, atopic dermatitis, atopy, eczema, filaggrin, flaky tail, type 2 innate lymphoid cells, innate immunity, mouse, mutation

Abbreviations used : AD, AHR, Cdyn, CFP, dLN, eGFP, FLG, Flg, iILC2, ILC2, IL-7Rα, NBNT, NF-κB, nILC2, RL, ROR, TSLP, WT


Plan


 Supported by the Wellcome Trust (Programme grant 092530/Z/10/Z [to P.G.F.] and Investigator Award 100963/Z/13/Z [to A.N.J.M.]), UK-MRC (to A.N.J.M.), Science Foundation Ireland (10/IN.1/B3004 [to P.G.F.]), the National Children's Research Centre (to P.G.F.), Misses Barrie Charitable Trust (to G.S.O.), the NIHR Biomedical Research Centre Programme (to G.S.O.), and the Comprehensive Research Network (to G.S.O.).
 Disclosure of potential conflict of interest: A. D. Irvine has received research support from the National Children's Research Centre and the Wellcome Trust. A. N. J. McKenzie has received research support from the American Asthma Foundation and Janssen Pharmaceuticals and has a patent with Janssen Pharmaceuticals. G. S. Ogg has received research support from the Medical Research Council, the Biomedical Research Centre, BMA, and Janssen; has received consultancy fees from Janssen, Novartis, and Lilly; is employed by Oxford University Hospitals and Oxford University; and has received travel support from Roche. P. G. Fallon has received research support from the Wellcome Trust, NCRC, and Science Foundation Ireland. The rest of the authors declare that they have no relevant conflicts of interest.


© 2015  The Authors. Publié par Elsevier Masson SAS. Tous droits réservés.
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P. 482-491 - février 2016 Retour au numéro
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