Filaggrin-null mutations are associated with increased maturation markers on Langerhans cells - 04/08/16
Abstract |
Background |
Mutations in the gene encoding filaggrin (FLG), an epidermal structural protein, are the strongest risk factor identified for the development of atopic dermatitis (AD). Up to 50% of patients with moderate-to-severe AD in European populations have FLG-null alleles compared with a general population frequency of 7% to 10%.
Objective |
This study aimed to investigate the relationship between FLG-null mutations and epidermal antigen-presenting cell (APC) maturation in subjects with and without AD. Additionally, we investigated whether the cis isomer of urocanic acid (UCA), a filaggrin breakdown product, exerts immunomodulatory effects on dendritic cells.
Methods |
Epidermal APCs from nonlesional skin were assessed by using flow cytometry (n = 27) and confocal microscopy (n = 16). Monocyte-derived dendritic cells from healthy volunteers were used to assess the effects of cis- and trans-UCA on dendritic cell phenotype by using flow cytometry (n = 11).
Results |
Epidermal APCs from FLG-null subjects had increased CD11c expression. Confocal microscopy confirmed this and additionally revealed an increased number of epidermal CD83+ Langerhans cells in FLG-null subjects. In vitro differentiation in the presence of cis-UCA significantly reduced costimulatory molecule expression on monocyte-derived dendritic cells from healthy volunteers and increased their ability to induce a regulatory T-cell phenotype in mixed lymphocyte reactions.
Conclusions |
We show that subjects with FLG-null mutations have more mature Langerhans cells in nonlesional skin irrespective of whether they have AD. We also demonstrate that cis-UCA reduces maturation of dendritic cells and increases their capacity to induce regulatory T cells, suggesting a novel link between filaggrin deficiency and immune dysregulation.
Le texte complet de cet article est disponible en PDF.Key words : Filaggrin, atopic dermatitis, Langerhans cells, urocanic acid, costimulatory molecules
Abbreviations used : AD, APC, FACS, FITC, FLG, FoxP3, IV, LC, LTA, MDCC, MFI, PD-L1, PE, PerCP, SASSAD, TEWL, UCA, WT
Plan
| Supported by grants from the Foundation for Skin Research (to R.B.W.), the British Skin Foundation (to C.S.L.), the University Of Edinburgh (to C.S.L.), the Edinburgh Dermatology Research Fund (to C.S.L.), the Medical Research Council (G0700507 to R.C.), the Commonwealth Scholarship Commission (to N.M.), and the Wellcome Trust (Programme grant 092530/Z/10/Z and Bioresources grant 090066/B/09/Z to W.H.I.M.). The Centre for Dermatology and Genetic Medicine, University of Dundee, is supported by a Wellcome Trust Strategic Award (098439/Z/12/Z to W.H.I.M.). |
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| Disclosure of potential conflict of interest: C. S. Leitch receives research funding from the British Skin Foundation, Edinburgh Dermatology Research Fund, and University of Edinburgh and received travel support from the Scottish Dermatological Society. C. Yu receives grant support from the Chinese Scholarship Council. N. Madarasingha received grant support from the Commonwealth Scholarship Commission. W. H. I. McLean receives research support from the Wellcome Trust. J. Schwarze receives research funding from the British Skin Foundation. S. E. M. Howie receives research funding from the British Skin Foundation. R. B. Weller receives research support from the British Skin Foundation and the Foundation for Skin Research. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 138 - N° 2
P. 482 - août 2016 Retour au numéro
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