Filaggrin-null mutations are associated with increased maturation markers on Langerhans cells

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• 作者：Claire S. Leitch ; MBChB (Hons) ; MMed Sci^a ; ^b ; Eenass Natafji ; MBChB ; MMed Sci^b ; Cunjing Yu ; MSc^b ; Sharizan Abdul-Ghaffar ; BM^a ; Nayani Madarasingha ; MBBS ; MD ; MMedSci^a ; ^b ; Zoë ; C. Venables ; MBChB ; MMed Sci^b ; Roland Chu ; BSc (Hons) ; MBChB ; PhD^a ; ^c ; Paul M. Fitch ; BSc (Hons) ; PhD^b ; Andrew J. Muinonen-Martin ; MBChB ; PhD^d ; Linda E. Campbell ; BSc^e ; W.H. Irwin McLean ; DSc ; FRS^e ; Jü ; rgen Schwarze ; MD^b ; Sarah E.M. Howie ; PhD^b ; Richard B. Weller ; MD ; FRCP (Ed)^a ; ^b ; ^{r.weller@ed.ac.uk" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Filaggrin ; atopic dermatitis ; Langerhans cells ; urocanic acid ; costimulatory molecules
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：138
• 期：2
• 页码：482-490.e7
• 全文大小：2002 K

文摘

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.