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

Claire Leitch, Eenass Natafji, Sharizan Abdul-Ghaffar, Nayani Madarasinga, Zoe Venables, Roland Chu, Paul Fitch, Andrew Muinonen-Martin, Linda Campbell, W H Irwin McLean, Jürgen Schwarze, Sarah Howie, Richard B. Weller

Research output: Contribution to journalArticlepeer-review

Abstract

Background
Mutations in the filaggrin gene, an epidermal structural protein, are the strongest risk factor identified for development of atopic dermatitis. Up to 50% of patients with moderate-to-severe atopic dermatitis in European populations have filaggrin-null alleles compared with a general population frequency of 7-10%.
Objective
This study aimed to investigate the relationship between filaggrin-null mutations and epidermal antigen-presenting cell maturation in individuals with and without atopic dermatitis. Additionally, we investigated whether the cis isomer of urocanic acid, a filaggrin breakdown product, exerts immunomodulatory effects on dendritic cells.
Methods
Epidermal antigen presenting cells from non-lesional skin were assessed by flow cytometry (n=27) and confocal microscopy (n=16). Monocyte-derived dendritic cells from healthy volunteers were used to assess effects of cis- and trans-urocanic acid on dendritic cell phenotype by flow cytometry (n=11).
Results
Epidermal antigen presenting cells from filaggrin-null individuals had increased CD11c expression. Confocal microscopy confirmed this, and additionally revealed an increased number of epidermal CD83+ Langerhans cells in filaggrin-null individuals. In vitro, differentiation in the presence of cis-urocanic acid significantly reduced co-stimulatory 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 individuals with filaggrin-null mutations have more mature Langerhans cells in non-lesional skin whether or not they have atopic dermatitis. We also demonstrate that cis-urocanic acid reduces maturation of dendritic cells and increases their capacity to induce regulatory T cells, suggesting a novel link between filaggrin deficiency and immune dysregulation.
Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
Early online date2 Mar 2016
DOIs
Publication statusE-pub ahead of print - 2 Mar 2016

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