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

Claire S. Leitch, Eenass Natafji, Cunjing Yu, Sharizan Abdul-Ghaffar, Nayani Madarasingha, Zoë C. Venables, Roland Chu, Paul M. Fitch, Andrew J. Muinonen-Martin, Linda E. Campbell, W. H Irwin McLean, Jürgen Schwarze, Sarah E M Howie, Richard B. Weller (Lead / Corresponding author)

Research output: Contribution to journalArticle

14 Citations (Scopus)
145 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)482-490.e7
Number of pages16
JournalJournal of Allergy and Clinical Immunology
Volume138
Issue number2
Early online date2 Mar 2016
DOIs
Publication statusPublished - Aug 2016

Keywords

  • Atopic dermatitis
  • Costimulatory molecules
  • Filaggrin
  • Langerhans cells
  • Urocanic acid

Fingerprint Dive into the research topics of 'Filaggrin-null mutations are associated with increased maturation markers on Langerhans cells'. Together they form a unique fingerprint.

  • Cite this

    Leitch, C. S., Natafji, E., Yu, C., Abdul-Ghaffar, S., Madarasingha, N., Venables, Z. C., Chu, R., Fitch, P. M., Muinonen-Martin, A. J., Campbell, L. E., McLean, W. H. I., Schwarze, J., Howie, S. E. M., & Weller, R. B. (2016). Filaggrin-null mutations are associated with increased maturation markers on Langerhans cells. Journal of Allergy and Clinical Immunology, 138(2), 482-490.e7. https://doi.org/10.1016/j.jaci.2015.11.040