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

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.