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

Abstract

BackgroundMutations 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%.ObjectiveThis 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.MethodsEpidermal 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).ResultsEpidermal 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.ConclusionsWe 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.

No difference in ultraviolet B-induced changes in antigen-presenting cells and cytokines between patients with and without loss-of-function mutations in FLG

“…Both CD86 and OX40L were significantly upregulated in UVB‐irradiated skin compared with nonirradiated skin (both P < 0·001; n = 16). A recent study suggested that FLG heterozygous patients may have increased LC maturation due to lower epidermal levels of cis ‐urocanic acid . However, we found no difference between FLG wild‐type and heterozygous patients in UVB‐induced upregulation of CD86 and OX40L.…”

The interplay between genetic and environmental factors in the pathogenesis of atopic dermatitis

“…In accordance with these mouse studies, LCs in the lesional skin of AD reportedly exhibit an activated phenotype, and TSLP is highly expressed in AD lesions . Moreover, mutations in the FLG gene may influence the activation of LCs not only in AD patients but also non‐AD healthy controls . These results suggest that LCs also induce Th2‐type immune responses in human AD.…”

“…11 Moreover, mutations in the FLG gene may influence the activation of LCs not only in AD patients but also non-AD healthy controls. 93 These results suggest that LCs also induce Th2-type immune responses in human AD.…”

The role of filaggrin in atopic dermatitis and allergic disease

“…FLG null mutations also heightened the immune imbalance between Th-1e, Th-2e, and Th-17elike Tregs in AD. 88 Leitch et al 89 showed that FLG null mutation carriers have more mature Langerhans cells in nonlesional skin irrespective of whether they have a diagnosis of AD. Also, filaggrin degradation products, including the cis-isomer of urocanic acid, were shown to down-regulate the expression of dendritic cells and increase the production of regulatory T-cells.…”

“…Also, filaggrin degradation products, including the cis-isomer of urocanic acid, were shown to down-regulate the expression of dendritic cells and increase the production of regulatory T-cells. 89 Filaggrin-deficient mice were shown to have higher levels of peripheral Th17 cells than their wild-type controls. This observation was present in adult ft/ft mice but not in 2-week-old ft/ft mice, indicating that this must be an acquired phenomenon.…”