Filaggrin null mutations are associated with altered circulating Tregs in atopic dermatitis

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease with a complex pathogenesis. Although regulatory T cells (Tregs) have previously been studied in AD, their role remains controversial, likely owing to patient heterogeneity. Thus, we recruited adult AD patients and age‐matched healthy controls, and assessed their filaggrin (FLG) genotype, serum IgE level, and eczema area and severity index (EASI). We found increased proportions of all circulating Treg subpopulations in AD patients. Moreover, we show positive correlations between circulating Tregs and serum IgE FLG null mutations limited the expansion of both memory and effector Tregs and enhanced that of recently thymus‐emigrated Tregs. Furthermore, proportions of circulating Th2‐ or Th17‐Tregs but not Th1‐Tregs were increased in AD patients, and accentuated by FLG null mutations, thereby mimicking the immune deviation observed in Th cell populations. Moreover, ICOS+ Tregs showed reduced production of interleukin‐10, suggesting impaired immunosuppression in AD. The level of demethylation of FOXP3i1, which reflects the stability of FOXP3 expression, was similar in the blood and skin of AD patients and healthy controls. Overall, these results show that Tregs may participate into AD pathogenesis and that FLG null mutations exert further modifications on specific subpopulations of circulating Tregs.

Characterization of CD19+CD24hiCD38hi B cells in Chinese adult patients with atopic dermatitis

“…This result suggests that these cells are functionally abnormal although the cell number could be unchanged. A similar result was reported in decreased IL‐10 production by ICOS + Tregs in patients with AD 46 . The CD19 + CD24 hi CD38 hi B cells from AD patients and healthy controls had similar proliferation profile upon stimulation with CpG, CD40L and LPS, which was consistent with the results of in vitro proliferation of CD19 + CD24 hi CD38 hi B cells upon IL‐2, IL‐4, CpG and CD40L stimulation.…”

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.…”

Xenobiotic Receptors and Their Mates in Atopic Dermatitis

“…AHR is expressed in immune cells, where it can modulate the immune response. In AD, the percentages of circulating regulatory T cells (T regs ) are consistently found to be increased, but their numbers may be insufficient to counteract ongoing inflammation, or they may even contribute to inflammation by re-differentiating into Th-like cells (e.g., “Th2-like” and “Th17-like” cells) [188,189,190,191,192]. AHR activation by synthetic (e.g., TCDD) or endogenous (e.g., ITE) ligands increased the differentiation of CD4+ T cells into functional T regs exhibiting suppressive activities in mice through various mechanisms, including effects on dendritic cells [55,155,193,194,195,196,197].…”