Epidermal filaggrin deficiency mediates increased systemic T‐helper 17 immune response4. (23rd June 2016) - Bonefeld, C.M.
Summary: Background: Cellular T‐helper (Th)17 infiltrates dominate skin inflammation in filaggrin‐deficient flaky tail ( ft/ft ) mice, and Th17 cells are found in both the skin and blood of patients with acute atopic dermatitis. However, the potential role of loss‐of‐function mutations in the filaggrin gene ( FLG ) for increased peripheral Th17 cells is unclear. Objectives: To study whether mutations in FLG influence the frequency of peripheral Th17 cells. Methods: We studied blood samples from six adults with mutations in FLG and five controls without mutations for frequencies of cytokine‐producing CD4 + T cells. We evaluated ft/ft mice and wild‐type (WT) control mice for interleukin (IL)‐17‐producing CD4 + T cells in naive mice and following 2, 4‐dinitrofluorobenzene (DNFB) challenge. In addition, the T‐cell receptor (TCR) Vβ‐chain repertoire was analysed by flow cytometry. Results: Human studies showed increased frequency of peripheral Th17 cells in FLG mutation carriers when compared with WT individuals. Mouse studies showed increased frequency of peripheral Th17 cells in adult ft/ft mice but not in 2‐week‐old ft/ft mice. Moreover, altered TCR Vβ‐chain repertoire was found in ft/ft mice when compared with WT mice. An increased frequency of CD4 + Vβ10 + T cells producing IL‐17 was found in the spleen of adult ft/ft mice when compared with WT mice. Finally, DNFB challenge induced an increased number of Th17 cells in ft/ft mice compared with WT mice. Conclusions: Deficiency of filaggrin appeared to be a driver of increased peripheral levels of Th17 cells. This increase must be acquired as peripheral Th17 cells were found in adult ft/ft mice but not in 2‐week‐old ft/ft mice indicating involvement of exogenous factors. Abstract : What's already known about this topic? An increased level of T‐helper (Th)17 cells is found in the skin of flaky tail mice. Th17 cells seem to be involved in the pathogenesis of atopic dermatitis. What does this study add? We show that loss‐of‐function mutations in the filaggrin gene could be a driver of increased frequency of peripheral Th17 cells in both humans and mice. The increase in Th17 cells is most likely mediated by extrinsic factors. What is the translational message? Atopic dermatitis owing to filaggrin deficiency appears to have a Th17 profile. Future experiments may examine whether anti‐interleukin‐17 medicaments may reduce disease severity. Linked Comment: Tokura. Br J Dermatol 2016;175 :669–670 . Plain language summary available online