TY - JOUR

T1 - Epidermal filaggrin deficiency mediates increased systemic T-helper 17 immune response

AU - Bonefeld, C. M.

AU - Petersen, T. H.

AU - Bandier, J.

AU - Agerbeck, Christina

AU - Linneberg, A.

AU - Ross-Hansen, K.

AU - Stender, S.

AU - Szecsi, P. B.

AU - Johansen, J. D.

AU - Geisler, C.

AU - Thyssen, J. P.

PY - 2016/10/1

Y1 - 2016/10/1

N2 - 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.

AB - 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.

U2 - 10.1111/bjd.14570

DO - 10.1111/bjd.14570

M3 - Journal article

C2 - 26997324

AN - SCOPUS:84990197993

VL - 175

SP - 706

EP - 712

JO - British Journal of Dermatology

JF - British Journal of Dermatology

SN - 0007-0963

IS - 4

ER -