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

Claire S. Leitch, Eenass Natafji, Cunjing Yu, Sharizan Abdul-Ghaffar, Nayani Madarasingha, Zoë C. Venables, Roland Chu, Paul M. Fitch, Andrew J. Muinonen-Martin, Linda E. Campbell, W. H Irwin McLean, Jürgen Schwarze, Sarah E M Howie, Richard B. Weller (Lead / Corresponding author)

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Abstract

Background: Mutations 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%. 

Objective: This 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. 

Methods: Epidermal 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). 

Results: Epidermal 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. 

Conclusions: We 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.

Original languageEnglish
Pages (from-to)482-490.e7
Number of pages16
JournalJournal of Allergy and Clinical Immunology
Volume138
Issue number2
Early online date2 Mar 2016
DOIs
Publication statusPublished - Aug 2016

Fingerprint

Langerhans Cells
Urocanic Acid
Mutation
NSC 153174
Dendritic Cells
Atopic Dermatitis
Regulatory T-Lymphocytes
Confocal Microscopy
Monocytes
Healthy Volunteers
Flow Cytometry
Phenotype
Skin
Mixed Lymphocyte Culture Test
filaggrin
Antigen-Presenting Cells
Population
Alleles

Keywords

  • Atopic dermatitis
  • Costimulatory molecules
  • Filaggrin
  • Langerhans cells
  • Urocanic acid

Cite this

Leitch, C. S., Natafji, E., Yu, C., Abdul-Ghaffar, S., Madarasingha, N., Venables, Z. C., ... Weller, R. B. (2016). Filaggrin-null mutations are associated with increased maturation markers on Langerhans cells. Journal of Allergy and Clinical Immunology, 138(2), 482-490.e7. https://doi.org/10.1016/j.jaci.2015.11.040
Leitch, Claire S. ; Natafji, Eenass ; Yu, Cunjing ; Abdul-Ghaffar, Sharizan ; Madarasingha, Nayani ; Venables, Zoë C. ; Chu, Roland ; Fitch, Paul M. ; Muinonen-Martin, Andrew J. ; Campbell, Linda E. ; McLean, W. H Irwin ; Schwarze, Jürgen ; Howie, Sarah E M ; Weller, Richard B. / Filaggrin-null mutations are associated with increased maturation markers on Langerhans cells. In: Journal of Allergy and Clinical Immunology. 2016 ; Vol. 138, No. 2. pp. 482-490.e7.
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abstract = "Background: Mutations 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{\%}. Objective: This 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. Methods: Epidermal 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). Results: Epidermal 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. Conclusions: We 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.",
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Leitch, CS, Natafji, E, Yu, C, Abdul-Ghaffar, S, Madarasingha, N, Venables, ZC, Chu, R, Fitch, PM, Muinonen-Martin, AJ, Campbell, LE, McLean, WHI, Schwarze, J, Howie, SEM & Weller, RB 2016, 'Filaggrin-null mutations are associated with increased maturation markers on Langerhans cells', Journal of Allergy and Clinical Immunology, vol. 138, no. 2, pp. 482-490.e7. https://doi.org/10.1016/j.jaci.2015.11.040

Filaggrin-null mutations are associated with increased maturation markers on Langerhans cells. / Leitch, Claire S.; Natafji, Eenass; Yu, Cunjing; Abdul-Ghaffar, Sharizan; Madarasingha, Nayani; Venables, Zoë C.; Chu, Roland; Fitch, Paul M.; Muinonen-Martin, Andrew J.; Campbell, Linda E.; McLean, W. H Irwin; Schwarze, Jürgen; Howie, Sarah E M; Weller, Richard B. (Lead / Corresponding author).

In: Journal of Allergy and Clinical Immunology, Vol. 138, No. 2, 08.2016, p. 482-490.e7.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Filaggrin-null mutations are associated with increased maturation markers on Langerhans cells

AU - Leitch, Claire S.

AU - Natafji, Eenass

AU - Yu, Cunjing

AU - Abdul-Ghaffar, Sharizan

AU - Madarasingha, Nayani

AU - Venables, Zoë C.

AU - Chu, Roland

AU - Fitch, Paul M.

AU - Muinonen-Martin, Andrew J.

AU - Campbell, Linda E.

AU - McLean, W. H Irwin

AU - Schwarze, Jürgen

AU - Howie, Sarah E M

AU - Weller, Richard B.

PY - 2016/8

Y1 - 2016/8

N2 - Background: Mutations 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%. Objective: This 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. Methods: Epidermal 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). Results: Epidermal 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. Conclusions: We 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.

AB - Background: Mutations 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%. Objective: This 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. Methods: Epidermal 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). Results: Epidermal 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. Conclusions: We 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.

KW - Atopic dermatitis

KW - Costimulatory molecules

KW - Filaggrin

KW - Langerhans cells

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U2 - 10.1016/j.jaci.2015.11.040

DO - 10.1016/j.jaci.2015.11.040

M3 - Article

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SN - 0091-6749

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