Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis.

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Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency Sanja Kezic, PhD, Gráinne M. O’Regan, MRCPI, René Lutter, PhD, Ivone Jakasa, PhD, Ellen S. Koster, PhD, Sean Saunders, BSc, Peter Caspers, PhD, Patrick M.J.H. Kemperman, MD, Gerwin J. Puppels, PhD, Aileen Sandilands, PhD, Huijia Chen, PhD, Linda E. Campbell, BSc, Karin Kroboth, MSc, Rosemarie Watson, MD, Padraic G. Fallon, PhD, W. H. Irwin McLean, DSc, FMedSci, Alan D. Irvine, MD, FRCPI Journal of Allergy and Clinical Immunology Volume 129, Issue 4, Pages 1031-1039.e1 (April 2012) DOI: 10.1016/j.jaci.2011.12.989 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Box-and-whiskers plot cytokine levels in the SC by FLG genotype showing the median (midline) and interquartile ranges. ∗P < .05 and ∗∗∗P < .001, as determined by using Kruskal-Wallis and Dunn multiple comparison tests. The differences in IL-18 and IL-1RA levels between the ADNON-FLG and ADFLG groups have been tested by using the 2-sided Mann-Whitney test. Journal of Allergy and Clinical Immunology 2012 129, 1031-1039.e1DOI: (10.1016/j.jaci.2011.12.989) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Correlation between levels of cytokines and NMF in the SC of patients with AD. Correlations are unadjusted for FLG mutations. a.u., Arbitrary units; r, Spearman (2-tailed) correlation coefficient. Journal of Allergy and Clinical Immunology 2012 129, 1031-1039.e1DOI: (10.1016/j.jaci.2011.12.989) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Distribution of pH values according to FLG status (mean ± SD). ∗∗P < .01, as determined by using the ANOVA post hoc Tukey test. Journal of Allergy and Clinical Immunology 2012 129, 1031-1039.e1DOI: (10.1016/j.jaci.2011.12.989) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Skin pH values in relation to NMF levels. Left, Patients with ADFLG. Right, Patients with ADFLG plus patients with ADNON-FLG. a.u., Arbitrary units; r, Pearson (2-tailed) correlation coefficient. Journal of Allergy and Clinical Immunology 2012 129, 1031-1039.e1DOI: (10.1016/j.jaci.2011.12.989) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 A and B, Expression of IL-1α and IL-1β in keratinocytes and skin from Flgft/Flgft mice. mRNA expression of IL-1β and IL-1RA in primary epidermal keratinocytes in the proliferative (Fig 5, A) and terminal differentiation (Fig 5, B) states. C, IL-1α and IL-1β mRNA expression in dorsal murine skin. Data are representative of 3 independent experiments (means ± SEMs). ∗P < .05. Journal of Allergy and Clinical Immunology 2012 129, 1031-1039.e1DOI: (10.1016/j.jaci.2011.12.989) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Levels of IL-1α in the SC of healthy control subjects and patients with AD FLG genotype. The differences have been tested by using the Student t test (∗P < .05). Data are presented as mean values ± SDs. CTRL+/+, Homozygote wild-type subject without AD. Journal of Allergy and Clinical Immunology 2012 129, 1031-1039.e1DOI: (10.1016/j.jaci.2011.12.989) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions