Progressive activation of TH2/TH22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis Julia K. Gittler, BA,

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Progressive activation of TH2/TH22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis Julia K. Gittler, BA, Avner Shemer, MD, Mayte Suárez-Fariñas, PhD, Judilyn Fuentes-Duculan, MD, Kara J. Gulewicz, BA, Claire Q.F. Wang, PhD, Hiroshi Mitsui, MD, PhD, Irma Cardinale, MSc, Cristina de Guzman Strong, PhD, James G. Krueger, MD, PhD, Emma Guttman-Yassky, MD, PhD Journal of Allergy and Clinical Immunology Volume 130, Issue 6, Pages 1344-1354 (December 2012) DOI: 10.1016/j.jaci.2012.07.012 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Clinical, histologic, and genomic differences among nonlesional (NL), acute, and chronic AD skin. A, Clinical images of NL, acute, and chronic AD skin demonstrate bright erythema of acute lesions and dullness and lichenification of chronic lesions. B-D, Representative IHC stainings of hematoxylin and eosin (H & E; Fig 1, B) and the proliferation markers K16 (Fig 1, C) and Ki67 (Fig 1, D) in tissue sections of nonlesional, acute, and chronic AD skin, as well as quantification of epidermal thickness (Fig 1, B); K16 determined by using real-time PCR (RT-PCR; Fig 1, C), represented in log2 (log2[expression/hARP]); and Ki67+ cell counts (Fig 1, D), showing significantly increased epidermal hyperplasia and abnormal proliferation in acute lesions, with further increases in chronic lesions. *P < .05, **P < .01, and ***P < .001 (n = 10). Bar plots represent means ± SEMs. Scale bar = 100 μm. E, Venn diagrams of upregulated and downregulated probe sets in acute and chronic skin lesions in comparison with nonlesional skin using criteria of an FCH of greater than 1.5 and a P value of less than .01 (n = 8). Journal of Allergy and Clinical Immunology 2012 130, 1344-1354DOI: (10.1016/j.jaci.2012.07.012) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Onset of acute lesions is associated with coordinated increases in S100A7, S100A8, and S100A9 levels. A, Unsupervised hierarchic clustering of terminal differentiation genes across normal, nonlesional (NL), acute, and chronic AD skin samples (red, upregulated; blue, downregulated). In contrast to the uniform downregulation of well-characterized EDC genes, such as filaggrin and loricrin, throughout nonlesional skin and acute and chronic skin lesions, there is a steep increase in expression of S100A7, S100A8, and S100A9 with the onset of acute disease, with further induction in chronic lesions, as indicated by the black highlighting. Probes with the largest FCHs were chosen when several probes represented single genes. *P < .05 and **P < .01 (n = 8 for patients with AD and n = 15 for healthy subjects). B and C, The significant induction of these S100 proteins has been validated by increases in protein expression of S100A7 and S100A8 in representative IHC stainings of acute and chronic lesions compared with nonlesional skin (Fig 2, B) and mRNA gene expression levels by using real-time PCR (RT-PCR; Fig 2, C), represented in log2 (log2[expression/hARP]) and natural scale (expression/hARP; approximate FCH of 8, P < .02). hARP, Human acidic ribosomal protein (n = 10). Journal of Allergy and Clinical Immunology 2012 130, 1344-1354DOI: (10.1016/j.jaci.2012.07.012) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Marked activation of TH2 and TH22 immune pathways in acute disease, with progressive activation in chronic skin lesions by means of real-time PCR (RT-PCR). Mean expression estimates normalized to human acidic ribosomal protein (hARP) are represented in log2 (log2[expression/hARP]) and natural scale (expression/hARP). The largest gene expression increases are associated with TH2- and TH22-associated products, including IL-31, IL-22, S100A7, S100A8, and S100A9. Small increases in TH1-related products are evident in both acute and chronic lesions. In contrast with the immune mediators, the mRNA expression levels of filaggrin (FLG) and corneodesmosin (CDSN) showed similarity across the disease. Bar plots represent means ± SEMs. *P < .05, **P < .01, and ***P < .001 (n = 10). FOXP3, Forkhead box protein 3; MX1, myxovirus resistance 1; OX40L, OX40 ligand; TD, terminal differentiation; TSLPR, thymic stromal lymphopoietin receptor. Journal of Allergy and Clinical Immunology 2012 130, 1344-1354DOI: (10.1016/j.jaci.2012.07.012) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Significant increases in immune cell infiltrates characterize acute disease onset and progression to chronic disease, as quantified by means of IHC and cell counts. A-E, Significant increases in (CD3+) T cells, myeloid (CD11c+) DCs, mature (CD83+) DCs, Langerhans (CD1a+) cells, and inflammatory dendritic epidermal cells (FcεRI+) characterize acute disease. F, Cell counts of plasmacytoid (blood dendritic cell antigen 2 [BDCA2+]) DCs, mature (dendritic cell lysosome-associated membrane glycoprotein [DC-LAMP+]) DCs, resident (CD1c+) DCs, inflammatory (TNF-related-apoptosis-inducing ligand [TRAIL+]) DCs, inflammatory dendritic epidermal cells (CD206+), and atopic (OX40 ligand [OX40L+]) DCs increase from nonlesional (NL) through chronic AD skin. *P < .05 and **P < .01 (n = 10). Bar plots represent means ± SEMs. Scale bar = 100 μm. Journal of Allergy and Clinical Immunology 2012 130, 1344-1354DOI: (10.1016/j.jaci.2012.07.012) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Disease profiles of IL-17–induced genes in patients with acute and chronic AD compared with those in patients with psoriasis. A and B, A scatter plot of FCHs between lesional and nonlesional (NL) skin for each disease (in log2 scale) demonstrates that although these genes are well associated with the genomic differences between nonlesional and lesional skin in patients with psoriasis, no such association was found for either acute or chronic AD. C, There is a similar distribution of the TH17-regulated genes between acute and chronic AD skin compared with nonlesional skin. D, Means and 95% CIs of the log2(FCH) among IL-17 genes in psoriasis and AD transcriptomes (n = 8 for patients with AD and n = 15 for patients with psoriasis). Journal of Allergy and Clinical Immunology 2012 130, 1344-1354DOI: (10.1016/j.jaci.2012.07.012) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 A schematic illustration of initiation of acute AD and progression to chronic skin lesions. Nonlesional AD skin lesions show some immune infiltrates that produce inflammatory mediators, which might contribute to a defective epidermal barrier. Barrier defects lead to penetration by epicutaneous antigens that encounter Langerhans cells in the epidermis and dermal DCs in the dermis, inducing marked immune activation and recruitment of inflammatory cells in acute AD lesions. Marked activation of TH2 and TH22 axes occurs in acute disease onset. Smaller increases in TH1 and TH17 immune axes were found in acute lesions. A progressive activation of TH2 and TH22, as well as TH1, pathways is characteristic of the chronic stage of AD. The relative induction of each T-cell subset according to disease stage is represented pictorially by their size relative to the other T-cell subsets. Cytokines (ie, IL-4 and IL-13) and chemokines (ie, CCL17, CCL18, CCL19, CXCL9, CXCL10, and CXCL11) produced by various T cells and DCs induce further activation and recruitment of additional immune cells. With the onset of acute disease, TH22 cells release IL-22, which induces epidermal hyperplasia and, synergistically with the TH17 cytokine IL-17, drives an abrupt increase in a subset of terminal differentiation genes, specifically S100A7, S100A8, and S100A9 proteins. The increases in these barrier proteins contrast with the uniformly disrupted epidermal differentiation gene products (eg, filaggrin, loricrin, and corneodesmosin) throughout nonlesional, acute, and chronic AD skin. The TH2 and TH22 cytokines contribute to inhibition of the terminal differentiation proteins. IL-31 is abruptly upregulated in acute disease, potentially reflecting its role as an itch mediator in patients with AD. Journal of Allergy and Clinical Immunology 2012 130, 1344-1354DOI: (10.1016/j.jaci.2012.07.012) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology 2012 130, 1344-1354DOI: (10.1016/j.jaci.2012.07.012) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Journal of Allergy and Clinical Immunology 2012 130, 1344-1354DOI: (10.1016/j.jaci.2012.07.012) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Journal of Allergy and Clinical Immunology 2012 130, 1344-1354DOI: (10.1016/j.jaci.2012.07.012) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Journal of Allergy and Clinical Immunology 2012 130, 1344-1354DOI: (10.1016/j.jaci.2012.07.012) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions