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Background: Our current understanding of atopic dermatitis (AD) and psoriasis pathophysiology is largely derived from skin biopsy studies that cause scarring and may be impractical in large-scale clinical trials. Although tape strips show promise as a minimally invasive technique in these common diseases, a comprehensive molecular profiling characterizing and differentiating the 2 diseases in tape strips is unavailable., Objective: Our aim was to construct a global transcriptome of tape strips from lesional and nonlesional skin of adults with moderate-to-severe AD and psoriasis., Methods: A total of 20 tape strips were obtained from lesional and nonlesional skin of patients with AD and psoriasis and skin from controls (n = 20 each); the strips were subjected to RNA sequencing (RNA-seq), with quantitative RT-PCR validation of immune and barrier biomarkers., Results: We detected RNA-seq profiles in 96 of 100 of samples (96%), with 4123 and 5390 genes differentially expressed in AD and psoriasis lesions versus in controls, respectively (fold change ≥ 2; false discovery rate [FDR] < 0.05). Nonlesional tape-stripped skin from patients with AD was more similar to lesional skin than to nonlesional skin of patients with psoriasis, which showed larger differentiation from lesions. AD and psoriasis tissues shared increases in levels of dendritic cell and T-cell markers (CD3, ITGAX/CD11c, and CD83), but AD tissues showed preferential T H 2 skewing (IL-13, CCL17/TARC, and CCL18), whereas psoriasis was characterized by higher levels of expression of T H 17-related (IL-17A/F and IL-36A/IL-36G), T H 1-related (IFN-γ and CXCL9/CXCL10), and innate immunity-related (nitric oxide synthase 2/inducible nitric oxide synthase and IL-17C) products (FDR < 0.05). Terminal differentiation (FLG2 and LCE5A), tight junction (CLDN8), and lipid biosynthesis and metabolism (FA2H and ALOXE3) products were significantly downregulated in both AD and psoriasis (FDR < 0.05). Nitric oxide synthase 2/inducible nitric oxide synthase expression (determined by quantitative PCR) differentiated AD and psoriasis with 100% accuracy., Conclusion: RNA-seq tape strip profiling detected distinct immune and barrier signatures in lesional and nonlesional AD and psoriasis skin, suggesting their utility as a minimally invasive alternative to biopsies for detecting disease biomarkers., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The circulating immune phenotype was defined in adults and young children with early atopic dermatitis (AD), but chronologic changes in the blood of infants and children with AD through adolescence have not been explored., Objective: We sought to compare immune activation and cytokine polarization in the blood of 0- to 5-year-old (n = 39), 6- to 11-year-old (n = 26), 12- to 17-year-old (n = 21) and 18-year-old or older (n = 43) patients with AD versus age-matched control subjects., Methods: Flow cytometry was used to measure IFN-γ, IL-9, IL-13, IL-17, and IL-22 cytokine levels in CD4 + /CD8 + T cells, with inducible costimulator molecule and HLA-DR defining midterm and long-term T-cell activation, respectively, within skin-homing/cutaneous lymphocyte antigen (CLA) + versus systemic/CLA - T cells. Unsupervised clustering differentiated patients based on their blood biomarker frequencies., Results: Although CLA + T H 1 frequencies were significantly lower in infants with AD versus all older patients (P < .01), frequencies of CLA + T H 2 T cells were similarly expanded across all AD age groups compared with control subjects (P < .05). After infancy, CLA - T H 2 frequencies were increased in patients with AD in all age groups, suggesting systemic immune activation with disease chronicity. IL-22 frequencies serially increased from normal levels in infants to highly significant levels in adolescents and adults compared with levels in respective control subjects (P < .01). Unsupervised clustering aligned the AD profiles along an age-related spectrum from infancy to adulthood (eg, inducible costimulator molecule and IL-22)., Conclusions: The adult AD phenotype is achieved only in adulthood. Unique cytokine signatures characterizing individual pediatric endotypes might require age-specific therapies. Future longitudinal studies, comparing the profile of patients with cleared versus persistent pediatric AD, might define age-specific changes that predict AD clearance., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Skin is replete with immunocompetent cells that modulate signaling pathways to maintain a salubrious immunogenic/tolerogenic balance. This fertile immune environment plays a significant role in the development of allergic responses and sensitivities, but the mechanisms underlying these pathways have been underappreciated and underused with respect to developing therapeutics. Among the complex repertoire of cells that promote tolerogenic pathways in the periphery, 2 key classes include dendritic cells and regulatory T (Treg) cells. Immature dendritic cells are the first line of defense, patrolling the periphery, sampling antigens, and secreting cytokines that suppress immune cells and promote the survival of Treg cells. Skin-homing Treg cells also play a critical role in mitigating the reactivity of immune cells, secreting high levels of cytokines that promote tolerance. Therapeutic approaches that capitalize on our knowledge of the rich cellular and molecular environment are emerging and show great promise. We will discuss the advantages and challenges of 5 such strategies and how these therapies might mitigate the atopic march by facilitating tolerance. We conclude that skin is a multifaceted structure that provides a fertile ground for therapeutic discovery. Accordingly, ongoing work in this domain will no doubt continue to deliver exciting progress for improved health outcomes., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Peripheral blood skin-homing/cutaneous lymphocyte antigen (CLA) + T cells emerge as biomarkers of cutaneous immune activation in patients with inflammatory skin diseases (atopic dermatitis [AD] and alopecia areata [AA]). However, blood phenotyping across these subsets is not yet available in patients with vitiligo., Objective: We sought to measure cytokine production by circulating skin-homing (CLA + ) versus systemic (CLA - ) "polar" CD4 + /CD8 + ratio and activated T-cell subsets in patients with vitiligo compared with patients with AA, AD, or psoriasis and control subjects., Methods: Flow cytometry was used to measure levels of the cytokines IFN-γ, IL-13, IL-9, IL-17, and IL-22 in CD4 + /CD8 + T cells in the blood of 19 patients with moderate-to-severe nonsegmental/generalized vitiligo, moderate-to-severe AA (n = 32), psoriasis (n = 24), or AD (n = 43) and control subjects (n = 30). Unsupervised clustering differentiated subjects into groups based on cellular frequencies., Results: Patients with Vitiligo showed the highest CLA + /CLA - T H 1/type 1 cytotoxic T-cell polarization, with parallel T H 2/T H 9/T H 17/T H 22 level increases to levels often greater than those seen in patients with AA, AD, or psoriasis (P < .05). Total regulatory T-cell counts were lower in patients with vitiligo than in control subjects and patients with AD or psoriasis (P < .001). Vitiligo severity correlated with levels of multiple cytokines (P < .1), whereas duration was linked with IFN-γ and IL-17 levels (P < .04). Patients and control subjects grouped into separate clusters based on blood biomarkers., Conclusions: Vitiligo is characterized by a multicytokine polarization among circulating skin-homing and systemic subsets, which differentiates it from other inflammatory/autoimmune skin diseases. Future targeted therapies should delineate the relative contribution of each cytokine axis to disease perpetuation., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: African Americans (AA) are disproportionately impacted by atopic dermatitis (AD), with increased prevalence and therapeutic challenges unique to this population. Molecular profiling data informing development of targeted therapeutics for AD are derived primarily from European American (EA) patients. These studies are absent in AA, hindering development of effective treatments for this population., Objective: We sought to characterize the global molecular profile of AD in the skin of AA patients as compared with that of EA AD and healthy controls., Methods: We performed RNA-Seq with reverse transcription polymerase chain reaction validation and immunohistochemistry studies in lesional and nonlesional skin of AA and EA AD patients vs healthy controls., Results: African American AD lesions were characterized by greater infiltration of dendritic cells (DCs) marked by the high-affinity immunoglobulin E (IgE) receptor (FcεR1+) compared with EA AD (P < .05). Both AD cohorts showed similarly robust up-regulation of Th2-related (CCL17/18/26) and Th22-related markers (interleukin [IL]-22, S100A8/9/12), but AA AD featured decreased expression of innate immune (tumor necrosis factor [TNF], IL-1β), Th1-related (interferon gamma [IFN-γ], MX1, IL-12RB1), and Th17-related markers (IL-23p19, IL-36G, CXCL1) vs EA AD (P < .05). The Th2 (IL-13) and Th22-related products (IL-22, S100A8/9/12) and serum IgE were significantly correlated with clinical severity (Scoring of Atopic Dermatitis [SCORAD]) in AA. Fillagrin (FLG) was exclusively down-regulated in EA AD, whereas loricrin (LOR) was down-regulated in both AD cohorts and negatively correlated with SCORAD in AA., Conclusion: The molecular phenotype of AA AD skin is characterized by attenuated Th1 and Th17 but similar Th2/Th22-skewing to EA AD. Our data encourages a personalized medicine approach accounting for phenotype-specific characteristics in future development of targeted therapeutics and clinical trial design for AD., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Recent research advancements indicate that atopic dermatitis (AD) is a complex disease characterized by different subtypes/phenotypes based on age, disease chronicity, ethnicity, filaggrin and IgE status, and underlying molecular mechanisms/endotypes. This heterogeneity advocates against the traditional "one-size-fits-all" therapeutic approaches still used to manage AD. Precision medicine approaches, striving for targeted, tailored, endotype-driven disease prevention and treatment, rely on detailed definitions of the disease's variability across different phenotypes. Studies have shown that AD harbors different endotypes across different age groups and ethnicities and according to IgE levels and filaggrin mutation status. These include European American versus Asian patients, children versus adults, intrinsic versus extrinsic (IgE status) disease, and patients with and without filaggrin mutations. Therapies targeting different cytokine axes and other mechanisms involved in disease pathogenesis, which are currently being tested for patients with AD across the disease spectrum, will expand our ability to dissect the relative contribution of each of these pathways to disease perpetuation., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The pathogenesis of hidradenitis suppurativa (HS) remains unclear. In order to develop effective treatment strategies, a deeper understanding of pathophysiology is needed. This is impaired by multiple small studies with inconsistent methodologies and the impact of co-occurring pro-inflammatory conditions such as smoking and obesity. Methods: This systematic review aimed to collate all published reports of cytokine studies in tissue, blood, serum and exudate. It was registered with PROSPERO (Registration number CRD42018104664) performed in line with the PRISMA checklist. Results: 19 studies were identified comprising 564 individual HS patients and 198 control patients examining 81 discrete cytokines. Methodology was highly varied and the quality of studies was generally low. There was a large degree of variance between the measured levels of cytokines. 78.2% of cytokines demonstrated heterogeneity by the chi-squared test for homogeneity and hence meta-analysis was not deemed appropriate. However, a strong and significant IL-17 signalling component was identified. Conclusions: Cytokines consistently elevated in lesional, peri-lesional and unaffected tissue are identified and discussed. Areas for further investigation include the role of dendritic cells in HS; the contribution of obesity, smoking, diabetes and the microbiome to cytokine profiles in HS; and examining the natural history of this disease through longitudinal measurements of cytokines over time., Competing Interests: No competing interests were disclosed.

The ichthyoses are rare skin disorders with immune and barrier aberrations. Identifying blood phenotypes may advance targeted therapeutics. We aimed to compare frequencies of skin homing/cutaneous lymphocyte antigen (+) versus systemic/cutaneous lymphocyte antigen (-) "polar" CD4 + /CD8 + and activated T-cell subsets in ichthyosis versus atopic dermatitis, psoriasis, and control blood, with appropriate clinical correlations. Flow cytometry was used to measure IFN-γ, IL-13, IL-9, IL-17, and IL-22 cytokines in CD4 + /CD8 + T cells, with inducible co-stimulator molecule and HLA-DR defining mid- and long-term T-cell activation, respectively. We compared peripheral blood from 47 patients with ichthyosis (congenital ichthyosiform erythroderma, lamellar ichthyosis, epidermolytic ichthyosis, and Netherton syndrome) with 43 patients with atopic dermatitis and 24 patients with psoriasis and 59 age-matched controls. Clinical measures included the ichthyosis severity score, with subsets for erythema and scaling, transepidermal water loss, and pruritus. All ichthyoses had excessive inducible co-stimulator molecule activation (P < 0.001), particularly epidermolytic ichthyosis. Significantly elevated IL-17- (P < 0.05) and IL-22-producing (P < 0.01) T cells characterized ichthyoses, mainly Netherton syndrome and congenital ichthyosiform erythroderma (P < 0.05). Increased T helper 2/cytotoxic T cell 2/T helper 9 (P < 0.05) and similar IFN-γ frequencies (P > 0.1) versus controls were also noted. IL-17/IL-22-producing cells clustered with clinical measures, whereas IFN-γ clustered with age. Our data show peripheral blood IL-17/IL-22 activation across the ichthyoses, correlating with clinical measures. Targeted therapies should dissect the relative contribution of polar cytokines to disease pathogenesis., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Patients with psoriasis have an increased risk of myocardial infarction, and psoriasis is now recognized as an independent risk factor for coronary heart disease and cardiovascular mortality. To understand the effects of psoriasis medications on systemic inflammation associated with cardiovascular risks, we studied blood proteins related to inflammation and cardiovascular disease archived from a phase 3 clinical trial of tofacitinib and etanercept in adults with moderate-to-severe psoriasis. A total of 157 blood proteins were quantified by a proximity extension assay from 266 patients at baseline and week 4. Protein changes in the blood after 1 month of treatment were compared between tofacitinib (10 mg two times a day) and etanercept (50 mg biweekly), and by response status at week 12. Tofacitinib and etanercept commonly reduced IL-6, CCL20, and CXCL10, but IL-17A was significantly reduced only in responders of either treatment. Compared with etanercept, tofacitinib showed a wider spectrum of cardiovascular blood protein reduction, but the protein reduction effects of tofacitinib were strictly confined to treatment responders. Tumor necrosis factor receptor 1, E-selectin, hK11, tumor necrosis factor-related activation-induced cytokine, CHI3L1, IL-16, and matrix metalloproteinase-12 were cardiovascular proteins significantly reduced only in tofacitinib responders. Our data suggest that a short-term systemic psoriasis treatment can cause reductions in circulating inflammatory and other proteins associated with cardiovascular risks., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Palmoplantar pustular psoriasis (PPPP) is a variant of psoriasis, which has significant negative impact on quality of life. The cellular and molecular inflammatory pathways involved in PPPP have not been well studied., Objective: Study the expression of cytokines and chemokines involved in the IL-17/IL-23 axis in palmoplantar pustular psoriasis and other difficult to treat psoriasis areas (palms, scalp, elbows and lower legs)., Methods: Skin biopsies were performed on a total of 80 patients with PPPP, non-pustular palmoplantar psoriasis (NPPPP), or psoriasis located on elbows, knees and scalp as well as 10 healthy subjects. RT-PCR, immunohistochemistry and flow cytometry on cells extracted from skin biopsies were used to compare PPPP to other forms of psoriasis., Results: There was a significant (p<0.05) increase in the expression of IL-1β, IL-6, LL-37, IL-19, IL-17A, CXCL1 and CXCL2 in PPPP as compared to NPPPP. However, there was no significant difference in expression of IL-23 in PPPP as compared to NPPPP and other forms of psoriasis. The proportion of IL-22 + but not IL-17A + mast cells was higher in PPPP as compared to NPPPP (p<0.05)., Conclusion: These results suggest that the IL-17A pathway may play a more important role in PPPP than in NPPPP., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Objective: To our knowledge, there is no broad genomic analysis comparing skin and synovium in psoriatic arthritis (PsA). Also, there is little understanding of the relative levels of cytokines and chemokines in skin and synovium. The purpose of this study was to better define inflammatory pathways in paired lesional skin and affected synovial tissue in patients with PsA., Methods: We conducted a comprehensive analysis of cytokine and chemokine activation and genes representative of the inflammatory processes in PsA. Paired PsA synovial tissue and skin samples were obtained from 12 patients on the same day. Gene expression studies were performed using Affymetrix HGU133 Plus 2.0 arrays. Confirmatory quantitative real-time polymerase chain reaction (PCR) was performed on selected transcripts. Cell populations were assessed by immunohistochemistry and immunofluorescence., Results: Globally, gene expression in PsA synovium was more closely related to gene expression in PsA skin than to gene expression in synovium in other forms of arthritis. However, PsA gene expression patterns in skin and synovium were clearly distinct, showing a stronger interleukin-17 (IL-17) gene signature in skin than in synovium and more equivalent tumor necrosis factor (TNF) and interferon-γ gene signatures in both tissues. These results were confirmed with real-time PCR., Conclusion: This is the first comprehensive molecular comparison of paired lesional skin and affected synovial tissue samples in PsA. Our results support clinical trial data showing that PsA skin and joint disease are similarly responsive to TNF antagonists, while IL-17 antagonists have better results in PsA skin than in PsA joints. Genes selectively expressed in PsA synovium might direct future therapies for PsA., (© 2015 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

Background: Atopic dermatitis (AD) is the most common inflammatory disease. The prevalence of allergic contact dermatitis to allergens (eg, fragrance) is higher in patients with AD, despite a trend toward weaker clinical allergic contact dermatitis reactions. The role of the AD skin phenotype in modulating allergic sensitization to common sensitizers has not been evaluated., Objective: We sought to investigate whether patients with AD have altered tissue immune responses on allergen challenge., Methods: Gene expression and immunohistochemistry studies were performed on biopsy specimens from 10 patients with AD and 14 patients without AD patch tested with common contact allergens (nickel, fragrance, and rubber)., Results: Although 1085 differentially expressed genes (DEGs) were commonly modulated in patch-tested skin from patients with AD and patients without AD versus control skin, 1185 DEGs were uniquely altered in skin from patients without AD, and only 246 DEGs were altered in skin from patients with AD. Although many inflammatory products (ie, matrix metalloproteinase 12/matrix metalloproteinase 1/S100A9) were upregulated in both groups, higher-magnitude changes and upregulation of interferon responses were evident only in the non-AD group. Stratification by allergen showed decreased expression of immune, TH1-subset, and TH2-subset genes in nickel-related AD responses, with increased TH17/IL-23 skewing. Rubber/fragrance showed similar trends of lesser magnitude. Negative regulators showed higher expression in patients with AD., Conclusions: Through contact sensitization, our study offers new insights into AD. Allergic immune reactions were globally attenuated and differentially polarized in patients with AD, with significant decreases in levels of TH1 products, some increases in levels of TH17 products, and inconsistent upregulation in levels of TH2 products. The overall hyporesponsiveness in skin from patients with background AD might be explained by baseline immune abnormalities, such as increased TH2, TH17, and negative regulator levels compared with those seen in non-AD skin., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Current approaches for the treatment of psoriasis with anti-cytokine therapies involve the blockade of TNF-α, or the p40 sub-unit of IL-12 and IL-23. However, the field is currently evolving to test more selective antagonists, such as anti-IL-23p19, IL-17 and other inflammatory cytokines. Here we discuss our current understanding of dendritic cell and T cell subsets that are relevant in psoriasis, and the pharmacologic strategies that temper their activity in this disease., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Introduction: Inflammatory skin diseases can be examined from many viewpoints. In this review, we consider three distinct cutaneous inflammatory diseases from the point of view of their major lesional dendritic cell (DC) subpopulations. The DC populations considered are Langerhans cells, myeloid DCs, and plasmacytoid DCs (pDCs), with specific attention to the presence and role of the inflammatory counterparts of these cells. From such a "dendritic cell-centric" focus, psoriasis, atopic dermatitis (AD), and cutaneous lupus erythematosus (CLE) are explored., Discussion: In psoriasis, there is a specific population of myeloid "inflammatory" DCs that appears to play an important pathogenic role, while pDCs have been recently implicated in the initiation of psoriatic lesions. In AD, Langerhans cells may be important during initiation, while "inflammatory dendritic epidermal cells" (IDECs) appear to be abundant in lesional epidermis and dermis and contribute to maintenance of AD. These IDECs may actually be analogous to the myeloid inflammatory DCs found in the epidermal and dermal compartments of the skin in psoriasis, although they express distinct surface markers and induce different T cell polarities as a result of different cytokine milieu in which they develop. CLE has been recently characterized as a type I IFN-mediated disease, and pDCs are integral to the pathogenesis of this disease., Conclusion: Thus, these DC subpopulations and their products will be reviewed in the context of these three cutaneous diseases to provide clinico-pathophysiological correlations between the lesional DCs, their products, and the skin diseases.

There is much evidence to support the concept that psoriasis is a type 1 autoimmune disease, primarily mediated by interferon gamma and other inflammatory cytokines. There has been renewed interest in the role of components of the innate immune system, however,and it may be that overlap between the innate and acquired arms of the immune system can better explain immunopathogenesis in psoriasis. Relevant cell types, receptors, and immune mediators within these traditional boundaries of the immune system are discussed.Finally, pathogenic contributions from important psoriatic mouse models and recent genomic data using the new gene chip technology are elaborated.

Purpose of Review: Discuss and update concepts and hypotheses for the pathogenesis of psoriasis based on new research reports (primarily from 2003 and early 2004)., Recent Findings: Increases in newly defined dendritic cell subsets, cytokines, and chemokines have been identified in psoriasis lesions and have modified views of T-cell-mediated pathogenesis. In addition, the psoriasis transcriptome has been defined by large-scale genomic expression studies, and these data suggest distinct molecular mechanisms of type 1 T-cell-mediated inflammation. Somewhat surprisingly, therapeutic clinical trials suggest that tumor necrosis factor is a major pathogenic cytokine in psoriasis, whereas translational studies point to roles of other innate pathways mediated by heat shock proteins, glycolipids, natural killer T cells, or dendritic cells in disease pathogenesis., Summary: An interactive network of inflammatory cytokines, chemokines, dendritic cells, and type 1 T cells or natural killer T cells potentially drives pathogenic inflammation in psoriasis vulgaris. Continued clinical studies with defined immune antagonists provide a critical means to dissect the contribution of different cell subsets and genomic pathways to the pathogenesis of psoriasis vulgaris.

Psoriasis vulgaris is a common inflammatory disease affecting 7.5 million adults just in the US. Previously, psoriasis immunopathogenesis has been viewed as the imbalance between CD4+ T-helper 17 (Th17) cells and regulatory T-cells (Tregs). However, current paradigms are rapidly evolving as new technologies to study immune cell subsets in the skin have been advanced. For example, recently minted single-cell RNA sequencing technology has provided the opportunity to compare highly differing transcriptomes of Type 17 T-cell (T17 cell) subsets depending on IL-17A vs. IL-17F expression. The expression of regulatory cytokines in T17 cell subsets provided evidence of T-cell plasticity between T17 cells and regulatory T-cells (Tregs) in humans. In addition to Tregs, other types of regulatory cells in the skin have been elucidated, including type 1 regulatory T-cells (Tr1 cells) and regulatory dendritic cells. More recently, investigators are attempting to apply single-cell technologies to clinical trials of biologics to test if monoclonal blockade of pathogenic T-cells will induce expansion of regulatory immune cell subsets involved in skin homeostasis.

BackgroundIn previous human skin single-cell data, inflammatory cells constituted only a small fraction of the overall cell population, such that functional subsets were difficult to ascertain.ObjectiveOur aims were to overcome the aforesaid limitation by applying single-cell transcriptomics to emigrating cells from skin and elucidate ex vivo gene expression profiles of pathogenic versus regulatory immune cell subsets in the skin of individuals with psoriasis.MethodsWe harvested emigrating cells from human psoriasis skin after incubation in culture medium without enzyme digestion or cell sorting and analyzed cells with single-cell RNA sequencing and flow cytometry simultaneously.ResultsUnsupervised clustering of harvested cells from psoriasis skin and control skin identified natural killer cells, T-cell subsets, dendritic cell subsets, melanocytes, and keratinocytes in different layers. Comparison between psoriasis cells and control cells within each cluster revealed that (1) cutaneous type 17 T cells display highly differing transcriptome profiles depending on IL-17A versus IL-17F expression and IFN-γ versus IL-10 expression; (2) semimature dendritic cells are regulatory dendritic cells with high IL-10 expression, but a subset of semimature dendritic cells expresses IL-23A and IL-36G in psoriasis; and (3) CCL27-CCR10 interaction is potentially impaired in psoriasis because of decreased CCL27 expression in basal keratinocytes.ConclusionWe propose that single-cell transcriptomics applied to emigrating cells from human skin provides an innovative study platform to compare gene expression profiles of heterogenous immune cells in various inflammatory skin diseases.

Atopic dermatitis (AD) is a common inflammatory skin disease associated with barrier disfunction and T SB H sb 2/T SB H sb 22 immune polarity.1,2 Patients with AD are often colonized or infected with I Staphylococcus aureus i ( I S. aureus i ).3 Recent large cohort studies and skin microbiome analyses have identified that AD is dominated by I S. aureus i .4 However, the interaction of cytokines and bacteria in AD skin remains unclear. Keywords: atopic dermatitis; dermatology; infections; inflammation; innate immunity; keratinocytes EN atopic dermatitis dermatology infections inflammation innate immunity keratinocytes 3534 3537 4 11/01/21 20211101 NES 211101 ACKNOWLEDGEMENTS KY was supported by Japan Society for the Promotion of Science (JSPS) overseas research fellowships from 2020 to 2022. TH2 cytokines and Staphylococcus aureus cooperatively induce atopic dermatitis-like transcriptomes. [Extracted from the article]

Molecular studies in atopic dermatitis (AD) are largely restricted to patients with moderate-to-severe disease. Our aim was to evaluate skin and blood abnormalities in mild, moderate, and severe AD. Skin and blood samples were obtained from 61 patients with AD (20 with mild or limited disease, 17 with moderate disease, and 24 with severe disease) and 20 healthy subjects. Immune and barrier markers were measured in lesional, nonlesional, and healthy skin by quantitative real-time PCR and immunohistochemistry, and in blood by using the OLINK proteomic assay. Cellular markers of epidermal hyperplasia and T-cell/dendritic cell infiltration were increased in AD tissues of all patients in all severity groups versus in those of controls, whereas downstream T H 2 cell–, T H 22 cell–, T H 1 cell–, and T H 17 cell–related mediators demonstrated incremental elevations with increasing disease severity, in both lesional and nonlesional skin. Whereas the levels of the T H 2 (IL13, CCL17, and CCL26) and T H 22 (IL-22) cytokines were significantly elevated in both AD lesional and nonlesional skin of all patients regardless of the severity of their disease, patients with mild or limited AD showed increases in their levels of T H 1 cell (IFNG, CXCL9, and CXCL10) and T H 17 cell (IL-17A, CCL20, and CXCL1) markers in lesional but not nonlesional skin. Regulatory T-cell–related mediators (IL-10 and FOXP3) were comparably upregulated in all groups, without displaying the severity-based gradient in other immune axes. Unsupervised clustering aligned samples along a severity spectrum, where nonlesional mild or limited AD skin clustered with the samples from healthy controls. Furthermore, whereas the blood profiles of patients with moderate and severe AD showed gradual increases in the levels of T H 1 cell–, T H 2 cell–, and T H 17 cell–related and atherosclerosis and/or cardiovascular risk (CCL7, FGF21, and IGFBP1) proteins, the blood profiles of patients with mild or limited AD lacked significant differences from those of the controls. Mild and limited AD show high levels of T H 2/T H 22 cell activation that is primarily localized to skin lesions and lacks the systemic inflammation of moderate and severe disease. [Display omitted] [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a prevalent inflammatory skin disease with a complex pathogenesis involving immune cell and epidermal abnormalities. Despite whole tissue biopsy studies that have advanced the mechanistic understanding of AD, single cell–based molecular alterations are largely unknown. Our aims were to construct a detailed, high-resolution atlas of cell populations and assess variability in cell composition and cell-specific gene expression in the skin of patients with AD versus in controls. We performed single-cell RNA sequencing on skin biopsy specimens from 5 patients with AD (4 lesional samples and 5 nonlesional samples) and 7 healthy control subjects, using 10× Genomics. We created transcriptomic profiles for 39,042 AD (lesional and nonlesional) and healthy skin cells. Fibroblasts demonstrated a novel COL6A5 + COL18A1 + subpopulation that was unique to lesional AD and expressed CCL2 and CCL19 cytokines. A corresponding LAMP3 + dendritic cell (DC) population that expressed the CCL19 receptor CCR7 was also unique to AD lesions, illustrating a potential role for fibroblast signaling to immune cells. The lesional AD samples were characterized by expansion of inflammatory DCs (CD1A + FCER1A +) and tissue-resident memory T cells (CD69 + CD103 +). The frequencies of type 2 (IL13 +)/type 22 (IL22 +) T cells were higher than those of type 1 (IFNG +) in lesional AD, whereas this ratio was slightly diminished in nonlesional AD and further diminished in controls. AD lesions were characterized by expanded type 2/type 22 T cells and inflammatory DCs, and by a unique inflammatory fibroblast that may interact with immune cells to regulate lymphoid cell organization and type 2 inflammation. [ABSTRACT FROM AUTHOR]

Psoriasis and atopic dermatitis (AD) are common T-cell mediated inflammatory diseases of the skin that can be treated by specific cytokine antagonists or more broad immunosuppressive drugs. The diseases are similar in that epidermal keratinocytes respond to T-cell derived cytokines by altering growth and differentiation responses, accounting for major parts of the overall disease phenotype. When studied across European-American populations, psoriasis and AD display differing T-cell polarity and different arrays of cytokines. Psoriasis is a disease largely driven by Th17 T-cells and associated IL-17 activation, while AD has a strong Th2 component associated with IL-4 and IL-13 over-production, and both diseases have activation of Th22 T-cells and Th1 pathways with increased IL-22 and IFNγ production, respectively. AD is a disease frequently associated with increased IgE production and overt allergies or asthma, most likely due to increased Th2 activation, which is largely lacking in psoriasis. Hence, psoriasis and AD can be viewed as distinct diseases with differing clinical, tissue, and molecular disease phenotypes, but this view does not account for specific subtypes of AD, including Asian-origin, intrinsic, and pediatric AD, that have a prominent IL-17 component and also tissue patterning that overlaps with distinctive psoriasis histopathology. Hence, when considering the range of AD phenotypes, a case can be made that psoriasis and AD exist across a spectrum where polar T-cell axes can be variably present and create some overlapping disease characteristics. Today, ∼90% of psoriasis patients have extremely controlled disease by targeting the IL-23/Th17 T-cell axis with IL-23 or IL-17-targeting antibodies. An outstanding question is whether targeting a single cytokine axis in AD, for example, Th2 axis, will lead to disease suppression in the majority of patients and across all subtypes, including those with higher IL-17 expression, or whether it is necessary to personalize therapies and target multiple T-cell axes to attain similar disease improvement to psoriasis. [ABSTRACT FROM AUTHOR]

Psoriasis vulgaris, affecting the skin, is one of the most common organ-specific autoimmune diseases in humans. Until recently, psoriasis was treated by agents or approaches discovered largely through serendipity. Many of the available drugs were inherently quite toxic when used as continuous treatment for many years in this chronic disease. However, an increasing understanding of disease-specific immune pathways has spurred development of pathway-targeted therapeutics during the past decade. Psoriasis is now the most effectively treated human autoimmune disease, with high-level clinical improvements possible in ∼90% of patients using a new generation of drugs that selectively target the IL-23/Type 17 T cell axis. Thus, psoriasis is a model for the success of a translational-medicine approach based on cellular and molecular dissection of disease pathogenesis in humans. [ABSTRACT FROM AUTHOR]

Alopecia areata ( AA) is a common inflammatory disease targeting the anagen-stage hair follicle. Different cytokines have been implicated in the disease profile, but their pathogenic role is not yet fully determined. We studied biopsies of pretreatment lesional and non-lesional ( NL) scalp and post-treatment (intra-lesional steroid injection) lesional scalp of 6 patchy patients with AA using immunohistochemistry and gene expression analysis. Immunohistochemistry showed increases in CD3+, CD8+ T cells, CD11c+ dendritic cells and CD1a+ Langerhans cells within and around hair follicles of pretreatment lesional scalp, which decreased upon treatment. qRT- PCR showed in pretreatment lesional scalp (compared to NL) significant increases ( P < 0.05) in expression of inflammatory markers ( IL-2, IL-2 RA, JAK3, IL-15), Th1 ( CXCL10 and CXCL9), Th2 ( IL-13, CCL17 and CCL18), IL-12/ IL-23p40 and IL-32. Among these, we observed significant downregulation with treatment in IL-12/ IL-23p40, CCL18 and IL-32. We also observed significant downregulation of several hair keratins in lesional scalp, with significant upregulation of KRT35, KRT75 and KRT86 in post-treatment lesional scalp. This study shows concurrent activation of Th1 and Th2 immune axes as well as IL-23 and IL-32 cytokine pathways in lesional AA scalp and defined a series of response biomarkers to corticosteroid injection. Clinical trials with selective antagonists coupled with cytokine-pathway biomarkers will be necessary to further dissect pathogenic immunity. [ABSTRACT FROM AUTHOR]

Scalp psoriasis shows a variable clinical spectrum and in many cases poses a great therapeutic challenge. However, it remains unknown whether the immune response of scalp psoriasis differs from understood pathomechanisms of psoriasis in other skin areas. We sought to determine the cellular and molecular phenotype of scalp psoriasis by performing a comparative analysis of scalp and skin using lesional and nonlesional samples from 20 Caucasian subjects with untreated moderate to severe psoriasis and significant scalp involvement and 10 control subjects without psoriasis. Our results suggest that even in the scalp, psoriasis is a disease of the inter-follicular skin. The immune mechanisms that mediate scalp psoriasis were found to be similar to those involved in skin psoriasis. However, the magnitude of dysregulation, number of differentially expressed genes, and enrichment of the psoriatic genomic fingerprint were more prominent in skin lesions. Furthermore, the scalp transcriptome showed increased modulation of several gene-sets, particularly those induced by interferon-gamma, compared with that of skin psoriasis, which was mainly associated with activation of TNFα/L-17/IL-22-induced keratinocyte response genes. We also detected differences in expression of gene-sets involving negative regulation, epigenetic regulation, epidermal differentiation, and dendritic cell or Th1/Th17/Th22-related T-cell processes. [ABSTRACT FROM AUTHOR]

Psoriasis, which presents as red, scaly patches on the body, is a common, autoimmune skin disease that affects 2 to 3 percent of the world population. To leverage recent molecular findings into the personalized treatment of psoriasis, we need a strategy that integrates clinical stratification with molecular phenotyping. In this study, we sought to stratify psoriasis patients by histological measurements of epidermal thickness, and to compare their molecular characterizations by gene expression, serum cytokines, and response to biologics. We obtained histological measures of epidermal thickness in a cohort of 609 psoriasis patients, and identified a mixture of two subpopulations—thick and thin plaque psoriasis—from which they were derived. This stratification was verified in a subcohort of 65 patients from a previously published study with significant differences in inflammatory cell infiltrates in the psoriatic skin. Thick and thin plaque psoriasis shared 84.8% of the meta-analysis-derived psoriasis transcriptome, but a stronger dysregulation of the meta-analysis-derived psoriasis transcriptome was seen in thick plaque psoriasis on microarray. RT-PCR revealed that gene expression in thick and thin plaque psoriasis was different not only within psoriatic lesional skin but also in peripheral non-lesional skin. Additionally, differences in circulating cytokines and their changes in response to biologic treatments were found between the two subgroups. All together, we were able to integrate histological stratification with molecular phenotyping as a way of exploring clinical phenotypes with different expression levels of the psoriasis transcriptome and circulating cytokines. [ABSTRACT FROM AUTHOR]

Background: IL-17 is the defining cytokine of the Th17, Tc17, and γδ T cell populations that plays a critical role in mediating inflammation and autoimmunity. Psoriasis vulgaris is an inflammatory skin disease mediated by Th1 and Th17 cytokines with relevant contributions of IFN-γ, TNF-α, and IL-17. Despite the pivotal role IL-17 plays in psoriasis, and in contrast to the other key mediators involved in the psoriasis cytokine cascade that are capable of inducing broad effects on keratinocytes, IL-17 was demonstrated to regulate the expression of a limited number of genes in monolayer keratinocytes cultured in vitro. Methodology/Principal Findings: Given the clinical efficacy of anti-IL-17 agents is associated with an impressive reduction in a large set of inflammatory genes, we sought a full-thickness skin model that more closely resemble in vivo epidermal architecture. Using a reconstructed human epidermis (RHE), IL-17 was able to upregulate 419 gene probes and downregulate 216 gene probes. As possible explanation for the increased gene induction in the RHE model is that C/CAAT-enhancer-binding proteins (C/EBP) -β, the transcription factor regulating IL-17-responsive genes, is expressed preferentially in differentiated keratinocytes. Conclusions/Significance: The genes identified in IL-17-treated RHE are likely relevant to the IL-17 effects in psoriasis, since ixekizumab (anti-IL-17A agent) strongly suppressed the “RHE” genes in psoriasis patients treated in vivo with this IL-17 antagonist. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) is a common disease with an increasing prevalence. The primary pathogenesis of the disease is still elusive, resulting in the lack of specific treatments. AD is currently considered a biphasic disease, with TH2 predominating in acute disease and a switch to TH1 characterizing chronic disease. Elucidation of the molecular factors that participate in the onset of new lesions and maintenance of chronic disease is critical for the development of targeted therapeutics. Objectives: We sought to characterize the mechanisms underlying the onset and maintenance of AD. Methods: We investigated intrapersonal sets of transcriptomes from nonlesional skin and acute and chronic lesions of 10 patients with AD through genomic, molecular, and cellular profiling. Results: Our study associated the onset of acute lesions with a striking increase in a subset of terminal differentiation proteins, specifically the cytokine-modulated S100A7, S100A8, and S100A9. Acute disease was also associated with significant increases in gene expression levels of major TH22 and TH2 cytokines and smaller increases in IL-17 levels. A lesser induction of TH1-associated genes was detected in acute disease, although some were significantly upregulated in chronic disease. Further significant intensification of major TH22 and TH2 cytokines was observed between acute and chronic lesions. Conclusions: Our data identified increased S100A7, S100A8, and S100A9 gene expression with AD initiation and concomitant activation of TH2 and TH22 cytokines. Our findings support a model of progressive activation of TH2 and TH22 immune axes from the acute to chronic phases, expanding the prevailing view of pathogenesis with important therapeutic implications. [Copyright &y& Elsevier]

Atopic dermatitis (AD) and psoriasis are among the most common inflammatory skin diseases. In the first part of this 2-part review, we discussed the similarities and differences between AD and psoriasis with respect to clinical features and pathology. The diseases are characterized by infiltration of skin lesions by large numbers of inflammatory cells; the second part of this review focuses on immune cell subsets that distinguish each disease and the therapeutic strategies that might be used or developed based on this information. We discuss the interactions among different populations of immune cells that ultimately create the complex inflammatory phenotype of AD and compare these with psoriasis. Therapeutic strategies have been developed for psoriasis based on the cytokine network that promotes inflammation in this disease. Antibodies against IL-12 and IL-23p40 antibody and antagonists of TNF are used to treat patients with psoriasis, and studies are underway to test specific antagonists of IL-23, IL-17, IL-17 receptor, IL-20, and IL-22. We discuss how these therapeutic approaches might be applied to AD. [ABSTRACT FROM AUTHOR]

Objective: To determine whether 312-nm UV-B alters production of effector and regulatory cytokines by viable T cells that remain in psoriatic lesions during UV-B phototherapy. Design: Prospective study. Setting: General clinical research center of The Rocke-feller University Hospital. Patients: Ten adult patients with moderate to severe psoriasis vulgaris that was difficult to manage were sequentially enrolled in our protocols, and biopsies were taken at various time points from resolving lesions. Intervention: Narrowband (312-nm) UV-B was given starting at 50% of a minimum erythema dose, then increased daily 10% to 15% if no apparent erythema was induced. Patients continued with treatment until maximal benefit was noted. In some experiments, T cells were irradiated ex vivo with standard TL-01 fluorescent bulbs (Philips Lighting Co, Somerset, NJ). Main Outcome Measures: Intracellular cytokine staining was done using flow cytometry to quantify numbers of cytokine-producing cells from epidermal and peripheral T cells. The production of messenger RNA for interleukin (IL) 12, interferon (IFN) γ, tumor necrosis factor α, IL-4, and IL-10 was measured by quantitative reverse transcription-polymerase chain reaction. Results: Ultraviolet-B treatment eliminated production of IL-12 messenger RNA and decreased production of IFN-γ messenger RNA by more than 60% in irradiated psoriasis lesions (P<.03 for both). Within 1 to 2 weeks of starting UV-B treatment, the frequency of viable T cells producing IFN-γ decreased 40% to 65%. In contrast, mRNA for IL-4 increased by 82% (P=.05) during UV-B treatment, and the number of IL-4-producing cells increased by 228% after 1 week of treatment. In vitro experiments established that, on the single-cell level, survival and cytokine production by type 1 T cells were differentially regulated by UV-B. Conclusions: Therapeutic UV-B suppresses the type 1 (proinflammatory) axis as defined by IL-12, IFN-γ,... [ABSTRACT FROM AUTHOR]

Psoriasis is characterized by epidermal hyperplasia, altered epidermal maturation, and local accumulation of acute and chronic inflammatory cells. Keratinocyte hyperplasia in psoriasis may be explained in part by overproduction of growth factors or cytokines which stimulate epidermal proliferation and by altered metabolism of growth-factor receptors in affected skin. Psoriatic epidermis displays overproduction of TGF-alpha and interleukin-6 (IL-6), factors produced by keratinocytes and other cell types in psoriatic skin. TGF-alpha and IL-6 are mitogens for normal human keratinocytes and act via specific receptors. The TGF-alpha receptor (EGF receptor) is overexpressed in psoriatic epithelium and its altered expression could be caused in part by gamma interferon which prevents normal receptor down-regulation in response to EGF binding. Several phenotypic features of the psoriatic keratinocyte, including growth activation and expression of HLA-DR, gamma-IP-10, ICAM-1, and other molecules, are best explained as resulting from the combined effects of TGF-alpha, IL-6, and gamma interferon (and possibly other cytokines) on epidermal keratinocytes. The multiple histologic features of psoriasis, including epidermal hyperplasia and accumulation of acute and chronic inflammatory cells, may be mediated by defined growth factors and cytokines that are produced in psoriatic skin and affect the function of diverse cell types. [ABSTRACT FROM AUTHOR]

The article offers information on a study related to psoriasis, an immune-mediated disease that affects the skin. As per the study, the psoriasis skin lesion contains homing T cells which are activated by cutaneous dendritic cells to produce inflammatory cytokines. The study further highlights that the disease is associated with increased risk of cardiovascular disease, obesity and diabetes.

Psoriasis vulgaris is a common inflammatory skin disease that involves infiltration of leukocytes, activation of skin-resident cells and increased production of numerous cytokines, chemokines and inflammatory molecules. This Review presents an integrated view of disease pathogenesis, taking into account immune biology, broad-scale genomic characterization and the response of psoriasis to immune-targeted therapies. Recent studies suggest that activated dendritic cells (DCs) and T cells are central to its pathogenesis, causing ‘inflammation’ through a pathway of sequential interleukin-23 (IL-23) synthesis, interferon-γ (IFN-γ) production, activation of STAT1 (signal transducer and activator of transcription 1) and subsequent transcription of a broad series of IFN- and STAT-1-regulated genes. In situ expression of macrophage inflammatory protein-3β (MIP-3β; CCL19), secondary lymphoid tissue chemokine (SLC; CCL21) and other chemokines normally confined to formal lymphoid tissues, might help to sustain DC accumulation and overall activation of this inflammatory pathway. [Copyright &y& Elsevier]

Diphencyprone (DPCP) is a hapten that induces delayed-type hypersensitivity (DTH) reactions. It is used as an immune-modulating therapeutic, but its molecular effects in human skin are largely unknown. We studied cellular and molecular characteristics of a recall response to 0.04% DPCP at 3-day (peak) and 14-day (resolution) time points using immune markers, reverse-transcriptase-PCR (RT-PCR), and gene array approaches. A peak response showed modulation of ∼7,500 mRNA transcripts, with high expression of cytokines that define all major effector T-cell subsets. Concomitant increases in T-cell and CD11c+ dendritic cell (DC) infiltrates were measured. The resolution reaction was characterized by unexpectedly high levels of T cells and mature (DC-lysosome-associated membrane glycoprotein positive (DC-LAMP+)) DCs, but with marked decreases in expression of IL-2, IFNγ, and other T cell-derived cytokines. However, negative immune regulators such as IDO1 that were high in peak reactions, continued to have high expression in resolution reactions. In the resolution reaction, ∼1,500 mRNA transcripts were significantly different from placebo-treated skin. These data suggest that the response to DPCP evolves from an inflammatory/effector peak at day 3 to a more regulated immune response after 14 days. This model system could be useful for further dissection of mechanisms of immune activation or negative immune regulation in human skin. [ABSTRACT FROM AUTHOR]

Inflammation-associated pigmentation changes are extremely common, but the etiology underlying this clinical observation remains elusive. Particularly, it is unclear how the myriad of cytokines known to be involved in inflammatory skin processes affect epidermal melanocytes. We sought to determine how IL-17 and tumor necrosis factor (TNF) influence normal human melanocytes, as these two cytokines have been implicated in various skin diseases. IL-17 and TNF jointly stimulated broad inductions of cytokines, including melanoma mitogens CXCL1 and IL-8. Moreover, IL-17 and TNF synergistically inhibited pigmentation-related signaling and melanin production, and induced keratinocyte production of β-defensin 3, an antagonist for melanocortin 1 receptor. When analyzing psoriasis lesions that are known to overexpress IL-17 and TNF, we observed an increase in melanocyte number and a simultaneous decrease in pigmentation signaling. Furthermore, therapeutic neutralization of TNF and IL-17 with mAbs resulted in a rapid recovery of pigment gene expression in psoriasis lesions. These results demonstrate that IL-17 and TNF can affect both the growth and pigment production of melanocytes, which may contribute to the pigmentation changes associated with psoriasis. These findings may allow the development of novel therapeutics for pigmentary disorders and bring new insights into the immune milieu surrounding melanocytes and related neoplasms. [ABSTRACT FROM AUTHOR]

Psoriasis is a complex inflammatory process resulting from activation of the well-defined interleukin (IL)-23/T17 cytokine axis. We review the role of key cytokines IL-17 and IL-23 in psoriasis, as well as tumor necrosis factor (TNF)α, focusing on therapeutic cytokine interventions and what they reveal about psoriatic inflammation. The potential role of recently described epidermal IL-36RN and CARD14 genetic mutations in psoriasis pathogenesis is also explored, because they augment keratinocyte responses to proinflammatory cytokines. The discovery of these genetic mutations in familial and pustular psoriasis suggests new links between cytokine-induced gene products and IL-1 family members from keratinocytes, which may regulate features of the disease, including epidermal hyperplasia and neutrophil infiltrating responses. [ABSTRACT FROM AUTHOR]

Although the histological changes seen in psoriasis have long been well characterized, the underlying cellular and molecular mechanisms have only begun to be elucidated over the past 20 years. Proinflammatory factors such as tumor necrosis factor (TNF)-α have a central role in psoriasis pathogenesis, and many T-helper 1 (Th1) cytokines and messenger RNAs are elevated in psoriatic lesions. IL-17A, IL-17F, and other Th17 cell-derived cytokines have been shown in murine models to induce features that mimic human psoriasis. This review focuses on the emerging biology of the IL-17 cytokine family in psoriasis, and on the molecular and genetic information gained from animal models and human clinical studies that confirm IL-17 as a crucial proinflammatory cytokine in psoriasis. Expression of IL-17A, IL-17C, and IL-17F is strikingly increased in psoriatic lesions, and successful therapy is associated with restoration of the expression of a wide range of genes (including effector molecules downstream of IL-17 such as cytokines, chemokines, and antimicrobial peptides) to near-normal levels. Therapeutic agents in development that target IL-17 are discussed, and an emerging model of the key role of IL-17 in the pathogenesis of psoriasis is presented. [ABSTRACT FROM AUTHOR]

Psoriasis is a complex inflammatory disease mediated by tumor necrosis factor (TNF)-α and cytokines secreted by specialized T-cell populations, e.g., IL-17, IL-22, and IFN-γ. The mechanisms by which innate and adaptive immune cytokines regulate inflammation in psoriasis are not completely understood. We sought to investigate the effects of TNF-α and IL-17 on keratinocyte (KC) gene profile, to identify genes that might be coregulated by these cytokines and determine how synergistically activated genes relate to the psoriasis transcriptome. Primary KCs were stimulated with IL-17 or TNF-α alone, or in combination. KC responses were assessed by gene array analysis, followed by reverse transcriptase-PCR confirmation for significant genes. We identified 160 genes that were synergistically upregulated by IL-17 and TNF-α, and 196 genes in which the two cytokines had at least an additive effect. Synergistically upregulated genes included some of the highest expressed genes in psoriatic skin with an impressive correlation between IL-17/TNF-α-induced genes and the psoriasis gene signature. KCs may be key drivers of pathogenic inflammation in psoriasis through integrating responses to TNF-α and IL-17. Our data predict that psoriasis therapy with either TNF or IL-17 antagonists will produce greater modulation of the synergistic/additive gene set, which consists of the most highly expressed genes in psoriasis skin lesions. [ABSTRACT FROM AUTHOR]

Psoriasis is now classified as an immune-mediated inflammatory disease (IMID) of the skin. It is being recognized that patients with various IMIDs, including psoriasis, are at higher risk of developing “systemic” co-morbidities, e.g., cardiovascular disease (CVD), metabolic syndrome, and overt diabetes. In non-psoriatic individuals, the pathophysiology of obesity, aberrant adipocyte metabolism, diabetes, and CVDs involves immune-mediated or inflammatory pathways. IMIDs may impact these co-morbid conditions through shared genetic risks, common environmental factors, or common inflammatory pathways that are co-expressed in IMIDs and target organs. Given that pathogenic immune pathways in psoriasis are now well worked out and a large number of inflammatory mediators have been identified in skin lesions, in this review we will consider possible mechanistic links between skin inflammation and increased risks of (1) obesity or metabolic alterations and (2) CVD. In particular, we will discuss how well-established risk factors for CVD can originate from inflammation in other tissues. [ABSTRACT FROM AUTHOR]

Myeloid dermal dendritic cells (DCs) accumulate in chronically inflamed tissues such as psoriasis. The importance of these cells for psoriasis pathogenesis is suggested by comparative T-cell and DC-cell counts, where DCs outnumber T cells. We have previously identified CD11c+-blood dendritic cell antigen (BDCA)-1+ cells as the main resident dermal DC population found in normal skin. We now show that psoriatic lesional skin has two populations of dermal DCs: (1) CD11c+BDCA-1+ cells, which are phenotypically similar to those contained in normal skin and (2) CD11c+BDCA-1− cells, which are phenotypically immature and produce inflammatory cytokines. Although BDCA-1+ DCs are not increased in number in psoriatic lesional skin compared with normal skin, BDCA-1− DCs are increased 30-fold. For functional studies, we FACS-sorted psoriatic dermal single-cell suspensions to isolate these two cutaneous DC populations, and cultured them as stimulators in an allogeneic mixed leukocyte reaction. Both BDCA-1+ and BDCA-1− myeloid dermal DC populations induced T-cell proliferation, and polarized T cells to become T helper 1 (Th1) and T helper 17 (Th17) cells. In addition, psoriatic dermal DCs induced a population of activated T cells that simultaneously produced IL-17 and IFN-γ, which was not induced by normal skin dermal DCs. As psoriasis is believed to be a mixed Th17/Th1 disease, it is possible that induction of these IL-17+IFN-γ+ cells is pathogenic. These cytokines, the T cells that produce them, and the inducing inflammatory DCs may all be important new therapeutic targets in psoriasis.Journal of Investigative Dermatology (2009) 129, 79–88; doi:10.1038/jid.2008.194; published online 17 July 2008 [ABSTRACT FROM AUTHOR]

We assessed expression of IL-20 and its receptors in psoriasis, given the recent implication of IL-20 in epidermal hyperplasia. Psoriatic lesional (LS) skin consistently expressed more IL-20 mRNA than nonlesional (NL) skin. Immunoreactivity to IL-20 protein was greater in LS tissue and mainly localized to infiltrating CD68+/CD11c+ (myeloid-derived) dermal leukocytes. Because this contrasted with earlier reports of a keratinocyte source, we assessed IL-20 mRNA expression in a variety of cells in vitro, and confirmed a myeloid-derived cellular source (monocytes). Plastic adhesion, activation of β2 integrins, and incubation with tumor necrosis factor-α stimulated expression in these cells. IL-20 receptor (IL-20R)α and IL-20Rβ mRNA was decreased in LS versus NL skin, which also contrasted with earlier findings. To investigate the relationship between IL-20 and disease activity, we examined psoriasis patients treated with the CD2-targeted agent alefacept. In therapeutic responders, lesional IL-20 mRNA decreased to NL levels, suggesting that CD2+ leukocytes may proximally regulate IL-20. Finally, to assess IL-20 function, we used microarrays to screen IL-20-treated keratinocytes, which demonstrated upregulation of disease-related and IFN-γ-induced genes. Hence, IL-20 may influence inflammation through IFN-like effects. Together, these data indicate that IL-20 may be an important effector cytokine in psoriasis, and that its inhibition may represent a potential therapeutic target.Journal of Investigative Dermatology (2006) 126, 1590–1599. doi:10.1038/sj.jid.5700310; published online 27 April 2006 [ABSTRACT FROM AUTHOR]

Psoriasis vulgaris is a skin disease potentially mediated by pro-inflammatory cytokines produced by type 1 lesional T cells. The capability of individual T cells to produce these cytokines in lesional skin is not known. In this study we measured the ability of lesional and peripheral blood T cells to produce intracellular interferon-γ, tumor necrosis factor-α, interleukin-2, interleukin-4, and interleukin-10 proteins as detected by flow cytometric analysis. Cytokine synthesis was induced by activation with ionomycin/phorbol myristate acetate (in the presence of Brefeldin A, which inhibits the exocytosis of these cytokines). After stimulation, we found relatively high percentages of epidermal CD8 and CD4 T cells capable of producing interferon-γ, tumor necrosis factor-α, and interleukin-2, whereas few T cells, < 11%, expressed interleukin-4 or interleukin-10. Hence both CD8[sup +] and CD4[sup +] T cells are capable of type 1 effector functions (TC1 and TH1, respectively). This activation scheme was repeated on peripheral blood T cells from psoriatic patients versus healthy controls, where we also found a type 1 bias. In order to evaluate quantitatively the type 1 cytokine bias, we compared the frequency of type 2 interleukin-4 producing versus type 1 interferon-γ producing T cells in our assay and found a shift towards type 1 producing cells. This shift reveals a type 1 differentiation bias in both lesional areas and in the peripheral blood, which may indicate an imbalance within the T cell population, which is contributing to the chronic or sustained immunologic activation of T cells found in this disease. [ABSTRACT FROM AUTHOR]