Dust mite induces multiple polar T cell axes in human skin.

BACKGROUND: House dust mite/HDM atopy patch test/APT elicits positive reactions in a high fraction of atopic dermatitis/AD and healthy individuals. Experimental systems for new-onset/chronic AD are needed to support rapid therapeutic development, particularly since animal models representing human AD are lacking. While HDM APT has been considered to simulate AD, its suitability to model AD's emerging Th2/Th22 phenotype with Th1 and Th17 components is unknown. OBJECTIVE: To assess whether HDM APT reproduces AD. METHODS: Positive HDM APTs (n = 15) from patients with and without AD were evaluated, using genomic and immunohistochemistry studies, against intrapersonal control skin. RESULTS: APT lesions showed higher T cell and dendritic cell infiltrates vs. CONTROLS: Seven hundred and forty-three up- and 326 downregulated genes were differentially expressed in HDM APT (fold change >2 and false discovery rate < 0.05), with increased expression of Th2, Th9, Th17/Th22 polar cytokines (i.e. IL-5, IL-13, IL-9, IL-17, IL-22). CONCLUSION: While HDM caused significant Th2 skewing, it also illustrated differences in Th2 induction and barrier defects; thus, HDM APT does not fully simulate AD. Given its widespread availability and sensitization rates, HDM may potentially be a useful tool that represents select aspects of AD, psoriasis, or contact dermatitis.

Identification of unique proteomic signatures in allergic and non-allergic skin disease.

BACKGROUND: Atopic dermatitis (AD), psoriasis (PS), and contact dermatitis (CD) are common skin diseases, characterized by barrier disruption and systemic inflammation, with unique epidermal signatures and common inflammatory pathways identified by transcriptomic profiling. This study profiled proteomic signatures in serum from subjects with AD, PS, and CD compared with healthy controls (HC). OBJECTIVE: Identify unique proteomic signatures to distinguish between inflammatory diseases with similar epidermal disruption and overlapping epithelial inflammation. METHODS: Sera from 20 subjects with moderate to severe AD, 10 subjects with CD, 12 subjects with moderate to severe PS, 10 subjects with both AD and CD, and 10 HC with no history of skin disease was analysed using high-throughput proteomic analysis that detects expression of 1129 protein targets. Protein expression was compared between disease and HC, and across diseases for statistical significance (fold change≥1.5 and false discovery rate≤0.05), to identify unique proteomic signatures for each disease. RESULTS: Complement C5A anaphylatoxin (C5A), lipopolysaccharide binding protein (LBP), C-reactive protein (CRP), ILT-4, C-C motif ligand 18 (PARC), and sialic acid-binding Ig-like lectin 14 (SIG14) were significantly modulated in all three diseases compared with HC. We identified unique signatures for AD (Immunoglobulin E (IgE), thymus- and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC)), CD (10 proteins), and PS (kynureninase (KYNU)). Proteomic profiling in subjects with both AD and CD identified additional dysregulated proteins compared with subjects with either condition alone, indicating an exacerbated inflammation reaction. CONCLUSIONS AND CLINICAL RELEVANCE: Unique sera proteomic signatures may distinguish between inflammatory skin diseases despite similar epidermal barrier disruption and epithelial inflammation. This may provide insight into disease pathogenesis, diagnosis, and therapeutic intervention in difficult-to-treat subjects.

Increased expression of interleukin-17 pathway genes in nonlesional skin of moderate-to-severe psoriasis vulgaris.

BACKGROUND: Psoriasis vulgaris is an inflammatory immune-mediated disease, with lesional skin characterized by sharply demarcated, erythematous scaly plaques. Uninvolved psoriatic skin appears clinically similar to normal skin. However, it has been hypothesized that inflammatory cytokines, e.g. interleukin (IL)-17, may affect any organ or tissue having a vascular supply; thus, distant uninvolved skin could be exposed to increased circulating IL-17. OBJECTIVES: To establish comparative genomic profiles between noninvolved skin and normal skin, in particular, determining immune abnormalities in distant uninvolved skin. METHODS: We performed a meta-analysis on three gene array studies, comparing the nonlesional (NL) psoriatic skin transcriptome with normal gene expression. We investigated immunological features of noninvolved skin, particularly linked to IL-17 signalling. RESULTS: We detected 252 differentially expressed gene transcripts in uninvolved skin compared with normal skin; multiple immune-related genes, including IL-17-downstream genes, were upregulated. Increased expression of IL-17-signature genes (e.g. DEFB4 and S100A7) was associated with an increased number of CD3+, CD8+ and DC-LAMP+ cells in NL skin vs. normal controls. Inducible T-cell costimulator (ICOS) expression was detected only in a few T-cells within NL skin. CONCLUSIONS: Our data described the genomic profile in NL skin, characterizing the immune activation that was mainly attributed to IL-17 signalling.

The mechanistic basis for psoriasis immunopathogenesis: translating genotype to phenotype. Report of a workshop, Venice, 2012.

The International Psoriasis Council, a global nonprofit organization dedicated to advancing psoriasis research and treatment, led an initiative to better define the pathogenic mechanisms that constitute psoriasis. In September 2012, a workshop was held at the 42nd Annual European Society for Dermatological Research in Venice, Italy. By assembling a panel of global dermatology and immunology experts, the objective was to evaluate the current status of the science explaining the mechanism of disease in psoriasis, e.g. dysregulation of the skin immune system and perturbations of epidermal homeostasis. The workshop consisted of four oral presentations, which addressed key topics in psoriasis, delivered by Hervé Bachelez (Paris, France), Antonio Costanzo (Rome, Italy), Michelle Lowes (New York, NY, U.S.A.) and Frank Nestle (London, U.K.). A global expert panel was assembled to stimulate dialogue and debate: Kevin Cooper (Cleveland, OH, U.S.A.), Michel Gilliet (Lausanne, Switzerland), Joerg Prinz (Munich, Germany), Martin Röcken (Tubingen, Germany), Jens Schroeder (Kiel, Germany), Manuelle Viguier (Paris, France), Mayte Suárez-Fariñas (New York, NY, U.S.A.) and Cristina Zielinski (Berlin, Germany). Collectively, the presentations demonstrated the significant advances in understanding immune regulation that have occurred over the past decade by virtue of the study of psoriasis subtypes, phenotypic manifestations and genetic associations. Elucidating the pathogenic and genetic basis of psoriasis holds the promise of a complete understanding of disease mechanisms, predictors of treatment response, novel drug development strategies and customized therapeutic regimens for the individual patient.

Erectile Dysfunction Is Highly Prevalent in Men With Newly Diagnosed Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Cross-sectional studies on sexual function in men with inflammatory bowel disease (IBD) yield mixed results. Using a prospective incidence cohort, we aimed to describe sexual function at baseline and over time and to identify factors associated with impaired sexual function in men with IBD. METHODS: Men 18 years and older enrolled between April 2008 and January 2013 in the Ocean State Crohn's and Colitis Area Registry (OSCCAR) with a minimum of 2 years of follow-up were eligible for study. Male sexual function was assessed using the International Index of Erectile Function (IIEF), a self-administered questionnaire that assesses 5 dimensions of sexual function over the most recent 4 weeks. To assess changes in the IIEF per various demographic and clinical factors, linear mixed effects models were used. RESULTS: Sixty-nine of 82 eligible men (84%) completed the questionnaire (41 Crohn's disease, 28 ulcerative colitis). The mean age (SD) of the cohort at diagnosis was 43.4 (19.2) years. At baseline, 39% of men had global sexual dysfunction, and 94% had erectile dysfunction. Independent factors associated with erectile dysfunction are older age and lower physical and mental component summary scores on the Short Form Health Survey (SF-36). CONCLUSION: In an incident cohort of IBD patients, most men had erectile dysfunction. Physicians should be aware of the high prevalence of erectile dysfunction and its associated risk factors among men with newly diagnosed IBD to direct multidisciplinary treatment planning.

Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways.

BACKGROUND: Psoriasis vulgaris is an inflammatory skin disease mediated by Th1 and Th17 cytokines, yet the relative contribution of interferon (IFN)-gamma, interleukin (IL)-17 and IL-22 on disease pathogenesis is still unknown. OBJECTIVES: In this study, we sought to identify the cytokines produced by skin-resident T cells in normal skin, localize the receptors for these cytokines, and examine how these cytokines alter gene expression profiles of the cells bearing cognate receptors. METHODS: We used intracellular cytokine staining and flow cytometry to evaluate T cell cytokine production, and immunohistochemistry and double-label immunofluorescence to localize cytokine receptors in skin. Gene array analysis of cytokine-treated keratinocytes was performed using moderated paired t-test controlling for false discovery rate using the Benjamini-Hochberg procedure. RESULTS: We demonstrate that T-helper cells producing IL-17, IL-22 and/or IFN-gamma, as well as the cells bearing cognate cytokine receptors, are present in normal human skin. Keratinocytes stimulated with IL-17 expressed chemokines that were different from those induced by IFN-gamma, probably contributing to the influx of neutrophils, dendritic cells and memory T cells into the psoriatic lesion. In contrast, IL-22 downregulated genes associated with keratinocyte differentiation and caused epidermal alterations in an organotypic skin model. CONCLUSIONS: Our results suggest that the Th17 cytokines IL-17 and IL-22 mediate distinct downstream pathways that contribute to the psoriatic phenotype: IL-17 is more proinflammatory, while IL-22 retards keratinocyte differentiation.