Psoriasis is an autoimmune-related chronic inflammatory skin disease that is strongly associated with IL-23 and T helper-17 (Th17) effector cytokines. In addition, CD4+CD25(high) regulatory T-cell (Treg) function appeared to be impaired in psoriasis. CD4+CD25(high)Foxp3+ Tregs are typically considered inhibitors of autoimmune responses. However, under proinflammatory conditions, Tregs can differentiate into inflammation-associated Th17 cells--a paradigm shift, with as yet largely unknown consequences for human disease initiation or progression. Th17 cells are highly proinflammatory T cells that are characterized by IL-17A and IL-22 production and expression of the transcription factor retinoic acid-related orphan receptor γt (RORγt). We here show that Tregs of patients with severe psoriasis, as compared with those of healthy controls, have an enhanced propensity to differentiate into IL-17A-producing cells on ex vivo stimulation. This enhanced Treg differentiation was linked to unexpectedly high RORγt levels and enhanced loss of Foxp3. Notably, IL-23 boosted this Treg differentiation process particularly in patients with psoriasis but less so in controls. IL-23 further reduced Foxp3 expression while leaving the high RORγt levels unaffected. The histone/protein deacetylase inhibitor, Trichostatin-A, prevented Th17 differentiation of Tregs in psoriasis patients. Importantly, IL-17A+/Foxp3+/CD4+ triple-positive cells were present in skin lesions of patients with severe psoriasis. These data stress the clinical relevance of Treg differentiation for the perpetuation of chronic inflammatory disease and may pave novel ways for immunotherapy.

Despite sensitive skin being highly prevalent, no consensus on the definition and pathomechanism of sensitive skin exists. Here we report the results of a systematic literature review of diagnostic methods for sensitive skin at clinical, histological and biophysical levels. A systematic search revealed 27 out of 1,701 articles which we appraised in detail. Impaired skin barrier function and increased vascular reactivity are most often associated with sensitive skin. We identified key reasons causing an ambiguity around the sensitive skin phenomenon. We propose using standardized selection methods of subjects by a multifactorial questionnaire spanning a range of provocations, including those of chemical, mechanical and environmental origin, followed by clinical, histological and top-notch biophysical measurements. This could lead to a breakthrough in the understanding of the sensitive skin phenomenon, fueling advances of biomedical and dermatological science. © 2014 S. Karger AG, Basel

Skin-derived antileukoproteinase (SKALP), also known as elafin, is a serine proteinase inhibitor first discovered in keratinocytes from hyperproliferative human epidermis. In addition to the proteinase inhibiting domain which is directed against polymorphonuclear leukocyte (PMN) derived enzymes such as elastase and proteinase 3, SKALP contains multiple transglutaminase (TGase) substrate domains which enable crosslinking to extracellular and cell envelope proteins. Here we show that SKALP is constitutively expressed in several epithelia that are continuously subjected to inflammatory stimuli, such as the oral cavity and the vagina where it co-localizes with type 1 TGase. All epithelia from sterile body cavities are negative for SKALP. In general, stratified squamous epithelia are positive, whereas pseudostratified epithelia, simple/glandular epithelia and normal epidermis are negative. SKALP was found in fetal tissues of the oral cavity from 17 wk gestation onwards where it continued to be expressed up to adult life. Remarkably, in fetal epidermis SKALP was found from week 28 onwards, but was downregulated to undetectable levels in neonatal skin within three months, suggesting a role during pregnancy in feto-maternal interactions or in the early maturation phase of the epidermis. Immunoelectron microscopy revealed the presence of SKALP in secretory vesicles including the lamellar granules. In culture models for epidermal keratinocytes we found that expression of the endogenous SKALP gene provided protection against cell detachment caused by purified elastase or activated PMNs. Addition of exogenous recombinant SKALP fully protected the keratinocytes against PMN-dependent detachment whereas superoxide dismutase and catalase were only marginally effective. These findings strongly suggest that

CD8+, CD45RO+, CD2+ and CD25+ T cells have a role in the early phase of the psoriatic process, whereas CD94- and CD161-expressing cells together with epidermal proliferation and keratinization are involved in a later phase.

The response rates of photodynamic therapy (PDT) vary widely. Limited uptake of topically applied 5-aminolaevulinic acid (ALA), or its methyl ester (MAL), and suboptimal production of protoporphyrin IX (PpIX) may account for these differences. Recently, we demonstrated that hyperkeratosis is an important negative factor in ALA uptake. This review has its focus on pretreatment of the skin in order to improve the clinical outcome of ALA/MAL PDT. Pretreatment of hyperkeratosis can be achieved with keratolytics, curettage/debulking, tape stripping, microdermabrasion or laser ablation. Penetration enhancers may alter the composition or organization of the intercellular lipids of the stratum corneum. Several studies have been performed on the use of dimethyl sulfoxide, azone, glycolic acid, oleic acid and iontophoresis to increase the penetration of ALA. As PpIX production is also dominated by temperature-dependent processes, elevating skin temperature during ALA application may also improve treatment results. Another approach is the use of additives that interact with the heme biosynthetic pathway, e.g. by removing ferrous iron with iron-chelating substances such as: ethylenediaminetetraacetic acid; 3-hydroxypyridin-4-ones; 1,2-diethyl-3-hydroxypyridin-4-one-hydrochloride; and desferrioxamine. In conclusion, simple pretreatments or additions to the regular practice of PDT, aimed to optimize intralesional PpIX content, improve the clinical outcome.

Psoriasis is a common chronic inflammatory skin disease that results from interplay between the immune system and the epithelium. In the light of very successful anticytokine therapies for psoriasis, the focus has been directed towards the adaptive immune system. Expression studies, genetic studies and treatments specifically targeting players of the IL-23/IL-17 pathway, point at an important role for IL-17 in the pathogenesis of psoriasis. IL-17 stimulates the keratinocytes to produce psoriasis-associated molecules, eventually leading to chronic skin inflammation. The current opinion is that IL-17 is mainly produced by T cells, so-called T-helper 17 (Th17) cells, in psoriasis. However, evidence is accumulating that cells of the innate immune system, like neutrophils, mast cells, cd T cells and innate lymphoid cells are the main source of IL-17 in psoriasis, rather than T cells. The paradigm in this field of research is shifting. With this viewpoint article, we will address this novel concept by critically summarizing the current literature on this subject. In psoriatic arthritis and atherosclerosis, important conditions related to psoriasis, it was also found that the majority of IL-17 is associated with cells of the innate immune system. This new concept changes our view of IL-17. Blocking IL-17 with targeted treatments might be more far-reaching than previously thought; not only IL-17 production by T cells but also by innate immune cells is blocked. Furthermore, therapies specifically targeting IL-17 may not only improve psoriasis, but also comorbidity that is associated with the IL-17 pathway, hereby preventing serious complications on the long term.

Clinical trials successfully using antibodies targeting IL-17 in psoriasis support the importance of IL-17 in the pathophysiology of this disease. However, there is a debate concerning the source and dynamics of IL-17 production in inflamed skin. Here we characterized IL-17-producing immune cells over time, using two established in vivo models of human skin inflammation that share many histological features with psoriasis, i.e., leukotriene B4 application and tape-stripping. Both treatments revealed a clear influx of neutrophils and T cells. Staining for IL-17 revealed that the majority of IL-17 was expressed by neutrophils and mast cells, in both models. Neutrophils, but not mast cells, coexpressed the IL-17-associated transcription factor RORγt and were able to form extracellular traps. While the presence of mast cells remained steady during the skin inflammatory process, the presence of neutrophils was clearly dynamic in time. Therefore, it is attractive to hypothesize that IL-17+/RORγt+ neutrophils contribute to human skin inflammation in vivo and possibly to the pathogenesis of skin diseases such as psoriasis. Surprisingly, T cells represented a minority of the IL-17-expressing cell population. These observations challenge the classical opinion that IL-17 is predominantly associated with T cells in skin inflammation.

Background: Reflectance confocal microscopy (RCM) is a noninvasive imaging technique. Currently, RCM is mainly used for the diagnosis of melanoma and nonmelanoma skin cancer including basal cell carcinoma (BCC). Until now, it has not been possible to distinguish between subtypes of BCC using RCM. Objective: To establish the RCM features for subtypes of BCC. Methods: 57 lesions were selected for RCM imaging. Clinical and dermatoscopic pictures were taken and a 3-mm biopsy was obtained. Results: It was demonstrated that tumor nests with peripheral palisading, branch-like structures, fibrotic septa and increase in vascular diameter were characteristic RCM features for nodular and micronodular BCC. The size and shape of the tumor nests allowed further distinction between these BCCs. Solar elastosis and tumor nests connected with the basal cell layer characterize superficial BCC. Conclusion: This study presents RCM features for BCC, which might allow in vivo diagnosis of the nodular, micronodular and superficial subtype of BCC. This could prevent a skin biopsy, resulting in direct proper treatment. Further, RCM allows to evaluate the total lesion, which makes it possible to detect mixed-type BCCs.