SUMMARYAtopic eczema (AE) is characterized by the persistence of infiltrating T lymphocytes in the dermis. To test the hypothesis that dysregulation of normal T cell apoptosis may contribute to the pathogenesis and chronicity of AE we compared patients with a normal resolving immune response (Mantoux reaction (MR)) induced in healthy volunteers by cutaneous PPD injection. Significantly less T cell apoptosis was observed in lesional skin of AE patients compared with either the peak or the resolution phase of the MR (P , 0´0001). The low incidence of T cell apoptosis in AE was associated with significantly increased levels of Bcl-2 relative to Bax (P , 0´0001) and significantly decreased CD95-L expression (P , 0´002) compared with the resolving MR. The cytokines IL-15 and interferon-beta (IFN-b ), which prevent activated T cell apoptosis, were expressed maximally on day 7 and day 14 of the MR, respectively. In contrast, AE patients expressed high levels of both IL-15 and IFN-b in cutaneous lesions at the same time. This suggests that the co-expression of two anti-apoptotic cytokines, which are not found together during resolving cutaneous responses, may contribute to excessive T cell survival which leads to the persistence of inflammation in patients with AE.

The human skin confers biophysical and immunological protection through a complex cellular network that is established early in development. We profiled ~500,000 single cells using RNA-sequencing from healthy adult and developing skin, and skin from patients with atopic dermatitis and psoriasis. Our findings reveal a predominance of innate lymphoid cells and macrophages in developing skin in contrast to T cells and migratory dendritic cells in adult skin. We demonstrate dual keratinocyte differentiation trajectories and activated cellular circuits comprising vascular endothelial cells mediating immune cell trafficking, disease specific clonally expanded IL13/IL22 and IL17A/F-expressing lymphocytes, epidermal IL23-expressing dendritic cells and inflammatory keratinocytes in disease. Our findings provide key insights into the dynamic cellular landscape of human skin in health and disease.

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Cutaneous sarcoidosis is rare in children. We report a case of a 5-year-old Bangladeshi girl who presented with fever, a papular eruption on the lower limbs and trunk, malaise, anorexia and weight loss. There was multisystem involvement with marked hepatosplenomegaly, generalized lymphadenopathy, parotid fullness and chronic uveitis. Pulmonary infiltrates were seen on the chest X-ray. Histology of a skin biopsy showed naked noncaseating granulomata and PCR for Mycobacterium tuberculosis was negative. A clinical diagnosis of sarcoidosis was made. The patient was treated with oral prednisolone (2 mg/kg per day). An excellent clinical response with resolution of the rash and improvement of extracutaneous signs was noted within 3 months and she remains well on low-dose prednisolone on alternate days. We discuss the presentation and management of sarcoidosis in children, and highlight the potential difficulty in differentiating this from disseminated tuberculosis.

Human Cell Atlas is an international initiative aiming at creating a comprehensive map of all cells in the human body. This project contributes to Skin Atlas in attempt to resolve the population of interfollicular epidermal stem cells (IFE SCs), previously described as homogeneous. These cells are located in the basal layer of the epidermis, which is distinguished by expression of a6 integrin. We used this marker to enrich keratinocytes from human skin for basal cells and perform single-cell RNA sequencing. We found three transcriptionally distinct populations of basal keratinocytes. Two of them showed classic stem cell signature (KRT5, KRT14). The differences between these stem cells were driven by genes associated with immunomodulatory function (CCL2, CXCL14). We compared our results to large published datasets with lower gene coverage and found correlation between keratinocyte heterogeneity and our genes of interest. The third population of basal keratinocytes was enriched in markers of early stem cell commitment (KRT10). The three groups formed a continuous trajectory after pseudotime reconstruction, reflecting IFE SCs differentiation. We used the same approach to address IFE SCs changes in psoriasis, an auto-immune disease with prominent keratinocyte hyperproliferation. We found that basal cells from psoriatic epidermis also have two stem cell sub-populations and one group with early commitment signature. We identified sub-populations of stem cells that are specific to healthy and disease skin and found non-linear pseudotime trajectory of basal cells in psoriasis, suggesting a stem cell state switch in disease. To address this further, we are expanding the study to compare keratinocytes from lesional and non-lesional sites of psoriatic skin. This will provide insight into stem cell role in psoriasis and contribute to the Skin Atlas generation.

Summary Arrhythmogenic Cardiomyopathy (AC) is a relatively rare inherited disorder of the heart muscle and can lead to sudden death in patients, often under 35 years of age. AC can be very difficult for doctors to diagnose because the initial symptoms are often subtle so they can go unnoticed. In a rare form of AC, affected patients also have striking curly hair and abnormally thickened skin on the palms and soles. This can make the diagnosis easier to make. This study, from London, UK, looked at families with a more common form of AC caused by mutations in desmoplakin, a protein which acts as a “glue” between cells in both the heart and skin. We show that the majority of family members with AC had curly hair, and a significant proportion of these patients also had the condition causing thickening of the skin. Skin biopsies from patients with AC revealed abnormalities in several proteins responsible for connecting cells to one another, these proteins are also critical in the heart for conducting impulses throughout the heart muscle and signalling contraction. Early diagnosis and family screening are the key goals in the management of AC. This study has identified two novel features in AC caused by desmoplakin mutation, the first is the presence of curly hair and the skin condition in the majority of affected family members. The second is the identification of abnormalities in several proteins in skin biopsies taken from patients with AC. Examination of the skin and hair could therefore provide a unique window of opportunity to facilitate the prompt diagnosis of AC.

To identify the function of TRPV1 in the progression of melanoma and investigate the underlying mechanism. Immunofluorescence, qRT-PCR and Western Blot were performed to detect the expression of TRPV1 in tissue samples of melanocytic nevus, primary melanoma, metastatic melanoma as well as in melanoma cell lines. In addition, using CCK8 assay, Edu and flow cytometry, we identified the effect of TRPV1-specific agonist, capsaicin, on the proliferation and apoptosis of melanoma cells. To identify the molecular mechanism by which TRPV1 regulates the progression of melanoma, we performed western blot assay to detect the expression of p53, PARP, Bcl2, Bax in TRPV-1 activated melanoma cells exposed to Calcinerin blocker FK506. TRPV1 expression was decreased in melanoma cell lines compared with normal melanocytes (P <0.01). Tissue TRPV1 level was drastically reduced in primary and metastatic melanoma compared with melanocytic nevus (P <0.01). Furthermore, TRPV1-specific agonist capsaicin suppressed the proliferation by inhibiting ERK signaling (P <0.05). Notably, TRPV1 activation induced the apoptosis of melanoma cells by activation of Ca 2+ /calcineurin-NFAT-ATF3 pathway, and resulting the elevated expression of p53 (P <0.01). TRPV1 was significantly down-regulated in melanoma, activated TRPV1 suppressed the progression of melanoma via ERK pathway and promote the apoptosis by activating calcineurin. Taken together, TRPV1 acts as a crucial repressor in melanoma progression and can be a promising target in melanoma treatment.

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