COVID-19 and cutaneous manifestations: a systematic review.

The cutaneous manifestations of COVID-19 patients have been increasingly reported, but not summarized, and the potential mechanisms remain to be investigated. Herein, we performed a comprehensive review of literatures (from inception to 30 May 2020) using PubMed, CNKI, medRxiv and bioRxiv with the terms "((novel coronavirus) OR (2019 novel coronavirus) OR (2019-nCoV) OR (Coronavirus disease 2019) OR (COVID-19) OR (SARS-CoV-2)) AND ((Dermatology) OR (skin) OR (rash) OR (cutaneous))" and "((ACE2) OR (Angiotensin-converting enzyme)) AND ((skin) OR (epidermis) OR (dermis))." Totally, 44 articles met the inclusion criteria. A total of 507 patients with cutaneous manifestations were summarized, and 96.25% patients were from Europe. The average age of the patients was 49.03 (range: 5-91) with a female ratio of 60.44%. The skin lesions were polymorphic, and erythema, chilblain-like and urticarial lesions were most common, occurring on an average of 9.92 days (range: 1-30) after the onset of systemic symptoms. The receptor of SARS-CoV-2, ACE2, was found to be expressed on skin, mainly on keratinocytes. Our review systematically presented the clinical characteristics of 507 patients and showed that skin might be the potential target of the infection according to ACE2 expression. More work should be done to better understand the underlying pathogenesis.

Senescent fibroblasts and innate immune cell activation might play a role in the pathogenesis of elderly atopic dermatitis.

BACKGROUND: Elderly atopic dermatitis (AD) is a subtype of AD defined by age (≥ 60 years). The molecular characteristics of elderly AD remain to be clarified. OBJECTIVE: We sought to characterize the molecular features of skin lesions and peripheral blood mononuclear cells (PBMCs) in patients with AD across different age, focusing on elderly AD. METHODS: Skin and PBMCs samples were used for RNA sequencing. Analysis of differentially expressed genes and gene set variation analysis were performed. Immunofluorescence staining, quantitative real-time PCR (qRT-PCR), flow cytometry and transwell assay were used for validation. RESULTS: Compared with healthy controls, the skin transcriptome of AD patients showed common signatures of AD, like barrier dysfunction and enhanced Th1/Th2/Th17 immune pathways. In PBMCs, the expression of Th1/Th2 response genes was more remarkable in adult AD, while expression of Th17-related genes was significantly higher in childhood AD. The gene modules associated with natural killer (NK) cells were downregulated in elderly AD. In skin lesions, elderly AD exhibited enrichment of macrophages, fibroblasts and senescence-associated secretory phenotype (SASP) related genes. The correlation among fibroblasts, SASP and innate immune cells were revealed by the co-localization of fibroblasts, macrophages and NK cells in the lesions across different age groups. Fibroblasts under inflammation or senescence could induce stronger chemotaxis of macrophages and NK cells. CONCLUSION: We identified the molecular phenotypes of skin lesions and PBMCs in elderly AD individuals. Fibroblasts, innate immune cells, and SASP might play important roles in the pathogenesis of elderly AD.

Comprehensive analysis of phenotypes and transcriptome characteristics reveal the best atopic dermatitis mouse model induced by MC903.

BACKGROUND: Although several mouse models of exogenous-agent-induced atopic dermatitis (AD) are currently available, the lack of certainty regarding their similarity with human AD has limited their scientific value. Thus, comprehensive evaluation of the characteristics of mouse models and their similarity with human AD is essential. OBJECTIVE: To compare six different exogenous-agent-induced AD mouse models and find out the optimum models for study. METHODS: Female BALB/c mice underwent induction of AD-like dermatitis by MC903 alone or in combination with ovalbumin (OVA), dinitrofluorobenzene (DNFB) alone or in combination with OVA, OVA alone, or Staphylococcus aureus. Gross phenotype, total immunoglobulin E (IgE) level, histopathological manifestations, and skin lesion transcriptome were analyzed, and metagenomic sequencing of the gut microbiome was performed. RESULTS: The DNFB plus OVA model showed the highest disease severity, while the OVA model showed the lowest severity. The MC903 and MC903 plus OVA models showed high expression of T-helper (Th)2- and Th17-related genes; the DNFB and DNFB plus OVA models showed upregulation of Th1-, Th2-, and Th17-related genes; while the S. aureus inoculation model showed more enhanced Th1 and Th17 immune responses. In contrast to the other models, the OVA-induced model showed the lowest expression levels of inflammation-related genes, while the MC903 model shared the largest overlap with human AD profiles. The intestinal microbiota of all groups showed significant differences after modeling. CONCLUSION: Each AD mouse model exhibited different characteristics. The MC903 model was the best to recapitulate most features of human AD among these exogenous-agent-induced AD models.

A Missense Mutation in TRPS1 in a Family with Trichorhinophalangeal Syndrome Type III Accompanied by Ankylosing Spondylitis.

Trichorhinophalangeal syndrome (TRPS) is a rare autosomal dominant genetic disorder characterized by distinctive craniofacial features, skeletal abnormalities and short stature; it is classified into three subtypes according to genetics and clinical manifestations. We report a Han Chinese family with 2 TRPS type III patients, the proband and his mother, with typical clinical presentation. There were also 3 ankylosing spondylitis (AS) patients in this family, the proband's mother and 2 uncles. A missense mutation, c.2762G>A (p.Arg921Gln), in the transcriptional repressor GATA binding 1 (TRPS1) gene was detected in the proband and his mother. The association between TRPS and AS and the diagnostic criteria for TRPS are discussed.

Transglutaminase 3 Attenuates Skin Inflammation in Psoriasis by Inhibiting NF-κB Activation through Phosphorylated STAT3-TET3 Signaling.

Transglutaminase 3 (TGM3) protects against skin inflammation in psoriasis, but the precise role and mechanism of action of TGM3 in the pathogenesis of psoriasis remain unclear. In this study, we show that TGM3 expression was increased in the skin lesions of patients with psoriasis and a mouse model of imiquimod-induced psoriatic dermatitis. TGM3 overexpression decreased the production of proinflammatory factors in cultured primary keratinocytes stimulated with psoriasis-related cytokines. TGM3 inhibited the phosphorylation of signal transducer and activator of transcription 3 and the recruitment of ten-eleven translocation 3 to the p65 gene promoter, resulting in decreased promoter demethylation and subsequent suppression of proinflammatory cytokine/chemokine production. TGM3-induced inhibition of phosphorylated p65 might also decrease ten-eleven translocation 3 expression. Moreover, topical application of Tgm3-specific small interfering RNA or the pan-transglutaminase inhibitor cysteamine exacerbated skin inflammation in mice with imiquimod-induced psoriatic dermatitis. Our study revealed an epigenetic pathway mediated by the interaction between TGM3 and ten-eleven translocation 3 in keratinocytes for regulation of skin inflammation in psoriasis, providing a potential target for psoriasis treatment.

A dysregulated sebum-microbial metabolite-IL-33 axis initiates skin inflammation in atopic dermatitis.

Microbial dysbiosis in the skin has been implicated in the pathogenesis of atopic dermatitis (AD); however, whether and how changes in the skin microbiome initiate skin inflammation, or vice versa, remains poorly understood. Here, we report that the levels of sebum and its microbial metabolite, propionate, were lower on the skin surface of AD patients compared with those of healthy individuals. Topical propionate application attenuated skin inflammation in mice with MC903-induced AD-like dermatitis by inhibiting IL-33 production in keratinocytes, an effect that was mediated through inhibition of HDAC and regulation of the AhR signaling pathway. Mice lacking sebum spontaneously developed AD-like dermatitis, which was improved by topical propionate application. A proof-of-concept clinical study further demonstrated the beneficial therapeutic effects of topical propionate application in AD patients. In summary, we have uncovered that the dysregulated sebum-microbial metabolite-IL-33 axis might play an initiating role in AD-related skin inflammation, thereby highlighting novel therapeutic strategies for the treatment of AD.

Whole-Exome Sequencing Enables the Diagnosis of Variant-Type Xeroderma Pigmentosum.

BACKGROUND: Xeroderma pigmentosum (XP) is a rare autosomal, recessive, inherited disease. XP patients exhibit high sensitivity to sunlight and increased incidence of skin cancer. The different XP subtypes, which are caused by mutations of eight distinct genes, show some specific clinical manifestations. XP variant (XPV) is caused by mutations in the gene encoding DNA polymerase eta (POLH). CASE PRESENTATION: We report a family that included two XP patients whose parents were first cousins. The proband is a 36-year-old male who developed a large number of pigmented freckle-like lesions starting at 4 years of age; later, he displayed typical psoriasis manifestation, abnormal renal function and hyperglycaemia. He was suspected as suffering from dyschromatosis symmetrica hereditaria (DSH), but negative results were obtained in candidate gene analyses. Whole-exome sequencing was performed in four subjects, including the two patients and two controls, and a new pathogenic homozygous nonsense mutation (c.353dupA, p. Y118_V119delinsX) of the POLH gene, which was identified in all nine family members by Sanger sequencing, was detected in the patients. CONCLUSION: A novel XPV pathogenic homozygous nonsense mutation in the POLH gene was identified. Our case proves that next-generation sequencing is an effective method for the rapid diagnosis and determination of XP genetic etiology.