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The melanocortin system is a major regulator of stress responses in the skin and is responsible for the induction of melanin synthesis through activation of melanogenesis enzymes. The expression of both melanocortin system genes and melanogenesis enzyme genes is altered in psoriasis, and the focus here was on twelve genes related to the signal transduction between them. Additionally, five endogenous opioid system genes that are involved in cutaneous inflammation were examined. Quantitative real-time-PCR was utilized to measure mRNA expression in punch biopsies from lesional and non-lesional skin of psoriasis patients and from the skin of healthy control subjects. Most of the genes related to melanogenesis were down-regulated in patients (CREB1, MITF, LEF1, USF1, MAPK14, ICAM1, PIK3CB, RPS6KB1, KIT, and ATRN). Conversely, an up-regulation occurred in the case of opioids (PENK, PDYN, and PNOC). The suppression of genes related to melanogenesis is in agreement with the reported reduction in pigmentation signaling in psoriatic skin and potentially results from the pro-inflammatory environment. The increase in endogenous opioids can be associated with their involvement in inflammatory dysregulation in psoriasis.

Contains fulltext : 218238.pdf (Publisher’s version ) (Open Access), BACKGROUND: Genetic predictors for treatment response could optimize allocation of biological treatment in patients with psoriasis. There is minimal knowledge about pharmacogenetics of anti-IL-17 agents. OBJECTIVES: To assess whether genetic variants in the protein-coding region or untranslated regions of the IL-17A gene are associated with response to IL-17A inhibitors in patients with psoriasis. METHODS: This was a multicenter European cohort study investigating pharmacogenetics of IL-17A inhibitors in patients with psoriasis. Patients with plaque psoriasis treated with secukinumab or ixekizumab in daily practice were included. For all participants, the protein-coding region and untranslated regions of the IL-17A gene were analysed using Sanger sequencing. Identified genetic variants were tested for association with response to secukinumab/ixekizumab, measured as PASI, after 12 weeks (primary outcome) and after 24 weeks (secondary outcome). Association was tested using a linear regression model with correction for baseline PASI as a fixed covariate and for biological naivety and body mass index as additional covariates. RESULTS: In total, 134 patients treated with secukinumab or ixekizumab were included. Genotyping of the cohort identified genetic variants present in untranslated regions and intronic DNA, but not in the protein-coding region of the IL-17A gene. Five genetic variants in non-coding DNA with a known or suspected functional effect on IL-17A expression were selected for association analyses: rs2275913, rs8193037, rs3819025, rs7747909 and rs3748067. After 12 weeks, 62% of patients achieved PASI75 and 39% achieved PASI90. At week 24, PASI75 and PASI90 response rates were 72% and 62%, respectively. No associations were found between the five genetic variants and PASI, PASI75 or PASI90 after 12 and 24 weeks of anti-IL-17A treatment. CONCLUSIONS: Response to IL-17A inhibitors secukinumab and ixekizumab cannot be explained by genetic variation in the protein

Importance Although palmoplantar pustulosis (PPP) can significantly impact quality of life, the factors underlying disease severity have not been studied. Objective To examine the factors associated with PPP severity. Design, Setting, and Participants An observational, cross-sectional study of 2 cohorts was conducted. A UK data set including 203 patients was obtained through the Anakinra in Pustular Psoriasis, Response in a Controlled Trial (2016-2019) and its sister research study Pustular Psoriasis, Elucidating Underlying Mechanisms (2016-2020). A Northern European cohort including 193 patients was independently ascertained by the European Rare and Severe Psoriasis Expert Network (2014-2017). Patients had been recruited in secondary or tertiary dermatology referral centers. All patients were of European descent. The PPP diagnosis was established by dermatologists, based on clinical examination and/or published consensus criteria. The present study was conducted from October 1, 2014, to March 15, 2020. Main Outcomes and Measures Demographic characteristics, comorbidities, smoking status, Palmoplantar Pustulosis Psoriasis Area Severity Index (PPPASI), measuring severity from 0 (no sign of disease) to 72 (very severe disease), or Physician Global Assessment (PGA), measuring severity as 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), and 4 (severe). Results Among the 203 UK patients (43 men [21%], 160 women [79%]; median age at onset, 48 [interquartile range (IQR), 38-59] years), the PPPASI was inversely correlated with age of onset (r = −0.18, P = .01). Similarly, in the 159 Northern European patients who were eligible for inclusion in this analysis (25 men [16%], 134 women [84%]; median age at onset, 45 [IQR, 34-53.3] years), the median age at onset was lower in individuals with a moderate to severe PGA score (41 years [IQR, 30.5-52 years]) compared with those with a clear to mild PGA score (46.5 years [IQR, 35-55 years]) (P = .04). In the UK sample, the median

Letter to the Editor

Background Plaque psoriasis is a non-contagious skin disease in which characteristic red and flaky lesions result from a dysregulation involving both innate and adaptive immune mechanisms. Several cytokines have been implicated in these processes and lately interleukin (IL)-36 family members have become more recognised among them. Thus far, genetic studies have only investigated IL36RN gene of this family in relation to pustular psoriasis. Since IL36G has previously demonstrated markedly increased levels in plaque psoriasis patients and is linked to IL-23/IL-17 axis critical in psoriasis pathology, it was chosen to be the focus of current report. Methods Eleven SNPs from IL36G region were genotyped in 728 plaque psoriasis patients and 320 healthy control individuals. Allele and haplotype frequencies between patients and controls were assessed by respective association tests. For more specific analyses, the patients were assigned into subgroups according to sex, age of disease onset, occurrence of psoriasis among relatives, seasonal aggravation, arthritis symptoms, body surface area (BSA) scores, and Psoriasis Area and Severity Index (PASI) scores. Results The most significant results were obtained with SNPs rs28947206, rs28947207 and rs28947211 that were associated in entire plaque psoriasis analysis (multiple testing adjusted p value (padj) = 0.0054, padj = 0.0017 and padj = 0.0001) and also several subgroups. The first two of those SNPs were included in the same haplotype block with rs28947205 and rs12328178, and two of the respective haplotypes, CAGC and TGTT, provided similarly significant associations (padj = 0.0462 and padj = 0.0047). Conclusions The associated SNPs of this study or those in linkage disequilibrium with them could potentially affect the functionality of IL-36γ cytokine, which in turn may impact plaque psoriasis pathology. For instance, these variants could influence IL-36γ expression or 3D structure, thereby altering its ability to induce chemo

Accurate biomarker-based diagnosis of psoriasis vulgaris has remained a challenge; no reliable disease-specific biomarkers have yet been identified. There are several different chronic inflammatory skin diseases that can present similar clinical and dermoscopy features to psoriasis vulgaris, making accurate diagnosis more difficult. Both literature-based and data-driven selection of biomarker was conducted to select candidates for a multicomponent biomarker for psoriasis vulgaris. Support vector machine-based classification models were trained using gene expression data from locally recruited patients and validated on 7 public datasets, which included gene expression data of other inflammatory skin diseases in addition to psoriasis vulgaris. The resulting accuracy of the best classification model based on the expression levels of 4 genes (IL36G, CCL27, NOS2 and C10orf99) was 96.4%, outperforming classification based on other marker gene combinations, which were more affected by variability in gene expression profiles between different datasets and patient groups. This approach has the potential to fill the void of clinically applicable diagnostic biomarkers for psoriasis vulgaris and other inflammatory skin diseases.

To evaluate skin tissue gene expression patterns correctly, extracting sufficient quantities of good quality RNA is essential. However, RNA extraction from skin tissue is challenging, as the hyaluronic acid-collagen matrix is extremely difficult to homogenize. Although there are multiple ways to extract RNA from skin, there are no comparative studies that identify the most critical steps, e.g. sample collection, storage and homogenization. We analysed the various steps involved in RNA extraction (i.e. biopsy collection as dry biopsy or into nucleotide stabilizing reagents, different storage conditions, enzymatic digestion, stator-rotor and bead motion-based homogenizing combined with column-based RNA purification). We hypothesised that domestic pig skin is applicable as a model for human skin studies. Altogether twenty different workflows were tested on pig skin and the four most promising workflows were tested on human skin samples. The optimal strategy for extracting human skin RNA was to collect, store and homogenize the sample in RLT lysis buffer from the RNeasy Fibrous Tissue Kit combined with beta-mercaptoethanol. Both stator-rotor and bead motion-based homogenizing were found to result in high quality and quantity of extracted RNA. Our results confirmed that domestic pig skin can be successfully used as a model for human skin RNA studies.

Short Communication

We report the changed levels of serum amyloid alpha, an immunologically active protein, in Parkinson’s disease (PD) patients’ peripheral tissues. We have previously shown that Saa-1 and -2 (serum amyloid alpha-1,-2, genes) were among the top downregulated genes in PD patients’ skin, using whole-genome RNA sequencing. In the current study, we characterized the gene and protein expression profiles of skin and blood samples from patients with confirmed PD diagnosis and age/sex matched controls. qRT-PCR analysis of PD skin demonstrated downregulation of Saa-1 and -2 genes in PD patients. However, the lowered amount of protein could not be visualized using immunohistochemistry, due to low quantity of SAA (Serum Amyloid Alpha, protein) in skin. Saa-1 and -2 expression levels in whole blood were below detection threshold based on RNA sequencing, however significantly lowered protein levels of SAA1/2 in PD patients’ serum were shown with ELISA, implying that SAA is secreted into the blood. These results show that SAA is differentially expressed in the peripheral tissues of PD patients.

Background: Atopic dermatitis (AD) is a chronic and complex inflammatory skin disease. At least two AD subtypes have been described: allergic (characterized by Type‐2‐cell‐mediated immunity and increased immunoglobulin E [IgE]) and non‐allergic (characterized by both Type‐2‐cell and Type‐1/17‐cell‐mediated immunity and normal IgE levels). MicroRNA (miR) are small non‐coding RNA molecules involved in genetic regulation. MiR‐146a negatively regulates inflammatory responses during chronic skin inflammation, however, its role in the modulation of immune responses in AD is uncovered. As recently miR‐146a was shown to promote IgE class switch in B cells in mice, we aimed to test whether there is association between miR‐ 146a and increased IgE levels in AD. Method: Serum samples from miR‐146a−/− and wild‐type C57BL/ 6J mice with MC903‐induced AD‐like inflammation were analysed (N = 8 mice/group) for IgE and cytokine levels. Additionally, 32 serum samples from AD patients were also analysed. Subjects were split into allergic (N = 22) and non‐allergic (N = 10) according to IgE threshold of 150 IU/mL. MiR‐146a relative expression was quantified by real‐time PCR, IgE and human IL‐12p40 by ELISA and mouse cytokines by Bioplex. Results: MiR‐146a−/− mice showed decreased IgE and increased IL‐ 12p40 serum levels (P < 0.001), while there were no changes in other detected cytokines. Human miR‐146a expression was not significantly different between allergic and non‐allergic subgroups divided based on serum IgE level. However, we observed a negative correlation of serum miR‐146a and IgE levels (P < 0.05) in allergic AD patients. In the allergic subgroup, miR‐146a expression remained independently negatively associated with IgE (β = −0.488, P < 0.05) after adjusting for confounding variables as gender. Conclusion: Low IgE and high IL‐12p40 serum levels in miR‐ 146a−/− mice indicate that miR‐146a is needed for the production of IgE and associated with the regulation of Type‐1/17‐cell‐me

Letter to the Editor

Background and aims: Next to characteristic motor triad of Parkinson’s Disease (PD) due to loss of nigrostriatal neurons, more symptoms associated with non-neuronal tissues are emerging. Little is known about the molecular alterations underlying dermatologic issues or epidemiologic associations like increased incidence of melanoma in PD. The aim is to give an overview of the altered gene expression profiles of PD skin and blood using the novel method of RNA Sequencing. Networks of different genes are analyzed to map affected pathways that contribute to pathomolecular mechanism of PD in the periphery. Methods: Whole transcriptomic profiling of 12+12 idiopathic PD patients’ and matched controls’ skin biopsies and venous whole blood was performed with highthroughput RNA-sequencing analysis. Followingly, pathway analysis of differentially changed gene expressions was performed. The results were validated using RT-qPCR. Results: PD skin RNA-Seq resulted in a large collection of over 1000 differentially expressed genes, among which a clear pattern of global downregulation appeared. In blood, the differential changes were more subtle, blood being a heterogenous tissue. Pathways associated with mitochondrial metabolism and protein degradation by the ubiquitin-proteasome system were dysregulated in both. Conclusion: The concordance of these results with previous gene expression profiling studies demonstrate that the molecular alterations in PD leading to neurodegeneration in the CNS are systemic and manifest also in peripheral tissues. Major affected pathways include dysfunction in protein metabolism, mitochondrial dysfunction and impaired immune system. Homeostatic imbalance in the skin can lead to increased susceptibility to mutagenic hazards and provide a possible molecular link between melanoma and PD.

Background Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP). Objectives To better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases [primarily GPP and palmoplantar pustular psoriasis (PPP)] for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN. Methods Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients – 61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy‐number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype–phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort. Results The majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype–phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutation carriers. Conclusions The identification of IL36RN mutation carriers harbouring additional rare variants in CARD14 or AP1S3 indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest that, in heterozygous IL36RN mutation carriers, there are additional disease‐causing genetic factors outside IL36RN.

Human endogenous retrovirus (HERV) sequences make up at least 8% of the human genome. Transcripts originating from these loci as well as proteins encoded by them have been detected in various tissues. HERVs are believed to be implicated in autoimmune diseases, however the extent to which, has remained unclear. Differential expression studies have so far been limited to certain HERV subfamilies with conserved sequences. No studies have been published describing the genome-wide expression pattern of HERVs and repetitive elements in the context of psoriasis. In the present study, we analysed total RNA sequencing data from skin samples of 12 psoriasis patients and 12 healthy controls, which enabled us to describe the entire transcriptional landscape of repetitive elements. We report high levels of repetitive element expression in the skin of psoriasis patients as well as healthy controls. The majority of differentially expressed elements were downregulated in lesional and non-lesional skin, suggesting active HERV suppression in the pro-inflammatory environment of psoriatic skin. However, we also report upregulation of a small subset of HERVs previously described in the context of autoimmune diseases, such as members of the HERV-K and W families, with the potential to affect the immunopathogenesis of psoriasis.

Toll-like receptor (TLR) are responsible for recognizing various molecular patterns associated with pathogens. Their expression have been detected in skin cells such as keratinocytes and melanocytes. Numerous experimental studies demonstrate the key role of TLRs in the pathogenesis of immune diseases, including psoriasis. The objective of this study is to analyze the associations of polymorphisms in TLR7 gene and the risk of psoriasis development. DNA samples were collected from 138 patients with psoriasis and 317 healthy controls. Genotyping of rs179003, rs179008, rs179020, rs850632, rs12013728 polymorphic loci in TLR7 gene was performed using the SNPlex™method (AB, USA). SNP in the TLR7 gene rs179008 (Gln11Leu) was associated with psoriasis in entire psoriasis, late onset and sporadic subgroups (Рс = 0.0065, OR = 1.95; Рс = 0.0004, OR = 2.50; Рс = 0.0078, OR = 2.2, respectively). In conclusion, this study is the first to identify genetic variants of the TLR7 gene significantly associated with psoriasis.

Psoriasis is a complex disease of skin with a prevalence of about 2%. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts, with a combined effective sample size >39,000 individuals. We identified 16 additional psoriasis susceptibility loci achieving genome-wide significance, increasing the number of identified loci to 63 for European-origin individuals. Functional analysis highlighted the roles of interferon signalling and the NFκB cascade, and we showed that the psoriasis signals are enriched in regulatory elements from different T cells (CD8+ T-cells and CD4+ T-cells including TH0, TH1 and TH17). The identified loci explain ∼28% of the genetic heritability and generate a discriminatory genetic risk score (AUC=0.76 in our sample) that is significantly correlated with age at onset (p=2 × 10−89). This study provides a comprehensive layout for the genetic architecture of common variants for psoriasis.