Human Psoriasis Research Articles

Effects of Autophagy Modulators and Dioxin on the Expression of Epidermal Differentiation Proteins on Psoriasis-Like Keratinocytes in vitro and ex vivo.

ObjectivePsoriasis is a chronic inflammatory skin disorder associated with impairment of epidermal differentiation. Many signaling pathways, including those involved in aryl hydrocarbon receptor (AHR) and autophagy dysfunction, are reportedly associated with the pathogenesis of psoriasis. However, the discrete effects of dioxin via AHR activation or autophagy on the epidermal barrier remain unclear. In the current study, we evaluated the effects of autophagy modulators (chloroquine [CQ] and rapamycin) and the AHR agonist TCDD on the expression of epidermal barrier proteins in psoriasis-like keratinocytes and psoriasis lesional skin tissue culture.MethodsPolycytokine-stimulated human keratinocytes and psoriasis skin biopsies were treated with TCDD, CQ, or rapamycin, and the expression of keratinocyte differentiation-related factors, such as S100A7, S100A8, HRNR, IVL, FLG, and KRT10, was examined by Western blotting or quantitative-polymerase chain reaction.ResultsTCDD upregulated S100A7 and S100A8 expression in polycytokine-stimulated HaCaT cells compared to that in unstimulated cells. CQ decreased HRNR, IVL, and KRT10 mRNA levels, while rapamycin increased HRNR, IVL, and KRT10 mRNA levels in HaCaT cells relative to that in unstimulated cells. Co-treatment with CQ reversed TCDD-induced elevation in FLG, HRNR, and IVL mRNA expression. In psoriasis skin tissue, TCDD induced the upregulation of HRNR, IVL, S100A7, and S100A8 compared with that in normal skin. In ex vivo cultures treated with CQ, IVL expression in psoriasis skin tissue was repressed compared to that in normal skin tissue.ConclusionOur data suggest that autophagy modulation or AHR activation affects processes involved in epidermal differentiation and relates to the pathogenesis of chronic inflammatory skin diseases with skin barrier abnormalities such as psoriasis.

Serine and arginine rich splicing factor 1 deficiency alters pathways involved in IL-17A expression and is implicated in human psoriasis

Serine and Arginine Rich Splicing Factor 1 (SRSF1) is a splicing factor that binds to exonic enhancers and stimulates splicing and is previously implicated with autoimmunity. Herein, we investigate the role of SRSF1 in regulating innate immune functions that are pertinent in the pathogenesis of auto-inflammatory diseases. Specifically, we show that conditional deletion of SRSF1 in mature lymphocytes resulted in higher expression of il-17a and il-17 f and an expansion of IL17A+ CD8 T cells. Mechanistically, the aberrant expression of IL-17A in SRSF1 cKO mice could not be attributed to alternative splicing of il-17a or il-17 f genes but possibly to defective CD11B+LY6C+ myeloid derived suppressor function in the spleen. Finally, meta-analysis of RNA-Seq collected from psoriasis patients demonstrate a clear correlation between SRSF1 and psoriasis that suggests a putative role of SRSF1 in IL-17A-induced psoriasis.

The PLAUR signaling promotes chronic pruritus.

Chronic itch is a complex sensation of the skin frequently associated with skin diseases, such as atopic dermatitis (AD) and psoriasis. Although Serpin E1 is implicated in chronic itch, its receptor and signaling pathways involved in itch are not known. In this study, the clinical relevance of a putative Serpin E1 receptor PLAUR to chronic itch, and the neuro‐cutaneous Serpin E1‐PLAUR signaling are explored. We found that PLAUR is overexpressed in skin specimens of human lesional AD and lesional psoriasis, and sensory neurons innervating MC903‐induced AD‐like murine skin. Murine PLAUR+ sensory neurons responded to Serpin E1, resulting in enrichment of numerous itch‐ and inflammation‐related genes and their protein release. PLAUR resides in TLR2+ neurons and Serpin E1 stimulus led to transcriptional upregulation of TLR2 and its co‐signaling proteins. Agonists of TLR2 propagated itch‐related gene transcription including BNP, OSM, and PAR2. OSM induced acute itch in mice and promoted G‐CSF and IL‐8 release from human keratinocytes. Serpin E1 inhibitor reduced MC903‐induced itch, epidermal hyperplasia, immunocyte infiltration, and resulted in lower transcription/expression levels of Serpin E1 and OSM. Taken together, the PLAUR‐TLR2‐OSM signaling promotes skin‐nerve communication, cutaneous inflammation, and itch, all feeding into an aggravation of AD and exaggerated itch circuits.

“Therapeutic targeting of tumor necrosis factor like weak inducer of apoptosis (TWEAK) in psoriasis”

Abstract Excessive activity of TNF and IL-17 in keratinocytes can drive psoriatic skin inflammation and their targeting is highly advantageous in psoriasis patients, but whether these cytokines act with other inflammatory molecules is unknown. Previously, we demonstrated with knockout mice that the TNF-related cytokine TWEAK (TNFSF12) was a major driver of skin inflammation in the imiquimod model of psoriasis. Here, we found that mice carrying a deletion of TWEAK’s receptor, Fn14 (TNFRSF12A), specifically in keratinocytes, exhibited reduced psoriasis features, including less epidermal hyperplasia and poor expression of genes associated with human psoriasis. Further, RNA-seq analysis in human keratinocytes demonstrated that TWEAK strongly synergizes with either TNF or IL-17A in upregulating the transcripts for psoriasis-associated chemokines and cytokines, implying that TWEAK co-operates with TNF and IL-17 to enhance feedback inflammatory activity. Correspondingly, administration of anti-TWEAK antibody demonstrated therapeutic efficacy in the psoriasis mouse model and was equally as effective as antibodies to IL-17A or TNF in reducing clinical and immunological features of psoriasis-like skin inflammation, while co-neutralization of TWEAK with either cytokine had no additional therapeutic effect, reinforcing the conclusion that all three cytokines act together. We conclude that TWEAK blockade could be another potential therapeutic avenue in patients with psoriasis that might be equally as useful as blocking TNF and IL-17. Future studies targeting TWEAK in clinical trials for psoriasis may then be warranted. Supported by NIH grant AR072640

TGFβ activating integrins β6 and β8 are dysregulated in inflammatory skin disease and cutaneous melanoma

BackgroundIntegrins avβ6 and avβ8 are expressed by keratinocytes and transactivate latent TGFβ. In a murine model, integrin mediated activation of TGFβ has been shown to be critical in maintaining skin homeostasis, specifically playing roles in epidermal retention of Langerhans cells and resident memory cells T cells (Trm). ObjectiveWe examine expression of Integrins β6 and β8 in human skin, inflammatory skin disease, benign nevi, and melanoma and hypothesize that integrin expression is dysregulated in disease. MethodsUsing immunohistochemistry, we stained tissue from normal human skin (n = 8), psoriasis (n = 6), atopic dermatitis (n = 6), lichen planus (n = 5), benign nevi (n = 24), and melanoma (n = 25) with anti-integrin β6 and anti-integrin β8 to survey expression pattern. We also performed a retrospective chart review in the melanoma cohort to examine if integrin β6 and β8 expression was associated with increased Breslow depth and worse prognostic staging. ResultsHere, we show that human keratinocytes express integrins β6 and β8, similar to murine keratinocytes. We also found that inflammatory skin conditions have increased Integrin β6, but not Integrin β8 expression. Furthermore, we identified that melanomas have greatly increased expression of integrin β8 compared to nevi. Additionally, high expression of integrin β8 was correlated with greater Breslow depth at diagnosis and with worse prognostic staging. ConclusionThese findings demonstrate that like murine keratinocytes, human keratinocytes express integrin β6 and β8 under steady state conditions. Moreover, altered integrin expression may participate in the development or maintenance of cutaneous inflammation as well as tumor immune evasion.

Forsythoside A Alleviates Imiquimod-Induced Psoriasis-like Dermatitis in Mice by Regulating Th17 Cells and IL-17A Expression.

Psoriasis is a recurrent inflammatory skin disease characterized by redness and scaly skin lesions with itchy or painful sensations. Forsythoside A, one of the main active compounds isolated from the fruit of Forsythia suspensa, has been widely applied to treat inflammatory diseases in the clinical use of traditional oriental medicine. However, the effect of forsythoside A on psoriasis remains unclear. This study aimed to explore the therapeutic effects and immune regulation of forsythoside A on psoriasis. C57BL/6 mice were divided into six groups and treated with imiquimod cream on their shaved back skin to induce psoriasis-like dermatitis. Different doses of forsythoside A (5 mg/kg, 10 mg/kg, or 20 mg/kg) were administered to the respective treatment groups. Skin redness, scaling, and ear thickness were measured; keratinocyte proliferation and inflammatory cytokine expression were detected by hematoxylin–eosin and immunohistochemical staining. Th17 cells in the inguinal lymph nodes were detected by flow cytometric analysis. IL-17A levels were measured using ELISA. The results showed that forsythoside A relieved psoriatic skin symptoms such as skin redness, thickness, scaling, and reduced epidermal thickening. The expression of IL-6, IL-17, and Ki-67 was downregulated in the forsythoside-A-treated groups. Th17 cell expression in inguinal lymph nodes and IL-17A secretion was suppressed by forsythoside A. In conclusion, forsythoside A was found to alleviate imiquimod-induced psoriasis-like dermatitis in mice by suppressing Th17 development and IL-17A secretion. These findings demonstrate the feasibility of forsythoside A in treating human psoriasis.

CD147 Is Essential for the Development of Psoriasis via the Induction of Th17 Cell Differentiation.

Th17 cells play an important role in psoriasis. The differentiation of naïve CD4+ T cells into Th17 cells depends on glycolysis as the energy source. CD147/basigin, an integral transmembrane protein belonging to the immunoglobulin superfamily, regulates glycolysis in association with monocarboxylate transporters (MCTs)-1 and -4 in cancer cells and T cells. We examined whether CD147/basigin is involved in the pathogenesis of psoriasis in humans and psoriasis-model mice. The serum level of CD147 was increased in patients with psoriasis, and the expression of CD147 and MCT-1 was elevated in their dermal CD4+ RORγt+ T cells. In vitro, the potential of naïve CD4+ T cells to differentiate into Th17 cells was abrogated in CD147−/− T cells. Imiquimod (IMQ)-induced psoriatic dermatitis was significantly milder in CD147−/− mice and bone marrow chimeric mice lacking CD147 in the hematopoietic cells of myeloid lineage. These findings demonstrate that CD147 is essential for the development of psoriasis via the induction of Th17 cell differentiation.

Keratinocyte-intrinsic BCL10/MALT1 activity initiates and amplifies psoriasiform skin inflammation.

Psoriasis is a chronic inflammatory skin disease arising from poorly defined pathological cross-talk between keratinocytes and the immune system. BCL10 (B cell lymphoma/leukemia 10) and MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) are ubiquitously expressed inflammatory signaling proteins that can interact with the psoriasis susceptibility factor CARD14, but their functions in psoriasis are insufficiently understood. We report that although keratinocyte-intrinsic BCL10/MALT1 deletions completely rescue inflammatory skin pathology triggered by germline Card14 gain-of-function mutation in mice, the BCL10/MALT1 signalosome is unexpectedly not involved in the CARD14-dependent interleukin-17 receptor (IL-17R) proximal pathway. Instead, it plays a more pleiotropic role by amplifying keratinocyte responses to a series of inflammatory cytokines, including IL-17A, IL-1β, and TNF. Moreover, selective keratinocyte-intrinsic activation of BCL10/MALT1 signaling with an artificial engager molecule is sufficient to initiate lymphocyte-mediated psoriasiform skin inflammation, and aberrant BCL10/MALT1 activity is frequently detected in the skin of human sporadic psoriasis. Together, these results establish that BCL10/MALT1 signalosomes can act as initiators and crucial amplifiers of psoriatic skin inflammation and indicate a critical function for this complex in sporadic psoriasis.

169 Eukaryotic Translation Initiation Factors (eIFs): Potential Therapeutic Targets in Psoriasis

Background: eIFs play a critical role in the regulation of gene expression in eukaryotes ans affect many essential cellular processes, including proliferation, apoptosis and differentiation. Purpose of the study: We hypothesized that eIFs are involved in the pathophysiology of psoriasis, are affected by anti-psoriatic treatments, and can serve as direct targets for anti-psoriatic treatment. Experimenetal design: We used the IMQ and TGFß transgenic mouse models, human psoriasis samples (lesional psoriatic and healthy control skin) as well as an 3D in vitro model of psoriasis to enable the study of the disease, and to screen therapeutic candidates (eIF1A and eIF3B) to assess the therapeutic potential and to determine the molecular mechanisms related to anti-psoriatic response with regard to the translation initiation machinery. Results: Our preliminary data showed significant increase of eIF1A and eIF3B in human psoriasis lesions, IMQ and TGFß mice, as well as in HaCaT cells on protein and mRNA level. Our preliminary 3D in vitro model and mouse model (IMQ and TGFß) data revealed that a systemically and topically treatment with eIF1A and eIF3B siRNA decrease epidermis and dermis thickness as well as reduced mRNA expression for eIF1A and eIF3B after treatment. Conclusion: We have demonstrated for the first time an increased expression of eIF1A and and eIF3B in psoriatic skin. This project will extend the knowledge of the mechanisms behind the translation initiation in particular of eIFs in psoriasis, but may also reveal novel cellular processes regulated by eIFs. Together, this may open up new therapeutic avenues by targeting eIFs in psoriasis.

Mesenchymal Stromal Cell-Conditioned Medium for Skin Diseases: A Systematic Review.

The skin is the largest organ of the human body, and its dysfunction is related to many diseases. There is a need to find new potential effective therapies for some skin conditions such as inflammatory diseases, wound healing, or hair restoration. Mesenchymal stromal cell (MSC)-conditioned medium (CM) provides a potential opportunity in the treatment of skin disease. Thus, the objective of this review is to evaluate the uses of MSC-CM for treating skin diseases in both animal and human models. A systematic review was conducted regarding the use of MSC-CM for treating skin conditions. One hundred one studies were analyzed. MSC-CM was evaluated in wound healing (55), hypertrophic scars (9), flap reperfusion (4), hair restoration (15), skin rejuvenation (15), and inflammatory skin diseases (3). MSC-CM was obtained from different MSC sources, mainly adipose tissue, bone marrow, and umbilical cord blood. MSC-CM was tested intravenously, intraperitoneally, subcutaneously, intradermally or intralesionally injected or topically applied. MSC-CM was used in both animals and humans. MSC-CM improved wound healing, hair restoration, skin rejuvenation, atopic dermatitis, and psoriasis in both animals and humans. MSC-CM also decreased hypertrophic scars and flap ischemia in animal models. In conclusion, MSC-CM is a promising therapy for skin conditions. Further studies are needed to corroborate safety and effectiveness and to standardize CM manufacturing.

Oxidant-resistant LRRC8A/C anion channels support superoxide production by NADPH oxidase 1.

LRRC8A-containing anion channels associate with NADPH oxidase 1 (Nox1) and regulate superoxide production and tumour necrosis factor-α (TNFα) signalling. Here we show that LRRC8C and 8D also co-immunoprecipitate with Nox1 in vascular smooth muscle cells. LRRC8C knockdown inhibited TNFα-induced O2•- production, receptor endocytosis, nuclear factor-κB (NF-κB) activation and proliferation while LRRC8D knockdown enhanced NF-κB activation. Significant changes in LRRC8 isoform expression in human atherosclerosis and psoriasis suggest compensation for increased inflammation. The oxidant chloramine-T (ChlorT, 1mM) weakly (∼25%) inhibited LRRC8C currents but potently (∼80%) inhibited LRRC8D currents. Substitution of the extracellular loop (EL1, EL2) domains of 8D into 8C conferred significantly stronger (69%) ChlorT-dependent inhibition. ChlorT exposure impaired subsequent current block by DCPIB, which occurs through interaction with EL1, further implicating external oxidation sites. LRRC8A/C channels most effectively sustain Nox1 activity at the plasma membrane. This may result from their ability to remain active in an oxidized microenvironment. Tumour necrosis factor-α (TNFα) activates NADPH oxidase 1 (Nox1) in vascular smooth muscle cells (VSMCs), producing superoxide (O2•- ) required for subsequent signalling. LRRC8 family proteins A-E comprise volume-regulated anion channels (VRACs). The required subunit LRRC8A physically associates with Nox1, and VRAC activity is required for Nox activity and the inflammatory response to TNFα. VRAC currents are modulated by oxidants, suggesting that channel oxidant sensitivity and proximity to Nox1 may play a physiologically relevant role. In VSMCs, LRRC8C knockdown (siRNA) recapitulated the effects of siLRRC8A, inhibiting TNFα-induced extracellular and endosomal O2•- production, receptor endocytosis, nuclear factor-κB (NF-κB) activation and proliferation. In contrast, siLRRC8D potentiated NF-κB activation. Nox1 co-immunoprecipitated with 8C and 8D, and colocalized with 8D at the plasma membrane and in vesicles. We compared VRAC currents mediated by homomeric and heteromeric LRRC8C and LRRC8D channels expressed in HEK293 cells. The oxidant chloramine T (ChlorT, 1mM) weakly inhibited 8C, but potently inhibited 8D currents. ChlorT exposure also impaired subsequent current block by the VRAC blocker DCPIB, implicating external sites of oxidation. Substitution of the 8D extracellular loop domains (EL1, EL2) into 8C conferred significantly stronger ChlorT-mediated inhibition of 8C currents. Our results suggest that LRRC8A/C channel activity can be effectively maintained in the oxidized microenvironment expected to result from Nox1 activation at the plasma membrane. Increased ratios of 8D:8C expression may potentially depress inflammatory responses to TNFα. LRRC8A/C channel downregulation represents a novel strategy to reduce TNFα-induced inflammation.

Galangin ameliorates Imiquimod-Induced psoriasis-like skin inflammation in BALB/c mice via down regulating NF-κB and activation of Nrf2 signaling pathways

Psoriasis is a most common chronic autoimmune-arbitrated cutaneous inflammatory skin disorder by unclear pathogenesis. In this current study we demonstrated the effect of galangin (GAL) on imiquimod (IMQ)-induced psoriasis-like skin inflammation and decipher its possible protective mechanism which has not been investigated. The in vivo results revealed that GAL at 1% w/w and 2% w/w for six consecutive days markedly reduced IMQ-induced PASI scoring, skin, ear thickness, hematological markers, levels of nitrites, TBARS, MPO, histopathological, as well modulated the protein levels of pro-inflammatory mediators of COX-2, iNOS, NF-κB pathway and pro-inflammatory cytokines IL-17, IL-23, IL-1β in the skin and also IL-6, TNF-α in both skin and serum. Besides, GAL restored the levels of antioxidants markers such as SOD, CAT, GST, GSH, GR and Vit-C, anti-inflammatory cytokine of IL-10, and the protein levels of Nrf2/HO-1 in the skin compared to the IMQ group. Finally, our study demonstrates that GAL exerted its protective effect by up-regulating the anti-inflammatory and the antioxidant markers against psoriasis pre-clinical models indicating its potency for treating psoriasis in humans.

BT-11 (omilancor), a first-in-class, topical therapeutic for psoriasis, ameliorates disease severity and inflammation through activation of LANCL2 pathway

Abstract BT-11 (omilancor) is a small molecule therapeutic that activates the LANCL2 pathway in immune and epithelial cells, resulting in regulatory effects at the intersection of immunity and metabolism. LANCL2 modulates the plasticity between Th17 and regulatory T cells (Tregs), favoring the stability and suppressive capacity of Tregs. Given the implication of the LANCL2 pathway in autoimmune disease and the demonstrated clinical efficacy and safety of BT-11 in a Phase 2 clinical trial of UC, we evaluated the therapeutic efficacy of BT-11 in psoriasis. In an imiquimod-induced mouse model of psoriasis, pharmacological activation of LANCL2 through topical BT-11 treatment ameliorates disease severity, resulting in over 60% reduction of PASI score. Indeed, BT-11 treatment decreased acanthosis and immune cell infiltration, with no signs of parakeratosis. The loss of LANCL2 in mice resulted in increased hyperkeratosis and parakeratosis. Local LANCL2 activation by BT-11 resulted in decreased TNF, IL17, IL6 and IL21-producing cells in the spleen. Additionally, LANCL2 activation regulated keratinocyte metabolism and function. Keratinocytes from BT-11-treated mice presented lower metabolic activation, reported as decreased ATP production, mitochondrial respiration and glucose metabolism. In translational studies with human PBMCs, BT-11 modulated the metabolic profile of CD4+ T cells at late state glycolysis, favoring oxidative pathways, and decreased expression of proinflammatory cytokines (IFNγ, TNFα), while upregulating IL-10. These results merit further exploration into the implication of LANCL2 signaling in human psoriasis and leverages the development of BT-11, as a first-in-class, topical therapeutic for psoriasis.

Single cell transcriptional zonation of human psoriasis skin identifies an alternative immunoregulatory axis conducted by skin resident cells

Psoriasis is the most common skin disease in adults. Current experimental and clinical evidences suggested the infiltrating immune cells could target local skin cells and thus induce psoriatic phenotype. However, recent studies indicated the existence of a potential feedback signaling loop from local resident skin cells to infiltrating immune cells. Here, we deconstructed the full-thickness human skins of both healthy donors and patients with psoriasis vulgaris at single cell transcriptional level, and further built a neural-network classifier to evaluate the evolutional conservation of skin cell types between mouse and human. Last, we systematically evaluated the intrinsic and intercellular molecular alterations of each cell type between healthy and psoriatic skin. Cross-checking with psoriasis susceptibility gene loci, cell-type based differential expression, and ligand-receptor communication revealed that the resident psoriatic skin cells including mesenchymal and epidermis cell types, which specifically harbored the target genes of psoriasis susceptibility loci, intensively evoked the expression of major histocompatibility complex (MHC) genes, upregulated interferon (INF), tumor necrosis factor (TNF) signalling and increased cytokine gene expression for primarily aiming the neighboring dendritic cells in psoriasis. The comprehensive exploration and pathological observation of psoriasis patient biopsies proposed an uncovered immunoregulatory axis from skin local resident cells to immune cells, thus provided a novel insight for psoriasis treatment. In addition, we published a user-friendly website to exhibit the transcriptional change of each cell type between healthy and psoriatic human skin.

IL-23 maintains tissue resident memory Th17 cells in murine and psoriatic skin

Abstract Tissue resident memory Th17 cells (TRM17) are the key cell type driving the chronic skin inflammation of psoriasis. Although IL-23 is strongly associated with autoimmunity and chronic inflammatory disorders including psoriasis, and anti-IL-23 biologic agents have remarkable efficacy in the treatment of psoriasis, the precise role of IL-23 in supporting IL-17-mediated skin inflammation remains unclear. In mice, we found that circulating memory T cells were dispensable for anamnestic protection from C. albicans skin infection, and TRM17 mediated protection from C. albicans reinfection required IL-23. Administration of anti-IL-23R antibody to dual Il17aCre Rosa26CAG-fl/fl-tdTomato Il17fThy1.1/Thy1.1 (17Fate) fate reporter mice following resolution of primary C. albicans infection resulted in a selective reduction in the number of CD69+CD103+TRM17 cells in skin compared with isotype controls. TRM17 proliferation was reduced and survival was unaffected. CD301b+ dermal dendritic cells (dDC) were an obligate source of IL-23 that supported TRM17 maintenance in skin after C. albicans challenge. These data demonstrate that locally produced IL-23 promotes in situ TRM17 proliferation to support their long term retention in skin. In normal human skin, we identified dermal cDC2 as the principal source of IL-23, although keratinocytes and CD4+ T cells were additional sources of IL-23 in psoriasis skin. Analysis of human psoriasis skin before and after clinical anti-IL-23 therapy revealed reduced TRM17 number and proliferation index, suggesting that targeted depletion of pathogenic TRM17 is the major mechanism by which anti-IL-23 therapy induces uniquely durable disease-free intervals in psoriasis patients.

Single-cell transcriptomics applied to emigrating cells from psoriasis elucidate pathogenic versus regulatory immune cell subsets

In previous human skin single-cell data, inflammatory cells constituted only a small fraction of the overall cell population, such that functional subsets were difficult to ascertain. Our aims were to overcome the aforesaid limitation by applying single-cell transcriptomics to emigrating cells from skin and elucidate exvivo gene expression profiles of pathogenic versus regulatory immune cell subsets in the skin of individuals with psoriasis. We harvested emigrating cells from human psoriasis skin after incubation in culture medium without enzyme digestion or cell sorting and analyzed cells with single-cell RNA sequencing and flow cytometry simultaneously. Unsupervised clustering of harvested cells from psoriasis skin and control skin identified natural killer cells, T-cell subsets, dendritic cell subsets, melanocytes, and keratinocytes in different layers. Comparison between psoriasis cells and control cells within each cluster revealed that (1) cutaneous type 17 T cells display highly differing transcriptome profiles depending on IL-17A versus IL-17F expression and IFN-γ versus IL-10 expression; (2) semimature dendritic cells are regulatory dendritic cells with high IL-10 expression, but a subset of semimature dendritic cells expresses IL-23A and IL-36G in psoriasis; and (3) CCL27-CCR10 interaction is potentially impaired in psoriasis because of decreased CCL27 expression in basal keratinocytes. We propose that single-cell transcriptomics applied to emigrating cells from human skin provides an innovative study platform to compare gene expression profiles of heterogenous immune cells in various inflammatory skin diseases.

PD-1 Expression Defines Epidermal CD8+CD103+ T Cells Preferentially Producing IL-17A and Using Skewed TCR Repertoire in Psoriasis

In psoriasis, CD8+CD103+ memory T cells residing in the epidermis represent an effector population capable of maintaining the condition and driving a recurrence of the disease. Tissue-infiltrating CD8+ T cells expressing PD-1 are regarded as antigen-primed effector cells in others chronic inflammatory diseases. However, the expression and significance of PD-1 on skin-infiltrating CD8+ T cells in human psoriasis is not known. By analyzing skin-infiltrating T cells from human psoriasis, we found that active psoriatic epidermis contained PD-1 expressing CD8+CD103+ T cells that correlated with the disease severity and histopathology. PD-1+CD8+CD103+ T cells possessed a canonical psoriasis-specific resident memory phenotype with IL-23R expression and produced IL-17A, whereas PD-1-CD8+CD103+ T cells preferentially produced IFN-γ. The diversity of skin-infiltrating T cells was dominated by CD4+ T cells, while CD8+ T cells, especially CD8+CD103+T cells, represented an oligoclonal population in active psoriasis. In addition, PD-1+CD8+CD103+T cells used different TCR Vβs from PD-1-CD8+CD103+T cells counterpart. In the early resolved lesion, the composition and functional status of PD-1+CD8+CD103+T cells were markedly altered, while PD-1-CD8+CD103+ T cells population was minimally changed. Collectively, PD-1 expression delineates a putative pathogenic subset of epidermal CD8+CD103+ T cells, which possibly play a role in psoriasis pathogenesis.

Sistem Pakar Metode Case Based Reasoning untuk Mengidentifikasi Penyakit Psoriasis

Proriasis is a type of chronic disease of the human skin.problem of psoriasis At the end of the day, theis becoming more interesting because the main cause of this disease has not been found, which has only been found while the cause of psoriasis is genetics. Because the cause is not known for sure, this disease is difficult to cure. Although this disease is not contagious and life-threatening to sufferers, it can damage internal organs if not handled properly. This study aims to determine the level of accuracy in identifying psoriasis in humans. There are several types of symptoms that refer to psoriasis. Furthermore, the data is processed manually with themethod Case Based Reasoning and continued by using a-based expert system software website. The processing stage is to use theprocess, which retrieve is a process of finding the similarities between new cases and existing cases in the knowledge base. The results of the data processing are continued with the calculation of the level of accuracy. The result of testing this method is that there are 100% of the 12 test data. Based on the accuracy of the identification results of this system, this study is very precise in the level of identifying the level of accuracy of psoriasis in humans. Expert testing system has been able to identify thedisease psoriasis specific. Through thismethod Case Based Reasoning , the level of accuracy that can be obtained is quite accurate and can help skin and genital specialists in improving accuracy in identifyingdiseases Case Based Reasoning in humans.

Evolutionary context of psoriatic immune skin response.

The skin is vital for protecting the body and perceiving external stimuli in the environment. Ability to adapt between environments is in part based on skin phenotypic plasticity, indicating evolved homeostasis between skin and environment. This homeostasis reflects the greater relationship between the body and the environment, and disruptions in this balance may lead to accumulation of susceptibility factors for autoimmune conditions like psoriasis. In this study, we examined the relationship between rapid, lineage-specific evolution of human skin and formation of psoriatic skin responses at the transcriptome level. We collected skin tissue biopsies from individuals with psoriasis and compared gene expression in psoriatic plaques to non-plaque psoriatic skin. We then compared these data with non-psoriatic skin transcriptome data from multiple primate species. We found 67 genes showing human-specific skin expression that are also differentially regulated in psoriatic skin; these genes are significantly enriched for skin barrier function, immunity and neuronal development. We identified six gene clusters with differential expression in the context of human evolution and psoriasis, suggesting underlying regulatory mechanisms in these loci. Human and psoriasis-specific enrichment of neuroimmune genes shows the importance of the ongoing evolved homeostatic relationship between skin and external environment. These results have implications for both evolutionary medicine and public health, using transcriptomic data to acknowledge the importance of an individual’s surroundings on their overall health.

Evaluation of the Effect of Topical Artemisia dracunculus Administration on Serum Levels of Selected Interleukins and Spleen Index in Imiquimod-Induced Psoriasis in Male Mice Compared to Clobetasol Propionate (Dermovate (R)) Ointment

Psoriasis is a long-lasting autoimmune disease that is characterized by swollen skin patches. Normally, these skin patches are dark, swollen, itchy and scaly. The single application of the innate TLR7/8 ligand Imiquimod (IMQ) in mice easily induces a dermatitis that closely resembles human psoriasis, critically dependent on the axis of IL-23/IL-17. Artemisia dracunculus prepared as an ointment and has been used topically to mice before imiquimod application. The results of the current study showed that A. dracunculus ointment can significantly reduce psoriasis area and severity index in (A. dracunculus ointment + imiquimod group as compared with both control group and (vehicle ointment + imiquimod) group.