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Abdallah, Florence, Elodie Henriet, Amandine Suet, Ali Arar, Rudy Clemençon, Jean-Marc Malinge, Gaël Lecellier, Patrick Baril, and Chantal Pichon. "miR-21-3p/IL-22 Axes Are Major Drivers of Psoriasis Pathogenesis by Modulating Keratinocytes Proliferation-Survival Balance and Inflammatory Response." Cells 10, no. 10 (September 26, 2021): 2547. http://dx.doi.org/10.3390/cells10102547.
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Psoriasis is a chronic inflammatory skin disease that is mediated by complex crosstalk between immune cells and keratinocytes (KCs). Emerging studies have showed a specific psoriatic microRNAs signature, in which miR-21 is one of the most upregulated and dynamic miRNAs. In this study, we focused our investigations on the passenger miR-21-3p strand, which is poorly studied in skin and in psoriasis pathogenesis. Here, we showed the upregulation of miR-21-3p in an IMQ-induced psoriasiform mouse model. This upregulation was correlated with IL-22 expression and functionality, both in vitro and in vivo, and it occurred via STAT3 and NF-κB signaling. We identified a network of differentially expressed genes involved in abnormal proliferation control and immune regulatory genes implicated in the molecular pathogenesis of psoriasis in response to miR-21-3p overexpression in KCs. These results were confirmed by functional assays that validated the proliferative potential of miR-21-3p. All these findings highlight the importance of miR-21-3p, an underestimated miRNA, in psoriasis and provide novel molecular targets for therapeutic purposes.
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Kvist-Hansen, Amanda, Hannah Kaiser, Xing Wang, Martin Krakauer, Peter Michael Gørtz, Benjamin D. McCauley, Claus Zachariae, Christine Becker, Peter Riis Hansen, and Lone Skov. "Neutrophil Pathways of Inflammation Characterize the Blood Transcriptomic Signature of Patients with Psoriasis and Cardiovascular Disease." International Journal of Molecular Sciences 22, no. 19 (October 6, 2021): 10818. http://dx.doi.org/10.3390/ijms221910818.
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Background: Patients with psoriasis have an increased risk of atherosclerotic cardiovascular disease (CVD). The molecular mechanisms behind this connection are not fully understood, but the involvement of neutrophils have drawn attention as a shared inflammatory factor. Methods: RNA sequencing using the Illumina platform was performed on blood from 38 patients with moderate to severe psoriasis; approximately half had prior CVD. The neutrophil to lymphocyte ratio (NLR) was obtained from blood samples. Subclinical atherosclerosis was assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography and ultrasound imaging. Transcriptomic analysis for differential expression and functional enrichment were performed, followed by correlation analyses of differentially expressed genes (DEGs), NLR and subclinical measurers of CVD. Results: 291 genes were differentially expressed between patients with psoriasis with and without CVD. These included 208 upregulated and 83 downregulated DEGs. Neutrophil degranulation was identified as the most significant process related to the upregulated DEGs. Genes for the neutrophil-associated markers MPO, MMP9, LCN2, CEACAM1, CEACAM6 and CEACAM8 were identified as being of special interest and their mRNA levels correlated with NLR, high-sensitive C-reactive protein and markers of subclinical CVD. Conclusions: Patients with psoriasis and CVD had an increased expression of genes related to neutrophil degranulation in their blood transcriptome compared with patients with psoriasis without CVD. NLR may be a potential biomarker of subclinical CVD in psoriasis.
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West, Peter W., Chiara Tontini, Haris Atmoko, Orsolya Kiss, Terence Garner, Rajia Bahri, Richard B. Warren, Christopher E. M. Griffiths, Adam Stevens, and Silvia Bulfone-Paus. "Human Mast Cells Upregulate Cathepsin B, a Novel Marker of Itch in Psoriasis." Cells 12, no. 17 (August 30, 2023): 2177. http://dx.doi.org/10.3390/cells12172177.
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Mast cells (MCs) contribute to skin inflammation. In psoriasis, the activation of cutaneous neuroimmune networks commonly leads to itch. To dissect the unique contribution of MCs to the cutaneous neuroinflammatory response in psoriasis, we examined their density, distribution, relation to nerve fibres and disease severity, and molecular signature by comparing RNA-seq analysis of MCs isolated from the skin of psoriasis patients and healthy volunteers. In involved psoriasis skin, MCs and Calcitonin Gene-Related Peptide (CGRP)-positive nerve fibres were spatially associated, and the increase of both MC and nerve fibre density correlated with disease severity. Gene set enrichment analysis of differentially expressed genes in involved psoriasis skin showed significant representation of neuron-related pathways (i.e., regulation of neuron projection along with dendrite and dendritic spine morphogenesis), indicating MC engagement in neuronal development and supporting the evidence of close MC–nerve fibre interaction. Furthermore, the analysis of 208 identified itch-associated genes revealed that CTSB, TLR4, and TACR1 were upregulated in MCs in involved skin. In both whole-skin published datasets and isolated MCs, CTSB was found to be a reliable indicator of the psoriasis condition. Furthermore, cathepsin B+ cells were increased in psoriasis skin and cathepsin B+ MC density correlated with disease severity. Therefore, our study provides evidence that cathepsin B could serve as a common indicator of the MC-dependent itch signature in psoriasis.
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Tapak, Leili, Saeid Afshar, Mahlagha Afrasiabi, Mohammad Kazem Ghasemi, and Pedram Alirezaei. "Application of Genetic Algorithm-Based Support Vector Machine in Identification of Gene Expression Signatures for Psoriasis Classification: A Hybrid Model." BioMed Research International 2021 (September 8, 2021): 1–10. http://dx.doi.org/10.1155/2021/5520710.
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Background. Psoriasis is a chronic autoimmune disease impairing significantly the quality of life of the patient. The diagnosis of the disease is done via a visual inspection of the lesional skin by dermatologists. Classification of psoriasis using gene expression is an important issue for the early and effective treatment of the disease. Therefore, gene expression data and selection of suitable gene signatures are effective sources of information. Methods. We aimed to develop a hybrid classifier for the diagnosis of psoriasis based on two machine learning models of the genetic algorithm and support vector machine (SVM). The method also conducts gene signature selection. A publically available gene expression dataset was used to test the model. Results. A number of 181 probe sets were selected among the original 54,675 probes using the hybrid model with a prediction accuracy of 100% over the test set. A number of 10 hub genes were identified using the protein-protein interaction network. Nine out of 10 identified genes were found in significant modules. Conclusions. The results showed that the genetic algorithm improved the SVM classifier performance significantly implying the ability of the proposed model in terms of detecting relevant gene expression signatures as the best features.
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Krishnan, Vidya S., and Sulev Kõks. "Transcriptional Basis of Psoriasis from Large Scale Gene Expression Studies: The Importance of Moving towards a Precision Medicine Approach." International Journal of Molecular Sciences 23, no. 11 (May 30, 2022): 6130. http://dx.doi.org/10.3390/ijms23116130.
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Transcriptome profiling techniques, such as microarrays and RNA sequencing (RNA-seq), are valuable tools for deciphering the regulatory network underlying psoriasis and have revealed large number of differentially expressed genes in lesional and non-lesional skin. Such approaches provide a more precise measurement of transcript levels and their isoforms than any other methods. Large cohort transcriptomic analyses have greatly improved our understanding of the physiological and molecular mechanisms underlying disease pathogenesis and progression. Here, we mostly review the findings of some important large scale psoriatic transcriptomic studies, and the benefits of such studies in elucidating potential therapeutic targets and biomarkers for psoriasis treatment. We also emphasised the importance of looking into the alternatively spliced RNA isoforms/transcripts in psoriasis, rather than focussing only on the gene-level annotation. The neutrophil and blood transcriptome signature in psoriasis is also briefly reviewed, as it provides the immune status information of patients and is a less invasive platform. The application of precision medicine in current management of psoriasis, by combining transcriptomic data, improves the clinical response outcome in individual patients. Drugs tailored to individual patient’s genetic profile will greatly improve patient outcome and cost savings for the healthcare system.
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Golden, Jackelyn, Brian Richardson, Divya Seth, Michael Cartwright, Rafick-Pierre Sekaly, Thomas S. McCormick, Kevin D. Cooper, Cheryl M. Cameron, and Mark J. Cameron. "Transcriptomic meta-analysis reveals signatures of chronic inflammation in the classical monocyte population." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 42.25. http://dx.doi.org/10.4049/jimmunol.200.supp.42.25.
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Abstract Individuals with chronic diseases are reported to have increased classical monocytes (CD14++CD16neg) which can be activated by an infectious agent and/or inflammatory milieu. Both psoriasis and HIV are considered chronic inflammatory diseases and affected individuals display alterations in monocyte phenotype and function. Moreover, individuals with either psoriasis or HIV demonstrate a significantly increased risk of developing cardiovascular disease (CVD). We sorted classical monocytes from psoriatic and healthy controls and compared them to classical monocytes from PLHIV individuals (elite controllers (EC) and non-controllers (NC, cART suppressed). Using RNA-Seq, we identified significant differentially expressed genes (DEG, p<0.05) in psoriasis monocytes (164 DEGs; compared to controls) and in HIV+ classical monocytes from ECs (540 DEGs; compared to NC). We then performed a meta-analysis of the psoriasis transcriptome to the EC-HIV+ transcriptome, revealing a common set of DEGs comprising a unique gene signature involving cellular stress, chemokines, adhesion, and the clotting cascade. We further analyzed the common DEGs via pathway analysis (p & false discovery rate<0.05) and STRING analysis to reveal a common dysregulated network of DEG between psoriasis and HIV. Importantly, we identified a focused network of DEG that may hallmark chronic inflammation in monocyte phenotypes. Therefore, our transcriptional meta-analysis identified candidate biomarkers that may underlie common pathologic mechanisms in psoriasis and HIV and serve as highly refined targets to treat not only primary disease, but also associated comorbidities (e.g. CVD) related to inflammation.
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Lu, Chih-Hao, Chao-Yang Lai, Da-Wei Yeh, Yi-Ling Liu, Yu-Wen Su, Li-Chung Hsu, Chung-Hsing Chang, S. L. Catherine Jin, and Tsung-Hsien Chuang. "Involvement of M1 Macrophage Polarization in Endosomal Toll-Like Receptors Activated Psoriatic Inflammation." Mediators of Inflammation 2018 (December 16, 2018): 1–14. http://dx.doi.org/10.1155/2018/3523642.
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Psoriasis is a chronic inflammatory skin disorder that affects ~2%–3% of the worldwide population. Inappropriate and excessive activation of endosomal Toll-like receptors 7, 8, and 9 (TLRs 7–9) at the psoriatic site has been shown to play a pathogenic role in the onset of psoriasis. Macrophage is a major inflammatory cell type that can be differentiated into phenotypes M1 and M2. M1 macrophages produce proinflammatory cytokines, and M2 macrophages produce anti-inflammatory cytokines. The balance between these two types of macrophages determines the progression of various inflammatory diseases; however, whether macrophage polarization plays a role in psoriatic inflammation activated by endosomal TLRs has not been investigated. In this study, we investigated the function and mechanism of macrophages related to the pathogenic role of TLRs 7–9 in the progression of psoriasis. Analysis of clinical data in database revealed significantly increased expression of macrophage markers and inflammatory cytokines in psoriatic tissues over those in normal tissues. In animal studies, depletion of macrophages in mice ameliorated imiquimod, a TLR 7 agonist-induced psoriatic response. Imiquimod induced expression of genes and cytokines that are signature of M1 macrophage in the psoriatic lesions. In addition, treatment with this TLR 7 agonist shifted macrophages in the psoriatic lesions to a higher M1/M2 ratio. Both of the exogenous and endogenous TLR 7–9 ligands activated M1 macrophage polarization. M1 macrophages expressed higher levels of proinflammatory cytokines and TLRs 7–9 than M2 macrophages. These results suggest that by rendering macrophages into a more inflammatory status and capable of response to their ligands in the psoriatic sites, TLR 7–9 activation drives them to participate in endosomal TLR-activated psoriatic inflammation, resulting in an amplified inflammatory response. Our results also suggest that blocking M1 macrophage polarization could be a strategy which enables inhibition of psoriatic inflammation activated by these TLRs.
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Choudhary, Saumya, Dibyabhaba Pradhan, Noor S. Khan, Harpreet Singh, George Thomas, and Arun K. Jain. "Decoding Psoriasis: Integrated Bioinformatics Approach to Understand Hub Genes and Involved Pathways." Current Pharmaceutical Design 26, no. 29 (September 4, 2020): 3619–30. http://dx.doi.org/10.2174/1381612826666200311130133.
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Background: Psoriasis is a chronic immune mediated skin disorder with global prevalence of 0.2- 11.4%. Despite rare mortality, the severity of the disease could be understood by the accompanying comorbidities, that has even led to psychological problems among several patients. The cause and the disease mechanism still remain elusive. Objective: To identify potential therapeutic targets and affecting pathways for better insight of the disease pathogenesis. Method: The gene expression profile GSE13355 and GSE14905 were retrieved from NCBI, Gene Expression Omnibus database. The GEO profiles were integrated and the DEGs of lesional and non-lesional psoriasis skin were identified using the affy package in R software. The Kyoto Encyclopaedia of Genes and Genomes pathways of the DEGs were analyzed using clusterProfiler. Cytoscape, V3.7.1 was utilized to construct protein interaction network and analyze the interactome map of candidate proteins encoded in DEGs. Functionally relevant clusters were detected through Cytohubba and MCODE. Results: A total of 1013 genes were differentially expressed in lesional skin of which 557 were upregulated and 456 were downregulated. Seven dysregulated genes were extracted in non-lesional skin. The disease gene network of these DEGs revealed 75 newly identified differentially expressed gene that might have a role in development and progression of the disease. GO analysis revealed keratinocyte differentiation and positive regulation of cytokine production to be the most enriched biological process and molecular function. Cytokines -cytokine receptor was the most enriched pathways. Among 1013 identified DEGs in lesional group, 36 DEGs were found to have altered genetic signature including IL1B and STAT3 which are also reported as hub genes. CCNB1, CCNA2, CDK1, IL1B, CXCL8, MKI 67, ESR1, UBE2C, STAT1 and STAT3 were top 10 hub gene. Conclusion: The hub genes, genomic altered DEGs and other newly identified differentially dysregulated genes would improve our understanding of psoriasis pathogenesis, moreover, the hub genes could be explored as potential therapeutic targets for psoriasis.
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Shalbaf, Mohammad, Adewonuola A. Alase, Anna Berekmeri, Md Yuzaiful Md Yusof, Jelena Pistolic, Mark J. Goodfield, Sara Edward, et al. "Plucked hair follicles from patients with chronic discoid lupus erythematosus show a disease-specific molecular signature." Lupus Science & Medicine 6, no. 1 (July 2019): e000328. http://dx.doi.org/10.1136/lupus-2019-000328.
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ObjectiveWhen faced with clinical symptoms of scarring alopecia—the standard diagnostic pathway involves a scalp biopsy which is an invasive and expensive procedure. This project aimed to assess if plucked hair follicles (HFs) containing living epithelial cells can offer a non-invasive approach to diagnosing inflammatory scalp lesions.MethodsLesional and non-lesional HFs were extracted from the scalp of patients with chronic discoid lupus erythematosus (CDLE), psoriasis and healthy controls. RNA was isolated from plucked anagen HFs and microarray, as well as quantitative real-time PCR was performed.ResultsHere, we report that gene expression analysis of only a small number of HF plucked from lesional areas of the scalp is sufficient to differentiate CDLE from psoriasis lesions or healthy HF. The expression profile from CDLE HFs coincides with published profiles of CDLE from skin biopsy. Genes that were highly expressed in lesional CDLE corresponded to well-known histopathological diagnostic features of CDLE and included those related to apoptotic cell death, the interferon signature, complement components and CD8+ T-cell immune responses.ConclusionsWe therefore propose that information obtained from this non-invasive approach are sufficient to diagnose scalp lupus erythematosus. Once validated in routine clinical settings and compared with other scarring alopecias, this rapid and non-invasive approach will have great potential for paving the way for future diagnosis of inflammatory scalp lesions.
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Sumner, Emma J., Daniel McCluskey, Satveer K. Mahil, Myles Lewis, and Francesca Capon. "P17 A signature of IL-36 activation in systemic lupus erythematosus skin." British Journal of Dermatology 189, no. 1 (July 2023): e20-e21. http://dx.doi.org/10.1093/bjd/ljad174.038.
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Abstract Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with heterogeneous presentation. Joint and kidney disease represent the largest cause of morbidity, and visually distinctive skin complications are often present. While it has long been established that organ damage is caused by autoantibodies forming large immune complexes in the affected tissues, a detailed understanding of disease processes is still lacking. Here, we propose that interleukin (IL)-36 cytokines, which drive cutaneous and systemic symptoms in psoriasis, are also implicated in the pathogenesis of SLE. Given that the IL-36 receptor is prominently expressed in keratinocytes, we investigated this hypothesis in skin. We first carried out a systematic review of SLE single-cell RNA sequencing studies, identifying two data sets (∼50 000 cells in total) generated from patient skin biopsies. We processed both data sets with the same standardized pipeline, using the Seurat package. This identified 10 distinct cell clusters, replicating the cell types described in the original studies and identifying the main cell populations observed in human skin. Subsequent gene expression analysis confirmed that, in both data sets, the expression of IL36G and IL1RL2 (the genes encoding IL-36γ and its receptor) was highest in keratinocytes. Interestingly, subclustering showed that this signal was driven by the expression of IL36G in supraspinous keratinocytes and of IL1RL2 in proliferating keratinocytes. In the first data set, the expression of IL36G and IL1RL2 was readily detectable in lesional keratinocytes but virtually nonexistent in their nonlesional counterparts. A comparison of lesional and nonlesional keratinocytes also identified 297 differentially expressed genes (DEGs; log2 fold change > 1.2, false discovery rate < 0.05) in the first study and 234 in the second. To further explore these findings, we compared the above DEG with a set of 182 genes (previously defined by our group) that are upregulated in IL-36-stimulated keratinocytes. This demonstrated a significant over-representation of the IL-36 signature genes among the DEGs observed in lesional SLE keratinocytes (P < 0.005 in both data sets). These observations indicate that IL-36 is likely to contribute to skin inflammation in SLE, warranting further studies of this cytokine in organs affected by the disease.
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Kunz, Manfred, and Saleh M. Ibrahim. "Cytokines and Cytokine Profiles in Human Autoimmune Diseases and Animal Models of Autoimmunity." Mediators of Inflammation 2009 (2009): 1–20. http://dx.doi.org/10.1155/2009/979258.
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The precise pathomechanisms of human autoimmune diseases are still poorly understood. However, a deepened understanding of these is urgently needed to improve disease prevention and early detection and guide more specific treatment approaches. In recent years, many new genes and signalling pathways involved in autoimmunity with often overlapping patterns between different disease entities have been detected. Major contributions were made by experiments using DNA microarray technology, which has been used for the analysis of gene expression patterns in chronic inflammatory and autoimmune diseases, among which were rheumatoid arthritis, systemic lupus erythematosus, psoriasis, systemic sclerosis, multiple sclerosis, and type-1 diabetes. In systemic lupus erythematosus, a so-called interferon signature has been identified. In psoriasis, researchers found a particular immune signalling cluster. Moreover the identification of a new subset of inflammatory T cells, so-called Th17 T cells, secreting interleukin (IL)-17 as one of their major cytokines and the identification of the IL-23/IL-17 axis of inflammation regulation, have significantly improved our understanding of autoimmune diseases. Since a plethora of new treatment approaches using antibodies or small molecule inhibitors specifically targeting cytokines, cellular receptors, or signalling mechanisms has emerged in recent years, more individualized treatment for affected patients may be within reach in the future.
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Muromoto, Ryuta, Toru Hirao, Keisuke Tawa, Koki Hirashima, Shigeyuki Kon, Yuichi Kitai, and Tadashi Matsuda. "IL-17A plays a central role in the expression of psoriasis signature genes through the induction of IκB-ζ in keratinocytes." International Immunology 28, no. 9 (March 3, 2016): 443–52. http://dx.doi.org/10.1093/intimm/dxw011.
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Muromoto, Ryuta, Toru Hirao, Keisuke Tawa, and Tadashi Matsuda. "Interleukin-17A plays a fundamental role in the expression of psoriasis signature genes in keratinocytes through the induction of IκB-ζ." Journal of Dermatological Science 84, no. 1 (October 2016): e97. http://dx.doi.org/10.1016/j.jdermsci.2016.08.293.
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Mahil, Satveer K., Marika Catapano, Paola Di Meglio, Nick Dand, Helena Ahlfors, Ian M. Carr, Catherine H. Smith, et al. "An analysis of IL-36 signature genes and individuals with IL1RL2 knockout mutations validates IL-36 as a psoriasis therapeutic target." Science Translational Medicine 9, no. 411 (October 11, 2017): eaan2514. http://dx.doi.org/10.1126/scitranslmed.aan2514.
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Ward, Nicole, Philip Klenotic, Doina Diaconu, Thomas McCormick, and Andrew Johnston. "IL-6 deletion attenuates psoriasis-like skin inflammation in K5-IL-17C mice. (CCR6P.270)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 182.2. http://dx.doi.org/10.4049/jimmunol.192.supp.182.2.
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Abstract IL-17C is the most abundant IL-17 family member found in lesional psoriasis skin. IL-17C elicits a 4-fold increase in TNFα (P<0.05) from primary human endothelial cells (ECs) and primary human keratinocytes (KCs) stimulated with IL-17C/TNFα produce synergistic increases in psoriasis signature genes. Mice engineered to overexpress IL-17C in KCs (K5-IL-17C) develop a psoriasiform skin phenotype that improves upon TNFα inhibition. IL-17C also elicits a 3-fold increase in IL-6 from ECs (P<0.05), and IL-6 protein levels significantly increase in uninvolved and involved skin of K5-IL-17C mice (42% and 480%; P<0.05). We hypothesized that IL-6 synergizes with IL-17C to elicit chronic skin inflammation, akin to IL-17C/TNFα. To test this, we mated K5-IL-17C mice with IL-6 KO mice. K5-IL-17C-IL-6 KO mice develop less severe skin disease at 8-10 weeks of age vs K5-IL-17C mice (40% decrease in mouse PASI; n=15, P<0.05) and have significant decreases in serum TNFα (64%; n=4; P<0.035). Histological analyses of involved skin show no differences between K5-IL-17C vs K5-IL-17C-IL-6 KO mice, however analyses of uninvolved skin reveal a significantly thinner epidermis (2-fold decrease; P<0.001), decrease in dermal angiogenesis (27%; P<0.04), and decreases in CD4+ and CD8+ T cells and F4/80+ macrophages (30-51%; P<0.05) in K5-IL-17C-IL-6 KO vs K5-IL-17C mice (n=8/group). These data suggest that IL-6 may contribute to proinflammatory IL-17C signaling critical for sustained psoriasis pathogenesis.
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Rahman, Saifur, Mary Collins, Cara Williams, and Hak Ma. "Role of Th1, Th2 and Th17 cytokines on the expression of various inflammatory cytokines, defensive proteins and chemokines by primary human epithelial keratinocytes (148.10)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 148.10. http://dx.doi.org/10.4049/jimmunol.186.supp.148.10.
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Abstract Psoriasis and Atopic Dermatitis are common autoimmune/inflammatory diseases of the skin. Although the exact etiology is not clear, recent data suggest a dysregulated interplay between skin infiltrates and keratinocytes may play a role in disease progression. To better understand this relationship primary human fetal epithelial keratinocytes were cultured in the absence or presence of various Th1 (IFNg), Th17 (IL-17, IL-21 and IL-22) and Th2 cytokines (IL-4, IL-13) that are known to play a role in either psoriasis or AD. Our results demonstrate that individual treatment with either Th1 or Th17 cytokines (IFN-γ, IL-17 or IL-21) induced the proinflammatory cytokine gene expression of IL-1a and IL-6. However, the Th2 cytokines IL-4 and IL-13 had no effect on expression of the proinflammatory molecules. Additionally, IFN-γ or IL-22 alone or in combination increased the expression of ICAM-1, highlighting the potential for these cells to facilitate leukocyte recruitment to the skin epidermis. Interestingly, only treatment with IL-22 individually or in combination was found to markedly increase Defensin b, Filaggrin, S100A7 and S100A8, genes important in maintaining and protecting the integrity of the skin whereas treatment with only IL-21 or in combination markedly increased the expression of Twist-1, a signature gene for epithelial mesenchymal transition. Taken together, these results suggest various cytokines have unique and redundant roles in regulating keratinocyte activity.
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Morelli, Martina, Claudia Scarponi, Laura Mercurio, Francesco Facchiano, Sabatino Pallotta, Stefania Madonna, Giampiero Girolomoni, and Cristina Albanesi. "Selective Immunomodulation of Inflammatory Pathways in Keratinocytes by the Janus Kinase (JAK) Inhibitor Tofacitinib: Implications for the Employment of JAK-Targeting Drugs in Psoriasis." Journal of Immunology Research 2018 (November 19, 2018): 1–18. http://dx.doi.org/10.1155/2018/7897263.
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IFN-γ and IL-22 are deeply involved in the pathogenesis of psoriasis, as they boost the expression of inflammatory genes and alter proliferative and differentiative programs in keratinocytes. The JAK1/JAK2/STAT1 and JAK1/TYK2/STAT3 pathways triggered by IFN-γ and IL-22, respectively, are aberrantly activated in psoriasis, as highlighted by the peculiar STAT1 and STAT3 signatures in psoriatic skin lesions. To limit the detrimental consequences of IFN-γ and IL-22 excessive stimulation, psoriatic keratinocytes activate suppressor of cytokine signaling (SOCS)1 and SOCS3, which in turn dampen molecular signaling by inhibiting JAK1 and JAK2. Thus, JAK targeting appears to be a reasonable strategy to treat psoriasis. Tofacitinib is an inhibitor of JAK proteins, which, similarly to SOCS, impedes JAK phosphorylation. In this study, we evaluated the immunomodulatory effects of tofacitinib on epidermal keratinocytes in in vitro and in vivo models of psoriasis. We demonstrated the selectivity of tofacitinib inhibitory action on IFN-γ and IL-22, but not on TNF-γ or IL-17 proinflammatory signaling, with suppressed expression of IFN-γ-dependent inflammatory genes, and restoration of normal proliferative and differentiative programs altered by IL-22 in psoriatic keratinocyte cultures. Tofacitinib also potently reduced the psoriasiform phenotype in the imiquimod-induced murine model of psoriasis. Finally, we found that tofacitinib mimics SOCS1 or SOCS3 activities, as it impaired the same molecular pathways in IFN-γ or IL-22-activated keratinocytes.
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Vecellio, M., A. Ceribelli, E. Paraboschi, N. Isailovic, F. Motta, M. De Santis, R. Asselta, S. Duga, and C. Selmi. "POS0361 DNA METHYLATION SIGNATURES CHARACTERIZE PSORIASIS AND PSORIATIC ARTHRITIS IN MONOZYGOTIC TWINS DISCORDANT FOR THE DISEASE." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 410.3–411. http://dx.doi.org/10.1136/annrheumdis-2021-eular.3948.
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Background:Psoriatic disease is a chronic inflammatory disorder spanning from skin disease (psoriasis) to psoriatic arthritis (PsA). The genetic background is insufficient to explain disease onset as illustrated by not very informative Genome Wide Association Studies and monozygotic (MZ) twin studies recently performed. It is strongly assumed that epigenetics may contribute to disease susceptibility modulating gene expression. DNA methylation has been found involved in several autoimmune inflammatory rheumatic diseases. Here we have analysed the DNA methylation profile of a selected cohort of MZ twins discordant for psoriasis/PsA.Objectives:To identify the methylome associated with psoriasis and PsA in the peripheral blood of MZ twins discordant for these conditions.Methods:Peripheral blood from 7 couples of MZ twins discordant for psoriatic disease was collected and DNA extracted for a genome-wide evaluation of the DNA methylation profile, with the Infinium MethylationEPIC BeadChip. Minfi and the packages of the Bioconductor were used to analyse the data obtained. Quality control and exclusion criteria were applied to the raw data having a final number of 762.451 probes, which accounts for 88% of the total.Results:The approach first identified 2564 differentially methylated positions (DMPs; *p<0.005) with 19 genes potentially affected (with at least two DMPs within 1 kb of distance), including SMAD3 and SMARCA4/BRG1 involved in the Interferon and TGFβ pathways. Gene Ontology (GO) analysis of DMP-associated genes showed a significative enrichment (*p<0.005) in transcription factor binding, transcription corepressor and transcription coactivator activity, SMAD binding and histone -lysine-N-methyltransferase activity. To further validate the results, 5’-methylcytosine immunoprecipitation (MedIP) followed by Real Time PCR was performed to assess the methylation level of SMAD3 and SMARCA4/BRG1 promoters in the same cohort of MZ twins. We found significantly DNA methylation enrichment in SMARCA4/BRG1 promoter in psoriatic disease twins (p<0.05). SMAD3 and SMARCA4/BRG1 mRNA expression was also assessed to evaluate any inverse correlation with promoter methylation level, on the MZ cohort used for the EPIC array (n=4) and on a cohort of PsA/Ps patients (n=8) and appropriate healthy controls (n=3). Reduced mRNA expression (p<0.05) was demonstrated for SMARCA4/BRG1 (n=4). Conversely, no changes were found for SMAD3.Conclusion:We report the first DNA methylation approach in MZ twins discordant for psoriatic disease. We believe that the observed changes in SMAD3 and SMARCA/BRG1 genes may suggest an epigenetic imbalance of chromatin remodelling factors involved in inflammation pathways with a potential role in PsA/psoriasis immunopathogenesis.Disclosure of Interests:None declared
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Schwartz, Daniella M., Aran Son, Francoise Meylan, Julio Gomez-Rodriguez, Zenia Kaul, McKella Sylvester, Moses Kitakule, et al. "Dynamic chromatin accessibility licenses STAT5- and STAT6-dependent innate-like function of Th9 cells to promote allergic inflammation." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 67.21. http://dx.doi.org/10.4049/jimmunol.210.supp.67.21.
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Abstract Allergic diseases are a major global health issue, causing significant morbidity and mortality. Interleukin-9 (IL-9) producing T helper 9 (Th9) cells promote allergic inflammation, yet Th9 effector functions are incompletely understood because the heterogeneity and instability of Th9 cells makes them challenging to study. Although the significance and mechanisms of Th9 instability are unknown, T cell receptor (TCR) activation is hypothesized to play a key role. Conversely to this paradigm, we found that resting Th9 cells did not require TCR restimulation for IL-9 production, which was induced by STAT5- and STAT6-dependent paracrine cytokines. This mechanism was seen in circulating T cells from allergic patients and was restricted to recently activated cells. Analysis of IL-9 +T cells from allergic subjects revealed a transcriptional program that was enriched for activation pathways and unstable over time, with IL9 amongst the least stable genes. Prolonged resting of cells decreased the accessibility of STAT5-dependent IL9 enhancers, inactivating the locus. In vivo, Th9 cells induced airway inflammation via TCR-independent, STAT-dependent mechanisms. In allergic patients, Th9 expansion was associated with STAT activation and responsiveness to JAK inhibitors. These findings suggest that Th9 instability is a negative checkpoint on TCR-independent inflammation that breaks down in allergic disease, and that JAK inhibitors should be considered for allergic patients with a Th9 signature. Supported by the NIAID intramural research program (2018-2022), University of Pittsburgh start-up funds (2022-current), and the National Psoriasis Foundation (Robertson Fellowship, 2018-2021; Translational Grant, 2022-current)
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Huang, Yu-Huei, Lun-Ching Chang, Ya-Ching Chang, Wen-Hung Chung, Shun-Fa Yang, and Shih-Chi Su. "Compositional Alteration of Gut Microbiota in Psoriasis Treated with IL-23 and IL-17 Inhibitors." International Journal of Molecular Sciences 24, no. 5 (February 26, 2023): 4568. http://dx.doi.org/10.3390/ijms24054568.
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Alterations in the gut microbiota composition and their associated metabolic dysfunction exist in psoriasis. However, the impact of biologics on shaping gut microbiota is not well known. This study aimed to determine the association of gut microorganisms and microbiome-encoded metabolic pathways with the treatment in patients with psoriasis. A total of 48 patients with psoriasis, including 30 cases who received an IL-23 inhibitor (guselkumab) and 18 cases who received an IL-17 inhibitor (secukinumab or ixekizumab) were recruited. Longitudinal profiles of the gut microbiome were conducted by using 16S rRNA gene sequencing. The gut microbial compositions dynamically changed in psoriatic patients during a 24-week treatment. The relative abundance of individual taxa altered differently between patients receiving the IL-23 inhibitor and those receiving the IL-17 inhibitor. Functional prediction of the gut microbiome revealed microbial genes related to metabolism involving the biosynthesis of antibiotics and amino acids were differentially enriched between responders and non-responders receiving IL-17 inhibitors, as the abundance of the taurine and hypotaurine pathway was found to be augmented in responders treated with the IL-23 inhibitor. Our analyses showed a longitudinal shift in the gut microbiota in psoriatic patients after treatment. These taxonomic signatures and functional alterations of the gut microbiome could serve as potential biomarkers for the response to biologics treatment in psoriasis.
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Natoli, V., A. Charras, S. Hofmann, S. Northey, S. Russ, F. Schulze, S. Abraham, and C. Hedrich. "OP0100 DNA METHYLATION PATTERNS IN CD4+ T CELLS DISCERN SKIN PSORIASIS FROM PSORIATIC ARTHRITIS." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 67–68. http://dx.doi.org/10.1136/annrheumdis-2023-eular.4069.
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BackgroundPsoriasis is a systemic inflammatory disease that primarily affects the skin. Approximately one third of psoriasis patients develop joint involvement and are therefore diagnosed with psoriatic arthritis (PsA). While, in adults, the development of arthritis usually follows skin psoriasis, approximately 15% of patients experience arthritis simultaneously or prior to skin disease. Thus, PsA can be missed, leading to disease progression, damage, and reduced quality of life. Individualized care is complicated by the absence of disease- or outcome-specific biomarkers.While the pathophysiology of psoriasis is incompletely understood, a key role of effector T-cells has been established. Recent studies linked altered DNA methylation with T-cell dysregulation and phenotypical variation between patients.ObjectivesThis project aimed to identify disease-associated DNA methylation signatures in CD4+T-cells from psoriasis and PsA patients as compared to healthy controls that may be used as diagnostic and/or prognostic biomarkers and inform future treatment.MethodsPeripheral blood samples were collected from 9 healthy controls, 11 skin psoriasis and 8 PsA patients. PBMCs were isolatedex vivo, CD4+T-cells were FACS separated, and genomic DNA was isolated. DNA methylation profiling was performed using the Illumina Human Methylation EPIC 850K platform. Bioinformatic analyses, including gene ontology (GO) and KEGG pathway analysis, were performed using R software (minfi,limma,ChAMP,DMRcate,clusterProfiler). Flow cytometry datasets were analyzed usingFlowJo. To identify genes under the control of interferon (IFN), theInterferomedatabase was consulted. DNA Methylation Scores were calculated for type I and type II interferons following the method suggested by Björket al.(2020).ResultsNumbers and proportions of CD4+T-cells did not vary between controls and patients with skin psoriasis or PsA. Furthermore, no differences between controls and patient groups were observed in the proportion of CD4+T-cell subsets (naïve, central memory, effector memory, CD45RA re-expressing effector memory cells).We detected 820 differentially methylated positions (DMPs) affecting 433 genes in CD4+T-cells from healthy controls when compared to psoriasis and PsA patients. Based on DMP analyses, groups segregated in principal component (PCA) or partial least-squares discriminant analyses (PLS-DA) (Figure 1). Separation in PLS-DA was centrally influenced by two CGs (cg07021052, cg10687131) localized inGDF7(Growth and Differentiation factor 7), which affects T-cell regulatory factors FOXP3 and CTLA4. GO analysis of genes with at least one DMP in their promoter region delivered hypomethylation of genes involved in “negative regulation of focal adhesion assembly”, “cell-substrate junction organization” and “regulation of the triglyceride biosynthetic”. DNA methylation profiles (855 DMPs affecting 551 genes) distinguished between skin psoriasis and PsA patients; a high proportion of DMPs associated with interferon-regulated genes (68% total: 8.8% type I, 33.5% type II, 23.8% type I and II IFN). GO analysis delivered an enrichment of hypomethylated genes affecting “carboxylic ester hydrolase”, “alkyl or aryl group transferase” and “glutathione transferase activity”. Notably, we observed a majority DMPs in IFN-related genes when comparing healthy controls with PsA patients (61.9% total: 9.1% type I, 29% type II, 23.8% type I and II IFN) and controls with skin psoriasis patients (62.7% total, 7.7% type I, 31% type II, 24% type I and II IFN). Moreover, DNA methylation calculated for type I and type II IFN-associated genes significantly differed between healthy controls, skin psoriasis and PsA patients.ConclusionDNA methylation profiles in CD4+ T-cells discriminate between controls, skin psoriasis and PsA. As DNA methylation signatures may predict disease progression from psoriasis to PsA, they may be applied for molecular patient stratification towards future individualized treatment and care.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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Wu, C., Y. Hu, M. K. Crow, A. Saxena, C. Arriens, C. Hobar, A. Coles, and I. M. Catlett. "AB0521 IDENTIFICATION OF AN INTERFERON 5-GENE SIGNATURE SCORE AS A PHARMACODYNAMIC AND POTENTIAL PREDICTIVE BIOMARKER FOR DEUCRAVACITINIB TREATMENT IN A PHASE 2 TRIAL IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 1456.1–1456. http://dx.doi.org/10.1136/annrheumdis-2023-eular.3952.
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BackgroundTyrosine kinase 2 (TYK2) mediates cytokine pathways (eg, Type I IFN) linked with systemic lupus erythematosus (SLE) pathogenesis. Deucravacitinib is a first-in-class, oral, selective, allosteric TYK2 inhibitor approved in multiple countries for the treatment of adults with plaque psoriasis[1,2]. Deucravacitinib was efficacious compared with placebo in a phase 2 SLE trial[3].ObjectivesTo develop a customized IFN 5-gene signature score, assess the pharmacodynamic effects of deucravacitinib on the IFN score, and evaluate the score’s association with SLE disease activity and clinical response in the phase 2 trial.MethodsPatients with active SLE were randomized equally to oral placebo or deucravacitinib (3 mg BID, 6 mg BID, or 12 mg QD). DxTerity chemical ligation-dependent probe amplification was used to measure 51 immune system-related genes from whole blood. IFN genes were selected based on distribution, correlations, hierarchical clustering, and consistency of k-means clusters. Serum proteins, blood cell subsets, and antibody profiles were measured by immunoassays and flow cytometry. SRI(4) and BICLA were measured at weeks 32 and 48.ResultsAn IFN 5-gene (MX1,HERC5,IFIT1,RSAD2, andEIF2AK2) signature score was identified and used to classify patients into IFN-high or IFN-low subgroups (Figure 1). Higher baseline IFN score was associated with higher baseline SLEDAI and CLASI disease activity scores, higher levels of IFN activity biomarker (eg, IFNα, IFNλ, BAFF, CXCL10) and anti-dsDNA, and lower complement and lymphocyte counts. Baseline IFN score was not predictive of SRI(4) response. A higher baseline IFN score was associated with a significantly higher probability of BICLA response with deucravacitinib 3 mg BID relative to placebo (P=0.014). Deucravacitinib reduced the IFN score from weeks 4 through 44 by >50%.ConclusionThese data support the IFN 5-gene signature score as a biomarker to classify patients with SLE into IFN-high or IFN-low subgroups; however, clinical response by IFN score was inconsistently improved (Table 1). IFN-regulated gene expression performs well as a pharmacodynamic biomarker to confirm deucravacitinib mechanism of action and to aid in phase 3 dose selection.References[1]Armstrong A, et al.J Am Acad Dermatol.2023;88(1):29-39.[2]Strober B, et al.J Am Acad Dermatol.2023;88(1):40-51.[3]Morand E, et al.Arthritis Rheumatol.2022; Nov 11 (Epub ahead of print).Table 1.Clinical response at week 32PlaceboN = 90Deucravacitinib3 mg BIDN = 91Deucravacitinib6 mg BIDN = 93Deucravacitinib12 mg QDN = 89SRI(4) response rate, n/N (%)IFN High21/65 (32.3)47/76 (61.8)37/73 (50.7)35/69 (50.7)IFN Low10/25 (40.0)8/15 (53.3)11/20 (55.0)5/20 (25.0)BICLA response rate, n/N (%)IFN High18/65 (27.7)39/76 (51.3)31/73 (42.5)30/69 (43.5)IFN Low13/25 (52.0)7/15 (46.7)13/20 (65.0)7/20 (35.0)BICLA, British Isles Lupus Assessment Group‒Based Composite Lupus Assessment; BID, twice daily; IFN, interferon; QD, once daily; SRI, Systemic Lupus Erythematosus Responder Index.AcknowledgementsThis study was sponsored by Bristol Myers Squibb.Disclosure of InterestsChun Wu Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Yanhua Hu Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Mary K. Crow Consultant of: AMPEL BioSolutions, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Lilly, Grant/research support from: Gilead Sciences, Amit Saxena Grant/research support from: AstraZeneca, Bristol Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Kezar Life Sciences, Cristina Arriens Speakers bureau: AstraZeneca, Aurinia, Bristol Myers Squibb, GlaxoSmithKline, Kezar, Grant/research support from: AstraZeneca, Bristol Myers Squibb, Coburn Hobar Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Adrian Coles Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Ian M. Catlett Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb.
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Xiao, Shiju, Xin Liu, Xiaoxu Wang, Hongpeng Lv, Junbo Zhao, Xinwei Guo, Fuyang Xian, Yunrun Ji, and Guangzhong Zhang. "Plasma MicroRNA Expression Profiles in Psoriasis." Journal of Immunology Research 2020 (January 16, 2020): 1–12. http://dx.doi.org/10.1155/2020/1561278.
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Background. Psoriasis is an immune-mediated inflammatory chronic skin disease characterized by chronic inflammation in the dermis, parakeratosis, and excessive epidermal growth. MicroRNAs (miRNAs) are key regulators of immune responses. Although differential expression of miRNAs has been reported in certain inflammatory autoimmune diseases, their role in psoriasis has not been fully illuminated. Our aims were to confirm plasma miRNA expression signatures in psoriasis and to examine their potential influence on psoriasis pathogenesis. Methods. A miRNome PCR array was used to analyse the plasma of psoriasis patients and healthy donors. We performed miRNA pathway enrichment and target gene network analyses on psoriasis plasma samples. Results. We found several specific plasma miRNA signatures relevant to psoriasis. The miRNAs targeted pathways associated with psoriasis, such as the VEGF, MAPK, and WNT signaling pathways. Network analysis revealed pivotal deregulated plasma miRNAs and their relevant target genes and pathways regulating psoriasis pathogenesis. Conclusions. This study analysed the expression of plasma miRNAs and their target pathways, elucidating the pathogenesis of psoriasis; these results may be used to design novel therapeutic strategies and to identify diagnostic biomarkers for psoriasis.
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Cheng, T., S. X. Zhang, J. Qiao, R. Zhao, S. Song, Y. Zhang, P. Zhao, G. Y. Liu, P. F. He, and X. Li. "POS0363 IDENTIFICATION OF MOLECULAR PHENOTYPES AND IMMUNE CELL INFILTRATION IN PSORIATIC ARTHRITIS PATIENTS’ SKIN TISSUES BY INTEGRATED BIOINFORMATICS ANALYSIS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 411.1–411. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2171.
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Background:Psoriatic arthritis (PsA) is an inflammatory musculoskeletal disease associated with cutaneous psoriasis1. Heterogeneity of clinical manifestation often makes differential diagnosis difficult 2. Thus, the underlying molecular pathogenesis of PsA need to be further studied to diagnose early and ensure optimal management of arthritis and key comorbidities.Objectives:This research was conducted to identify molecular phenotypes and immune infiltration in the skin tissues of psoriatic arthritis patients according to bioinformatics analysis.Methods:The mRNA expression profiles of GSE13355 (116 samples), GSE14905 (56 samples) and GSE30999 (162 samples) were obtained from the publicly GEO databases. Non-negative matrix factorization (NMF), functional enrichment and cibersort algorithm were applied to illustrate the conditions of PsA patients’ skin tissues for classification after screening the differentially expressed genes (DEGs) between lesion biopsy and non-lesion biopsy.Results:Two subsets (Sub1 and Sub2) were identified and validated by NMF typing of 612 detected DEGs (Figure 1a). A total of 54 signature genes (18 in Sub1 and 36 in Sub2) were obtained (Figure 1b). GO and KEGG enrichment analysis showed the signature genes in Sub1 were mainly involved in proliferation and differentiation of immune cells, whereas genes in Sub2 were related to humoral immune response mediated by antimicrobial peptide (Figure 1c.1d). Further, immune cell infiltration results revealed Sub2 had higher levels of resting NK cells (P<0.001), macrophages M1(P<0.001), resting mast cells (P<0.001) and regulatory T cells (P<0.001) but lower concentrations of activated CD4+ memory T cells (P<0.001), activated NK cells (P<0.05), activated dendritric cells(P<0.001), eosinophils (P<0.05) and neutrophil (P<0.001) (Figure 1e).Conclusion:The pathogenesis of psoriatic arthritis is related to both cellular immunity and humoral immunity. It is indispensable to adjust the treatment strategies according to patient’s immune status.References:[1]Ritchlin CT, Colbert RA, Gladman DD. Psoriatic Arthritis. The New England journal of medicine 2017;376(10):957-70. doi: 10.1056/NEJMra1505557 [published Online First: 2017/03/09].[2]Veale DJ, Fearon U. The pathogenesis of psoriatic arthritis. Lancet (London, England) 2018;391(10136):2273-84. doi: 10.1016/s0140-6736(18)30830-4 [published Online First: 2018/06/13].Acknowledgements:This project was supported by National Science Foundation of China (82001740), Open Fund from the Key Laboratory of Cellular Physiology (Shanxi Medical University) (KLCP2019) and Innovation Plan for Postgraduate Education in Shanxi Province (2020BY078).Disclosure of Interests:None declared
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Yue, Qi, Zhaoxiang Li, Qi Zhang, Quanxin Jin, Xinyuan Zhang, and Guihua Jin. "Identification of Novel Hub Genes Associated with Psoriasis Using Integrated Bioinformatics Analysis." International Journal of Molecular Sciences 23, no. 23 (December 4, 2022): 15286. http://dx.doi.org/10.3390/ijms232315286.
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Psoriasis is a chronic, prolonged, and recurrent inflammatory skin disease and the current therapeutics can only alleviate the symptoms rather than cure it completely. Therefore, we aimed to identify the molecular signatures and specific biomarkers of psoriasis to provide novel clues for psoriasis and targeted therapy. In the present study, the Gene Expression Omnibus (GEO) database was used to retrieve three microarray datasets (GSE166388, GSE50790 and GSE42632) and to explore the differentially expressed genes (DEGs) in psoriasis using the Affy package in R software. The gene ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment were utilized to determine the common DEGs and their capabilities. The STRING database was used to develop DEG-encoded proteins and a protein–protein interaction network (PPI) and the Cytohubba plugin to classify hub genes. Using the NetworkAnalyst platform, we detected transcription factors (TFs), microRNAs and drug candidates interacting with hub genes. In addition, the expression levels of hub genes in HaCaT cells were detected by western blot. We screened the up- and downregulated DEGs from the transcriptome microarrays of corresponding psoriasis patients. Functional enrichment of DEGs in psoriasis was mainly associated with positive regulation of leukocyte cell–cell adhesion and T cell activation, cytokine binding, cytokine activity and the Wnt signaling pathway. Through further data processing, we obtained 57 intersecting genes in the three datasets and probed them in STRING to determine the interaction of their expressed proteins and we obtained the critical 10 hub genes in the Cytohubba plugin, including TOP2A, CDKN3, MCM10, PBK, HMMR, CEP55, ASPM, KIAA0101, ESC02, and IL-1β. Using these hub genes as targets, we obtained 35 TFs and 213 miRNAs that may regulate these genes and 33 potential therapeutic agents for psoriasis. Furthermore, the expression levels of TOP2A, MCM10, PBK, ASPM, KIAA0101 and IL-1β were observably increased in HaCaT cells. In conclusion, we identified potential biomarkers, risk factors and drugs for psoriasis.
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Yin, Xianyong, Hui Cheng, Yan Lin, Xing Fan, Yong Cui, Fusheng Zhou, Changbing Shen, et al. "Five regulatory genes detected by matching signatures of eQTL and GWAS in psoriasis." Journal of Dermatological Science 76, no. 2 (November 2014): 139–42. http://dx.doi.org/10.1016/j.jdermsci.2014.07.007.
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Zhang, Y., S. X. Zhang, J. Qiao, R. Zhao, S. Song, Y. Li, M. J. Chang, G. Y. Liu, P. F. He, and X. Li. "POS0199 TIME-SERIES ANALYSIS IN MODERATE TO SEVERE PLAQUE PSORIASIS UNDER DIFFERENT BIOLOGICS TREATMENTS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 315–16. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2669.
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Background:Moderate to Severe Plaque Psoriasis is an inflammatory skin disease that is associated with multiple comorbidities and substantially diminishes patients’ quality of life. As one of the most significant therapeutic advancements in the field of dermatology, Biologics such as TNF inhibitors, IL-12/23 inhibitor, IL-17 inhibitors, and IL-23 inhibitors, have higher efficacy compared with oral medications or phototherapy1. However, the previous studies did not focus on the simultaneous comparison of molecular changes in different classes of biologics. The identification of time-series genes (TSGs) could help to uncover the mechanisms underlying transcriptional regulation2.Objectives:In this study, we aimed to compare the differences in expression patterns and functions of time-series genes in Moderate to Severe Plaque Psoriasis under different biologics treatments.Methods:The transcription profile of GSE117239 and GSE51440 were obtained from the Gene Expression Omnibus database (GEO). The GSE117239 included 19 samples treated with Etanercept (TNF inhibitors) and 16 samples treated with Ustekinumab (IL-12/23 inhibitor). The GSE51440 included 4 samples treated with Guselkumab (IL-23 inhibitors). Skin biopsy samples (LS: lesion, NL: non-lesion) were collected at baseline, weeks 1 and 12, respectively. After background adjustment and other pre-procession, differentially expressed genes (DEGs) were extracted from LS skin biopsy and untreated NL skin biopsy at different times after three different biologics treatments, respectively. The Short Time-series Expression Miner (STEM) software was used to cluster and compare average DEGs with coherent changes. Afterward, the different expression patterns of TSGs under the three treatment groups were compared. GO analysis and KEGG pathway enrichment analysis of TSGs were performed by Metascape.Results:Different DEGs varied in LS skin compared with those of NL skin biopsy: 976 genes in Ustekinumab group, 996 genes in Etanercept group, and 601 genes in Guselkumab group detailly (P < 0.05 and [log FC] > 1). Gene landscapes suggested the signatures of LS gradually changed during the treatment process, and gradually converge to NL signatures (Fig.1a, 2a,3a). Time-series genes in the three treatment groups had different expression patterns and functions. In the Ustekinumab group, a total of 448 TSGs in profile 3 showed a stable-stable-decreasing expression trend and significantly associated with mitotic nuclear division and defense response to other organism, whereas in profile 4 represented a stable-stable-increasing expression trend and significantly associated with positive regulation of cellular response to organic 9 compound (Fig.1). With the treatment of Etanercept, 22 TSGs had a stable-increasing-increasing expression tendency and closely associated with fatty acid metabolism and steroid metabolic process (Fig.2). After Guselkumab treatment, 13 TSGs also represented a stable-increasing-increasing expression tendency that mainly characterized by defense response to other organism and epidermis development (Fig.3). Interestingly, both Ustekinumab and Guselkumab treatment dramatically influenced defense response to other organism-related genes, while Etanercept mainly affected genes involved in fatty acid metabolism and steroid metabolic process.Conclusion:Biologics effectively reconstituted the gene signatures of psoriasis in different aspects. TSG features could be one of indicator for precise intervention for psoriasis.References:[1]Armstrong AW, Read C. Pathophysiology, Clinical Presentation, and Treatment of Psoriasis: A Review. Jama 2020;323(19):1945-60. doi: 10.1001/jama.2020.4006 [published Online First: 2020/05/20][2]Ernst J, Bar-Joseph Z. STEM: a tool for the analysis of short time series gene expression data. BMC Bioinformatics 2006;7:191. doi: 10.1186/1471-2105-7-191 [published Online First: 2006/04/07]Acknowledgements:This project was supported by National Science Foundation of China (82001740), Open Fund from the Key Laboratory of Cellular Physiology (Shanxi Medical University) (KLCP2019) and Innovation Plan for Postgraduate Education in Shanxi Province (2020BY078).Disclosure of Interests:None declared
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Pelosi, Andrea, Claudio Lunardi, Piera Filomena Fiore, Elisa Tinazzi, Giuseppe Patuzzo, Giuseppe Argentino, Francesca Moretta, Antonio Puccetti, and Marzia Dolcino. "MicroRNA Expression Profiling in Psoriatic Arthritis." BioMed Research International 2018 (2018): 1–15. http://dx.doi.org/10.1155/2018/7305380.
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Background. Psoriatic arthritis (PsA) is an inflammatory arthritis, characterized by bone erosions and new bone formation. MicroRNAs (miRNAs) are key regulators of the immune responses. Differential expression of miRNAs has been reported in several inflammatory autoimmune diseases; however, their role in PsA is not fully elucidated. We aimed to identify miRNA expression signatures associated with PsA and to investigate their potential implication in the disease pathogenesis. Methods. miRNA microarray was performed in blood cells of PsA patients and healthy controls. miRNA pathway analyses were performed and the global miRNA profiling was combined with transcriptome data in PsA. Deregulation of selected miRNAs was validated by real-time PCR. Results. We identified specific miRNA signatures associated with PsA patients with active disease. These miRNAs target pathways relevant in PsA, such as TNF, MAPK, and WNT signaling cascades. Network analysis revealed several miRNAs regulating highly connected genes within the PsA transcriptome. miR-126-3p was the most downregulated miRNA in active patients. Noteworthy, miR-126 overexpression induced a decreased expression of genes implicated in PsA. Conclusions. This study sheds light on some epigenetic aspects of PsA identifying specific miRNAs, which may represent promising candidates as biomarkers and/or for the design of novel therapeutic strategies in PsA.
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Tzemach, R., O. Elkayam, A. Polachek, V. Furer, S. Y. Wang, E. David, and I. Amit. "OP0110 SINGLE CELL RNA-SEQ DISSECTION OF THE SYNOVIAL FLUID IN PSORIATIC ARTHRITIS PATIENTS IDENTIFIES MYELOID CELL SUBSETS RELATED TO TREATMENT RESPONSE WITH BDMARDS." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 73–74. http://dx.doi.org/10.1136/annrheumdis-2023-eular.6410.
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BackgroundPsoriatic arthritis (PsA) is a complex chronic inflammatory disease involving aberrant activation of the innate and the adaptive immune systems[1]. While the adaptive system in the synovial fluid of PsA patients has been recently described at a single cell level[2], a comprehensive map of the myeloid compartment is still lacking.Anti TNF agents are commonly used as the first biologic DMARDs (bDMARDs) after failure of conventional DMARDs (cDMARDs), though up to 30-40% of PsA patients are anti TNF non-responders[3]. The inflammatory pathways leading to anti TNF or other bDMARDs resistance are unknown and biomarkers to predict treatment response are scarce.Objectives1. To construct a comprehensive immune map of the myeloid compartment in the synovial fluid of naïve and treated PsA patients. 2. To identify gene signatures and immune pathways characteristic of anti TNF or other bDMARDs non-responders.MethodsThis pilot study included PsA patients with active knee arthritis enrolled according to CASPAR criteria, including naïve and treated patients.We obtained synovial fluid by intra-articular aspiration of the involved knee.For each patient we performed single-cell sorting for CD45+ and MHCII+/CD11c+ to enrich for the myeloid compartment (particularly, dendritic cells and monocytes).We used single cell RNA-seq to dissect the immune landscape of the synovial fluid in PsA patients. Osteoarthritis patients with knee involvement were enrolled as a control.PsA Patients were followed for a minimum of 7 months from sampling day (range 7-30 months) and categorized as responders or non-responders according to the DAPSA score.ResultsWe analyzed a total of 91,837 cells from 33 PsA Patients (11 naive, 22 under cDMARDs and bDMARDs: 9 anti-TNF and other 9 bDMARDs) and 7 controls (OA).The synovial fluid myeloid compartment of PsA patients was composed of intermediate monocytes (CD14+ CD16+); TREM2 macrophages; conventional dendritic cells: cDC1 (XCR1, CLEC9A), cDC2 (CD1c, CLEC10A) and migratory DCs (mDC: CCR7, LAMP3, IDO1).Intermediate monocytes were the most abundant cell type in the myeloid compartment.Compared to OA controls, PsA patients’ synovial fluid was enriched with T regulatory cells (Treg: CD4+ FOXP3+) and migratory DCs (mDC: CCR7, LAMP3, IDO1).Tregs and TREM2 macrophages were more prevalent among treated than naïve PsA patients.We identified a unique cluster of cDC2 and monocytes with shared molecular signature, characteristic of anti TNF or other bDMARDs non-responders. These clusters demonstrated a high expression of interferon signature genes (ISG15, ISG20, IFI27, IFI6, IFIT3, STAT1) and genes related to the immunoproteasome (PSMB9, PSMB8, PSME2, PSME1, POMP).Two patients with severe deformative PsA highly refractory to treatment demonstrated a distinct cDC1 cluster with a high expression of inhibitory genes, such as IDO1, IL4I1, CMTM6 and NFKB1A.Figure 1.ConclusionOur study provides the first unbiased map of the myeloid compartment of the synovial fluid of PsA patients.We identified clinically significant cell-subsets within the cDC2 and monocytes populations associated with anti -TNF or other bDMARDs non-response, illuminating potential biomarkers and future therapeutic targets.References[1]Veale DJ, Fearon U. The pathogenesis of psoriatic arthritis.Lancet. 2018.[2]Penkava F, Velasco-Herrera MDC, Young MD, et al. Single-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis.Nat Commun. 2020.[3]Noviani M, Feletar M, Nash P, Leung YY. Choosing the right treatment for patients with psoriatic arthritis.Ther Adv Musculoskelet Dis. 2020.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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Zheng, L. L., J. W. Hao, L. C. Zhang, J. Qiao, M. J. Chang, S. X. Zhang, and X. Li. "POS0977 DEEP ANALYSIS OF SKIN MOLECULAR HETEROGENEITIES AND THEIR IMPLICATIONS ON THE PRECISE TREATMENT OF PATIENTS WITH PSORIASIS." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 804. http://dx.doi.org/10.1136/annrheumdis-2023-eular.2305.
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BackgroundPsoriasis is a highly heterogeneous autoinflammatory disease[1]. Molecular and cellular characteristics of the patient skin are major determinants of clinical outcome for a given treatment[2].Current disease heterogeneity has not been sufficiently translated to specific treatment option.ObjectivesWe aimed to develop and validate a novel stratification scheme by integrating large-scale transcriptomic profiles to determine the heterogeneity of psoriasis, identify patient subtypes, and provide insights for designing stratified treatments.MethodsWe performed functional enrichment and network analysis of upregulated differentially expressed genes (DEGs) using microarray datasets of lesional and non-lesional skin samples from 250 patients with psoriasis. Unsupervised clustering methods were used to identify the skin subtypes[3]. Finally, the Xgboost classifier was constructed to predict the responses of stratified subtypes to commonly used biologics.ResultsBased on the 163 upregulated DEGs, the patients with psoriasis were categorized into three subtypes (subtypes Ased biologics. datasets of lesional and non-lesional skin samples from 250 patients with psoriasiselated pathways were markedly activated in subtype A, named immune activation. Contrastingly, subtype C, named stroma proliferation, was enriched in integrated stroma cells and tissue proliferation-related signaling pathways. Subtype B was modestly activated in all the signaling pathways. Notably, subtypes A and B presented good responses to methotrexate (MTX) and IL-12/23 inhibitors (ustekinumab) but inadequate responses to TNF-α inhibitors and IL-17A receptor (IL-17RA) inhibitors. In contrast, subtype C exhibited excellent responses to TNF-α inhibitors (etanercept) and IL-17RA inhibitors (brodalumab) but not MTX and IL-12/23 inhibitors.ConclusionDeep stratification based on skin heterogeneities was employed to categorize patients with psoriasis into three subtypes with distinct molecular and cellular signatures, which determined the clinical responses of different conventional therapies.References[1]Kim WB, Jerome D, Yeung J.Diagnosis and management of psoriasis.Can Fam Physician2017; 63(4):278-285.[2]Armstrong AW, Read C.Pathophysiology, Clinical Presentation, and Treatment of Psoriasis: A Review.Jama2020; 323(19):1945-1960.[3]Wilkerson MD, Hayes DN.ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking.Bioinformatics2010; 26(12):1572-1573.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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Wu, Christina, Emanuela M. Ghia, Fitzgerald Lao, Minya Pu, Karen Messer, Laura Z. Rassenti, Thomas J. Kipps, Dennis A. Carson, and Michael Y. Choi. "Tecfidera Modulates Activation of Malignant B-Cells: Correlative Analysis from a Phase 1 Clinical Trial in Patients with Chronic Lymphocytic Leukemia." Blood 132, Supplement 1 (November 29, 2018): 3143. http://dx.doi.org/10.1182/blood-2018-99-119292.
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Abstract Tecfidera (Dimethylfumarate, DMF) is an immunomodulatory drug currently approved in the United States for the treatment of patients with multiple sclerosis (MS). DMF formulations have also been utilized for the treatment of patients with psoriasis. The ability of DMF to Inhibit autoreactive T-lymphocytes may also be applicable to malignant T- and B- lymphocytes. Indeed, preclinical studies by multiple groups have highlighted its potential efficacy as a treatment for patients with various lymphoid cancers, though inhibition of STAT, NF-KB, Wnt signaling pathways, and glycolysis. This information provided rationale to conduct a phase 1 clinical trial of DMF as a treatment for patients with relapsed chronic lymphocytic leukemia (CLL). In this study we report the correlative assessment of the initial patients who received DMF. Patients with relapsed or refractory CLL received DMF 120 mg PO BID (based on preclinical modeling with primary CLL cells in vitro and in vivo and 50% lower than the standard DMF dose for patients with MS). Treatment was planned for a short duration of 2 months to evaluate tolerability and effects on CLL cell signaling and tolerability of the drug by patients with CLL. Peripheral blood leukemic cell were isolated and analyzed by RNAseq and phosphoprotein immunoblotting at times just prior to, and 6 hours immediately following drug administration. Consistent with preclinical results (Brennan et al, PLOS one 2015; Selman et al, Science Trans Med 2018), STAT1 phosphorylation at Y701 was decreased 6 hours following the initial dose, compared to high baseline levels. Differential expression analyses for RNAseq of total RNA isolated from peripheral blood CLL cells weere performed using limma models, which compared pretreatment versus post-treatment at a specific time point. Functional annotations of these genes revealed a significant enrichment related to B-cell activation, B-cell receptor (BCR) signaling, B-cell differentiation, and immune signaling generally. Specifically, several known CLL therapy targets including SYK, LYN, and BTK were significantly downregulated. Gene-set-enrichment analysis (GSEA) revealed that the "CLL-BCR gene signature" previously described by Herishanu et al. (Blood 2011) was consistently down-regulated after DMF treatment in samples from different time points (C1D1 post, C1D8 and C2D1) compared to pretreatment samples (FDR q of 0.24, 0.01 and 0.04, respectively). In conclusion, this is the first report of the clinical use of DMF for patients with CLL in which inhibition of leukemic cell activation has been demonstrated. The inhibitory effect of DMF on leukemic cell gene expression, in particular its antagonism of BCR signaling, is valuable information for the development of novel combination strategies for CLL or other B-cell malignancies. Disclosures Kipps: F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Research Funding; Genentech Inc: Consultancy, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Choi:Gilead: Speakers Bureau; Genentech: Speakers Bureau; Rigel: Consultancy; AbbVie, Inc: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau.
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Rajan, J., D. Gibson, S. D. Zhang, and A. Bjourson. "AB0188 A BIOINFORMATIC APPROACH TO IDENTIFYING SENSITIZING THERAPEUTICS FOR RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 1275.1–1276. http://dx.doi.org/10.1136/annrheumdis-2023-eular.488.
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BackgroundRheumatoid Arthritis (RA) is a systemic and chronic autoimmune disorder that has significant impact on quality of life and work capacity for the patient. Treatment and management of RA is aimed at gaining control of inflammation and alleviating pain, however, achieving remission and low disease activity with minimal toxicity is frequently not possible with the current suite of drugs. Additionally with escalating de novo drug development costs, alternate bioinformatic approaches which scope the potential to repurpose already licenced compounds and their ability to work synergistically have become attractive.Objectives:1)Develop, test and refine a bespoke connectivity mapping based bioinformatic pipeline, DrugExpress, with capability of mining treatment response gene signatures using public RNAseq and microarray datasets.2)Verify treatment response signatures and prioritise novel drugs to generate a list of robust sensitising drugs.MethodsPublic RNAseq (GSE198529) and microarray datasets (GSE93777 and GSE24742) were mined based on the presence of DAS score, clinical features, sample size and technological platform. R/Bioconductor packages and Perseus software were used to pre-process and carry out differential expression (DE) analysis to obtain a list of differentially expressed genes (DEGs), based on the cut off criteria of padj < 0.05 and a minimal 2-fold change of expression, and derive gene signatures characteristic of treatment response. DEGs from multiple datasets were combined to create a master gene list consisting of 21 DEGs. Gene Ontology (GO) enrichment analysis was performed on the genes in the master list to identify the top biological pathways. A list of inferred genes involved in each of these pathways was compiled to determine the overall direction of expression with response to treatment. DEGs in the master list were extracted and mapped to Affymetrix probeset IDs to create treatment response gene signatures to be entered into a sscMap search for candidate drugs. Connectivity mapping (CMap) analysis was used to establish networks between DEGs in the gene signature and FDA approved drugs. P-value and connection score of each reference drug in the CMap was obtained and used to determine statistical significance and perturbation stability.ResultsGO enrichment analysis performed on the master gene list identified the top 3 pathways: transport of connexons to the plasma membrane, oligomerization of connexins into connexons, and gap junction assembly. CMap analysis identified a total of 36 statistically significant compounds with a perturbation stability score of 1. Candidate compounds were selected based on whether they enhanced a theoretical response phenotype. The top 3 ranked compounds (by p value) which would induce theoretical reduction in disease activity were: ciclosporin (p-value = 0.0001), demecarium bromide (p-value = 0.0002) and 2-aminobenzenesulfonamide (p-value = 0.0002).ConclusionThe analysis using the DrugExpress pipeline illustrates the process of treatment response DEG extraction from public expression datasets. These response signatures can be used for CMap analysis to predict new compounds for treatment refractive patients and can potentially simulate the effective changes observed in responders. Next step in the pipeline would be to implementin silicotoxicity screening methods to identify any contraindications with existing treatments.References[1]Rosa-Gonçalves, D., Bernardes, M. and Costa, L. (2018) Quality of life and functional capacity in patients with rheumatoid arthritis - Cross-sectional study. Reumatologia Clinica, 14(6), 360-366.[2]Scott, I.C., Whittle, R., Bailey, J., Twohig, H., Hider, S.L., Mallen, C.D., Muller, S. and Jordan, K.P. (2022) Rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis epidemiology in England from 2004 to 2020: An observational study using primary care electronic health record data. The Lancet Regional Health. Europe, 23, 100519.[3]Versus Arthritis. (2019) The State of Musculoskeletal Health 2019.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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Chen, Chin-Fu, and Albert Y. Leung. "Gene response of human monocytic cells for the detection of antimigraine activity of feverfew extractsThis article is one of a selection of papers published in this special issue (part 2 of 2) on the Safety and Efficacy of Natural Health Products." Canadian Journal of Physiology and Pharmacology 85, no. 11 (November 2007): 1108–15. http://dx.doi.org/10.1139/y07-097.
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The herb feverfew is a folk remedy for various conditions, including inflammation, fever, psoriasis, rheumatism, and asthma. Like many herbal medicines, feverfew's mechanisms of action in the human body are largely unknown and its active ingredients remain elusive. Very often, different extraction methods of herb material produce different physical and biochemical properties and variation in clinical efficacy. We identified 3 major methods of extraction for feverfew aerial parts and used microarray technology to test the hypothesis that extracts produced by different methods elicit different gene expression profiles. We have identified approximately 200 genes that are consistently regulated by the 2 presumptive active antimigraine feverfew extracts but not associated with the inactive extract. Our results suggest that the presumptive active feverfew extracts potently stimulate more genes in human cells than the inactive extracts. We also identified several genes as unique signatures for these active extracts. All 3 feverfew extracts exhibited similar blockades on lipopolysaccharide-mediated TNF-α (tumor necrosis factor alpha) release, implicating that TNF-α is not responsible for the differences in the effects of the 3 feverfew extracts in human cells. In contrast, the active extracts more effectively suppressed CCL2 (also known as monocyte chemoattractant protein 1, MCP-1) than the inactive extracts, suggesting that CCL2 is a potential cellular target for feverfew’s antimigraine effects.
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Xiao, M., and J. Gu. "POS0415 BLOOD-DERIVED DNA METHYLATION EPI-SIGNATURES ASSOCIATED WITH ANKYLOSING SPONDYLITIS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 437.3–437. http://dx.doi.org/10.1136/annrheumdis-2021-eular.4257.
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Background:Most (~90%) of the ankylosing spondylitis (AS) susceptibility loci are undefined and located in non-coding regions. Epigenetic changes may alter the expression of genes involved in AS and explain part of the missing heritability. 1Objectives:To identify novel DNA methylation sites significant for AS and comprehensively understand the underlying pathological mechanism.Methods:Genome-wide DNA methylation of blood samples from 30 AS patients and 15 health controls was measured on the Infinium® MethylationEPIC BeadChip microarray. Methylome data were analyzed with ChAMP package in R.Results:The epigenome-wide association analysis identified 4,794 differentially methylated positions (DMPs) (FDR <0.05 and delta β >0.05), including 3,294 (68.7%) hypermethylated and 1,500 (31.3%) hypomethylated positions in AS patients (Figure 1A). The identified DMPs allowed clear distinction of most AS cases from controls in the PCA (Figure 1B) and unsupervised hierarchical clustering (Figure 1C). KEGG pathway analysis of AS associated DMPs enriched in T cell receptor signaling pathway, Th1 and Th2 cell differentiation. Besides, a total of 1,048 differentially variable positions (DVPs) were identified, the majority of which (974, 92.9%) were hypervariable in AS, while only 74 DVPs were hypovariable. The increased DNA methylation variability in disease were in line with the previous observation in other diseases, indicating the intrinsic heterogeneity in AS patients, which might be influenced by diverse factors, such as disease activity and treatment.Figure 1.Conclusion:Peripheral blood mononuclear cells from AS patients display aberrant DNA methylome and increased DNA methylation variability. The results enhanced our understanding of the important role of DNA methylation in pathology of AS and offered the possibility of identifying new targets for intervention.References:[1]Whyte JM, Ellis JJ, Brown MA, et al. Best practices in DNA methylation: lessons from inflammatory bowel disease, psoriasis and ankylosing spondylitis. Arthritis Res Ther 2019; 21:133.Acknowledgements:We appreciate all the staff members of the department of rheumatology of the Third Affiliated Hospital of Sun Yat-sen University for assistance and support in the patient’s recruitment and sample collection.Disclosure of Interests:None declared
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Morawski, Peter A., Hannah DeBerg, Stephan Pribitzer, Mitch Fahning, Caroline Stefani, Adam Lacy-Hulbert, Iris Gratz, and Daniel J. Campbell. "Cutaneous T cells promote distinct outcomes in human skin structural cells associated with inflammatory disease." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 170.16. http://dx.doi.org/10.4049/jimmunol.210.supp.170.16.
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Abstract The skin is an immunologically active barrier tissue specialized to deal with a litany of external stresses. Immune cells coordinate with structural cells in the skin to promote appropriate inflammatory responses and subsequent restoration of barrier integrity following insult. Recent single cell analyses of human skin have defined previously unappreciated transcriptional heterogeneity in structural cells, including disease-associated changes in keratinocytes and fibroblasts. Cutaneous T cell activity is implicated in the development of inflammatory skin disease, but the mechanisms by which T cells promote disease-associated changes in the skin remain unclear. We now show that distinct subsets of circulating and resident CD4 +cutaneous T cells promote a diverse array of cytokine-dependent transcriptional outcomes in human keratinocytes and fibroblasts. We used these in vitro generated transcriptional signatures to identify T cell-dependent gene modules associated with inflammatory skin disease in vivo. For example, we find that T helper17 cells regulate the expression of epigenetic modifiers in keratinocytes, genes that are enriched in the skin of patients with psoriasis and normalized in response to anti-IL-17 therapy. Thus, we have identified T cell-dependent cytokine-driven transcriptional changes associated with inflammatory skin disease that can be used to dissect immune mechanisms of anti-cytokine therapeutic activity.
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Grivas, A., M. Grigoriou, G. Sentis, A. Filia, P. Katsimpri, P. Verginis, and D. Boumpas. "POS0326 THE ΤRANSCRIPTOMIC LANDSCAPE OF ACTIVE PSORIATIC ΑRTHRITIS: ACTIVATED INNATE ΙMMUNITY, EXTRACELLULAR MATRIX (ECM) TURNOVER, ABERRANT METABOLISM AND HEMOPOIETIC CELL - SKIN CROSSTALK." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 414.2–414. http://dx.doi.org/10.1136/annrheumdis-2022-eular.3202.
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BackgroundPsoriatic arthritis (PsA) is a chronic inflammatory disease whereby activated T lymphocytes and myeloid cells interact with tissue-resident cells in the skin and joints. Gene expression studies, mainly based on the microarray platforms, have provided an initial glimpse into disease pathogenesis highlighting, among others, the role of the TNFα and IL17 cytokine axis. Yet, the transcriptomic landscape of PsA remains largely unexplored, and the specific contribution of skin fibroblasts to disease pathogenesis remains elusive.ObjectivesTo comprehensively characterize the gene expression profile in PsA, specifically in the blood and skin fibroblasts through next-generation RNA sequencing.MethodsPeripheral blood (PB) was collected from PsA patients (n=30) after informed consent. Healthy individuals (HC) and patients with rheumatoid arthritis (RA) were used as healthy and disease controls (n=10/group) respectively. Psoriatic skin biopsies were obtained from a subset of three PsA patients and three HC. All PsA patients fulfilled the CASPAR criteria and displayed peripheral polyarthritis of moderate- to high- disease activity. Patient’s clinical and laboratory data were recorded at the time of sampling. Disease activity in PsA and RA was assessed using the Disease Activity Index for Psoriatic arthritis (DAPSA) and the Disease Activity Score-28 (DAS28), respectively. RNA from PB and skin fibroblasts was extracted, RNA libraries were prepared and sequenced. EdgeR package was used to call differentially expressed genes (DEGs). Statistical significance was set at p value<0.05 and fold-change |FC| >1.5. Functional enrichment analysis and weighted gene co-expression network analysis (WGCNA) was implemented. Inference and analysis of blood immune cells-skin fibroblasts communication were performed with CellChat.Results8 males and 22 female patients with PsA were included with median age 49 years old and median disease duration 4 years. The median DAPSA score was 44.3 and the median DAS28 score was 5.5 for RA patients, suggesting high disease activity in both groups. We found 466 DEGs in PsA versus HC blood (303 up- and 163 down-regulated). DEGs were significantly enriched in biological pathways related to immunity (i.e. inflammatory response, TNFa signaling via NFkB, IFNa & IFNγ response, complement, IL2 signaling), metabolism (i.e. oxidative phosphorylation, adipogenesis, fatty acid metabolism) and other signaling cascades of pathophysiologic relevance (i.e. WNTb catenin signaling, TGFβ signaling, MTORC1 signaling). WGCNA in blood revealed four gene modules containing highly correlated genes. These modules were enriched in myeloid leukocyte mediated immunity, neutrophil-mediated immunity, ECM and collagen metabolism, TGFβ and PDGF signaling. Next, we characterized the “PsA specific activity signature”, taking the intersection of DEGs in ‘PsA vs. HC’ and ‘PsA vs. RA’, which resulted in 67 DEGs enriched in response to TGF and PDGF, ECM organization and degradation. CellChat analysis identified a higher number of interactions between blood immune cells and skin fibroblasts and increased strength of interactions in PsA compared to healthy state. Aberrant interactions between blood and skin fibroblasts in PsA included, among others, ligand-receptor pairs of the WNT, Notch, and GDF11 signaling pathways.ConclusionOur findings confirm the presence of an IFNα signature and complement activation in PsA. The increased cardiometabolic burden and enhanced bone remodeling are reflected by the presence of pathways related to aberrant metabolism and ECM metabolism, respectively. The myeloid cell signature in active disease supports the emerging role of monocytes/macrophages in driving inflammation in PsA, while the aberrant blood-skin fibroblast interactions suggest a novel role for these resident cells in disease pathophysiology.References[1]Bravo A. et al. Nat Rev Rheumatol. 2019 Nov;15(11):645-656. doi: 10.1038/s41584-019-0285-8.Disclosure of InterestsNone declared
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Kristensen, M. B., U. Ahmadov, M. A. Nielsen, L. S. Kristensen, and T. W. Kragstrup. "POS0293 IN VITRO RESPONSE TO DISEASE MODIFYING ANTIRHEUMATIC DRUGS LINK MOLECULAR DRUG TARGET WITH SYNOVIAL TRANSCRIPTIONAL SIGNATURE." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 392.1–392. http://dx.doi.org/10.1136/annrheumdis-2022-eular.2512.
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BackgroundImmune-mediated inflammatory arthritis (IMIA) is a group of diseases characterized by chronic synovitis including rheumatoid arthritis (RA), psoriatic arthritis (PsA), and spondyloarthritis (SpA). Some disease modifying antirheumatic drugs (DMARDs) have demonstrated efficacy in several of these diseases (e.g. TNFα inhibitors) while others have not (e.g. IL-17A inhibitors in RA). Furthermore, within each disease there are patient subgroups experiencing different responses to the same drug, which underlines the need for further elucidation of pathogenic processes to guide personalized in IMIAs.ObjectivesHere we investigated if clinical features and synovial transcriptional signature could predict in vitro efficacy of specific DMARDs across different IMIAs.MethodsSynovial fluid mononuclear cells (SFMCs) from patients with SpA (n=13), RA (n=16), PsA (n=13), juvenile idiopathic arthritis (JIA) (n=7) or undifferentiated arthritis (n=5) were included. SFMCs from each patient were cultured for 48 hours (drugs listed in Table 1). Culture medium and DMSO were used as negative controls. In vitro drug response was assessed by measuring monocyte chemoattractant protein 1 (MCP-1) by ELISA. SFMC baseline gene expression of 270 genes related to inflammation was measured using the NanoString nCounter Human Inflammation V2 Panel. Drug responses (ΔMCP-1) were compared with clinical diagnosis, serostatus in RA patients, HLA-B27 status in SpA patients, DAS28-CRP score, years since diagnosis, failed modes of action and transcriptional signatures.Table 1.DrugTargetAdalimumabTNFαEtanerceptTNFαTocilizumabIL-6AnakinraIL-1βUstekinumabIL-12/23SecukinumabIL-17ATofacitinibJAK1/3BaricitinibJAK2/3ResultsDMARDs with a similar molecular target had comparable effects on ΔMCP-1. The TNFα inhibitors adalimumab and etanercept (r=0.86) had similar drug responses, and so had the JAK inhibitors tofacitinib and baricitinib (r=0,71). In contrast, drugs with different modes of action had diverse responses (Figure 1). High HLA-DRA gene expression associated with high responses to TNFα inhibitors (both p<0.05). JAK inhibitors reduced MCP-1 secretion significantly more in SFMCs from seropositive than seronegative RA patients (p<0.05). Drug response was greater in SFMCs from patients with low DAS28-CRP scores (DAS28-CRP <2.5) compared with patients with a high DAS28-CRP score (DAS28-CRP >5.2) for TNFα inhibitors, tocilizumab and JAK inhibitors (all p<0.05). Patients clustered with either an overall high or an overall low response to almost all DMARDs, or with a significant response to only one or a few of the DMARDs. Transcriptional signature of patient SFMCs primarily responding to TNFα inhibitors was different compared with the signature of patient SFMCs primarily responding to JAK inhibitors. Diagnosis, HLA-B27 status, failed modes of action and years since diagnosis did not affect ΔMCP-1 in this in vitro setup.Figure 1.Association between DMARD molecular target and in vitro response as measured by change in MCP-1 secretion.ConclusionSimilarities and differences in mode of action for 8 different DMARDs were captured in drug response as measured by MCP-1 change in SFMC cultures from 54 patients with inflammatory arthritis. We were able to identify interesting differences in gene expression when comparing cells responding to TNF inhibitors to cells responding to JAK inhibitors. Drug responses were only to a minor extent associated with clinical features.AcknowledgementsSincere thanks to Stinne Greisen, Malene Hvid, Maithri Aspari and Amalie Broksø for continuous guidance during the laboratory work.Disclosure of InterestsMads Brüner Kristensen: None declared, Ulvi Ahmadov: None declared, Morten Aagaard Nielsen: None declared, Lasse Sommer Kristensen: None declared, Tue Wenzel Kragstrup Shareholder of: Co-founder and clinical developer in iBio tech ApS., Speakers bureau: Speaking fees from Pfizer, Bristol-Myers Squibb, Eli Lilly, Novartis, UCB, and Abbvie., Consultant of: Consultancy fees from Bristol-Myers Squibb and Gilead., Grant/research support from:. Research grants from Gilead.
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Wang, R., A. Singaraju, K. E. Marks, L. Shakib, G. Dunlap, A. Cunningham-Bussel, S. R. Greisen, et al. "POS0402 CLONALLY EXPANDED CD38hi CYTOTOXIC CD8 T CELLS DEFINE THE T CELL INFILTRATE IN CHECKPOINT INHIBITOR-ASSOCIATED ARTHRITIS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 457.1–457. http://dx.doi.org/10.1136/annrheumdis-2022-eular.3779.
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BackgroundImmune checkpoint inhibitor (ICI) therapies that promote T cell activation have improved outcomes for advanced malignancies yet can also elicit harmful autoimmune reactions. The T cell mechanisms mediating these iatrogenic autoimmune events remain unclear.ObjectivesTo investigate the immunophenotype, transcriptomic feature and clonotypes of T cells from joints of patients affected by ICI-induced inflammatory arthritis (ICI-arthritis).MethodsDetailed immunophenotyping was performed on mononuclear cells from synovial fluid (SF) using mass cytometry and flow cytometry to identify significantly altered populations in ICI-A compared to seropositive rhrumatoid arthritis (RA) and psoriatic arthritis (PsA) (p<0.05). Bulk RNA-seq was performed on altered SF CD8 T cell subsets from ICI-A, RA and PsA to investigate their transcriptomic features. Cytokine profile and pathways enriched in ICI-A CD8 T cells were examined using differentially expressed genes, intracellular staining, and in vitro culture. TCR clonotypes were examined using single cell RNA-seq of T cells from synovial fluid, tissue and blood of ICI-A.ResultsCompared to the autoimmune arthritides RA and PsA, ICI-arthritis joints contained an expanded CD38hi CD127- CD8+ T cell subset that displays cytotoxic, effector, and interferon (IFN) response signatures. Exposure of synovial T cells to Type I IFN, more so than IFN-γ, induced the CD38hi cytotoxic phenotype. Single cell transcriptomic and T cell repertoire (TCR) analyses indicated that the abundance of CD38hi CD8 T cells in ICI-arthritis resulted from proliferation of a limited number of clones. The CD38hi population appeared distinct from dysfunctional T cells and clonally most related to TCF7+ memory populations. Comparison of synovial tissue from bilateral knees of the same patient demonstrated considerable sharing of TCR clonotypes among CD38hi CD8 T cells between the two joints. Further, TCR clonotypes expanded in synovial fluid of ICI-arthritis patients were detected in circulating T cells, and circulating CD38hi CD8 T cells are also expanded in ICI-arthritis patients.ConclusionThese results define a distinct CD8 T cell subset in the synovial fluid and in the circulation of patients with ICI-A that may be directly activated by ICI therapy to mediate a tissue-specific autoimmune response.Disclosure of InterestsNone declared.
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Simone, D., F. Penkava, A. Ridley, S. Sansom, H. Al Mossawi, and P. Bowness. "OP0032 SINGLE CELL ANALYSIS OF SPONDYLOARTHRITIS REGULATORY T CELLS IDENTIFIES DISTINCT SYNOVIAL GENE EXPRESSION PATTERNS AND CLONAL FATES." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 17.2–18. http://dx.doi.org/10.1136/annrheumdis-2021-eular.4278.
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Background:Regulatory T cells (Tregs) play an important role in controlling inflammation and limiting autoimmunity, but their phenotypes at inflammatory sites in human disease are poorly understood. Whilst the phenotype and transcriptional profile of Tregs have been studied in some immune mediated conditions, they have been little studied (especially at the single cell level) in synovial fluid in the course of inflammatory arthritis. In Spondyloarthritis (SpA), in particular, where pathogenesis and inflammation is driven by dysregulated effector immunity, the role of the regulatory arm of immunity is largely unknown.Objectives:We aimed to draw an atlas of Tregs in the context of SpA joint inflammation using single cell RNA sequencing of blood and SF Tregs of patients with Ankylosing Spondylitis (AS) and Psoriatic Arthritis (PsA). Functionally distinct specialised Treg subtypes, and specific changes in transcriptional profile occurring in synovial fluid Tregs, providing an insight on Treg adaptation during inflammation. Furthermore, by coupling gene expression analysis with TCR sequencing, we aimed to describe clonally expanded and likely antigen-driven Tregs in the SF.Methods:Fluorescent activated cell sorting (FACS) was used to isolate 13,400 memory CD3+ CD45RA-ve CD25 + 127low Tregs from the blood and synovial fluid (SF) of 2 patients with HLA-B27+ AS presenting with active knee arthritis. Single-cell RNA sequencing (scRNA-seq) using 5’ V(D)J 10x Genomics technology allowed both transcriptional definition of Tregs, and exploration of their immune TCR repertoire. Findings were compared to >3,000 SF and blood Tregs from 3 patients with olygoarticular PsA 1. Multicolor flow cytometry and in vitro cell-based assays using patient-derived cells were used to confirm and expand, at protein and functional level, the findings that emerged from the gene expression analysis.Results:We report a large scRNAseq dataset (approx. 17,000 cells) comparing Tregs from SpA blood and joints. We identify multiple Treg clusters with distinct transcriptomic profiles, including, among others, a regulatory CD8+ subset expressing cytotoxic markers/genes, and a Th17-like RORC+ Treg subset characterized by IL-10 and LAG-3 expression. Synovial Tregs show upregulation of interferon signature and TNF receptor superfamily genes, and marked clonal expansion, consistent with tissue adaptation and antigen contact respectively. Individual synovial Treg clones map to different clusters indicating cell fate divergence. Finally, we demonstrate that LAG-3 directly inhibits IL-12/23 and TNF secretion by patient-derived monocytes, a mechanism with translational potential in SpA.Conclusion:Our detailed characterization of Tregs at an important inflammatory site illustrates the marked specialization of Treg subpopulations and identifies a broad transcriptional profile upregulated across all synovial regulatory cells. Our TCR analysis provides evidence of Treg clonal expansion, which may be driven by antigen, and confirms functional specialisation of individual clones. We also propose a new insight into a Treg functional mechanism through LAG-3 that suggests a novel therapeutic approach to immune-driven diseases.References:[1]Penkava et al., Nature Communications, 2020Disclosure of Interests:Davide Simone: None declared, Frank Penkava: None declared, Anna Ridley: None declared, Stephen Sansom: None declared, Hussein Al Mossawi Employee of: UCB, Paul Bowness Grant/research support from: Regeneron, Celgene/BMS and GSK
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Lin, Qingyuan, Jinchao Zhu, Jun Chen, Shouqiang Jia, and Shengdong Nie. "Significance of cuproptosis- related genes in the diagnosis and classification of psoriasis." Frontiers in Molecular Biosciences 10 (April 7, 2023). http://dx.doi.org/10.3389/fmolb.2023.1115091.
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Cuproptosis is a novel form of cell death linked to mitochondrial metabolism and is mediated by protein lipoylation. The mechanism of cuproptosis in many diseases, such as psoriasis, remains unclear. In this study, signature diagnostic markers of cuproptosis were screened by differential analysis between psoriatic and non-psoriatic patients. The differentially expressed cuproptosis-related genes (CRGs) for patients with psoriasis were screened using the GSE178197 dataset from the gene expression omnibus database. The biological roles of CRGs were identified by GO and KEGG enrichment analyses, and the candidates of cuproptosis-related regulators were selected from a nomogram model. The consensus clustering approach was used to classify psoriasis into clusters and the principal component analysis algorithms were constructed to calculate the cuproptosis score. Finally, latent diagnostic markers and drug sensitivity were analyzed using the pRRophetic R package. The differential analysis revealed that CRGs (MTF1, ATP7B, and SLC31A1) are significantly expressed in psoriatic patients. GO and KEGG enrichment analyses showed that the biological functions of CRGs were mainly related to acetyl-CoA metabolic processes, the mitochondrial matrix, and acyltransferase activity. Compared to the machine learning method used, the random forest model has higher accuracy in the occurrence of cuproptosis. However, the decision curve of the candidate cuproptosis regulators analysis showed that patients can benefit from the nomogram model. The consensus clustering analysis showed that psoriasis can be grouped into three patterns of cuproptosis (clusterA, clusterB, and clusterC) based on selected important regulators of cuproptosis. In advance, we analyzed the immune characteristics of patients and found that clusterA was associated with T cells, clusterB with neutrophil cells, and clusterC predominantly with B cells. Drug sensitivity analysis showed that three cuproptosis regulators (ATP7B, SLC31A1, and MTF1) were associated with the drug sensitivity. This study provides insight into the specific biological functions and related mechanisms of CRGs in the development of psoriasis and indicates that cuproptosis plays a non-negligible role. These results may help guide future treatment strategies for psoriasis.
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Vecellio, Matteo, Elvezia Maria Paraboschi, Angela Ceribelli, Natasa Isailovic, Francesca Motta, Giulia Cardamone, Michela Robusto, et al. "DNA Methylation Signature in Monozygotic Twins Discordant for Psoriatic Disease." Frontiers in Cell and Developmental Biology 9 (November 24, 2021). http://dx.doi.org/10.3389/fcell.2021.778677.
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Background: Psoriatic disease is a multifactorial inflammatory condition spanning from skin and nail psoriasis (Pso) to spine and joint involvement characterizing psoriatic arthritis (PsA). Monozygotic twins provide a model to investigate genetic, early life environmental exposure and stochastic influences to complex diseases, mainly mediated by epigenetics.Methods: We performed a genome-wide DNA methylation study on whole blood of monozygotic twins from 7 pairs discordant for Pso/PsA using the Infinium Methylation EPIC array (Illumina). MeDiP—qPCR was used to confirm specific signals. Data were replicated in an independent cohort of seven patients with Pso/PsA and 3 healthy controls. Transcriptomic profiling was performed by RNAsequence on the same 7 monozygotic twin pairs.Results: We identified 2,564 differentially methylated positions between psoriatic disease and controls, corresponding to 1,703 genes, 59% within gene bodies. There were 19 regions with at least two DMPs within 1 kb of distance and significant within-pair Δβ-values (p < 0.005), among them SNX25, BRG1 and SMAD3 genes, all involved in TGF-β signaling pathway, were identified. Co-expression analyses on transcriptome data identified IL-6/JAK/STAT3 and TNF-α pathways as important signaling axes involved in the disease, and they also suggested an altered glucose metabolism in patients’ immune cells, characteristic of pro-inflammatory T lymphocytes.Conclusion: The study suggests the presence of an epigenetic signature in affected individuals, pointing to genes involved in immunological and inflammatory responses. This result is also supported by transcriptome data, that altogether suggest a higher activation state of the immune system, that could promote the disease status.
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Boonpethkaew, Suphagan, Jitlada Meephansan, Sasin Charoensuksira, Onjira Jumlongpim, Pattarin Tangtanatakul, Jongkonnee Wongpiyabovorn, Mayumi Komine, and Morita Akimichi. "Elucidating the NB-UVB mechanism by comparing transcriptome alteration on the edge and center of psoriatic plaques." Scientific Reports 13, no. 1 (March 16, 2023). http://dx.doi.org/10.1038/s41598-023-31610-y.
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AbstractNarrow band-ultraviolet B (NB-UVB) is an effective treatment for psoriasis. We aim to generate a potential mechanism of NB-UVB through comparing the transcriptomic profile before and after NB-UVB treatment between the peripheral edge of lesional skin (PE skin) and the center of lesional skin (CE skin) on the basis of molecular mechanisms of these two areas display different downstream functions. More than one-fourth of the NB-UVB-altered genes were found to be plaque-specific. Some of them were psoriasis signature genes that were downregulated by NB-UVB in, both, PE and CE skin (core alteration), such as IL36G, DEFB4A/B, S100A15, KRT16, and KRT6A. After NB-UVB treatment, the activity score of upstream cytokines, such as interferons, interleukin (IL)-6, IL-17, and IL-22 in pathogenesis decreased. In addition, NB-UVB could restore normal keratinization by upregulating LORICRIN and KRT2, particularly in the CE skin. Finally, we illustrated that NB-UVB is capable of suppressing molecules from the initiation to maintenance phase of plaque formation, thereby normalizing psoriatic plaques. This finding supports the usefulness of NB-UVB treatment in clinical practice and may help in the development of new treatment approaches in which NB-UVB treatment is included for patients with psoriasis or other inflammatory skin diseases.
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Xi, Li, Sandra Garcet, Zhan Ye, Kenneth Hung, Mina Hassan-Zahraee, Elizabeth Kieras, James G. Krueger, Craig Hyde, and Elena Peeva. "A shared tissue transcriptome signature and pathways in psoriasis and ulcerative colitis." Scientific Reports 12, no. 1 (November 17, 2022). http://dx.doi.org/10.1038/s41598-022-22465-w.
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AbstractDespite multiple efficacious therapies in common between psoriasis (PS) and Ulcerative Colitis (UC), mechanisms underlying their common pathophysiology remain largely unclear. Here we sought to establish a link by evaluating expression differences and pathway alterations in diseased tissues. We identified two sets of differentially expressed genes (DEGs) between lesional and nonlesional tissues in meta-analyses of data collected from baseline samples in 3 UC and then 3 PS available clinical studies from Pfizer. A shared gene signature was defined by 190 DEGs common to both diseases. Commonly dysregulated pathways identified via enrichment analysis include interferon signaling, partly driven by genes IFI6, CXCL9, CXCL10 and CXCL11, which may attract chemotaxis of Th1 cells to inflammatory sites; IL-23 pathway (IL-23A, CCL20, PI3, CXCL1, LCN2); and Th17 pathway except IL-17A. Elevated expression of costimulatory molecules ICOS and CTLA4 suggests ongoing T-cell activation in both diseases. The clinical value of the shared signature is demonstrated by a gene set improvement score reflecting post-treatment molecular improvement for each disease. This is the first study using transcriptomic meta-analysis to define a tissue gene signature and pathways dysregulated in both PS and UC. These findings suggest immune mechanisms may initiate and sustain inflammation similarly in the two diseases.
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Garshick, Michael S., Macintosh Cornwell, Kamelia Drenkova, Tessa A. Barrett, Maria Florencia Schlamp, Kelly Ruggles, Caron Rockman, Harmony Reynolds, and Jeffrey Berger. "Abstract 15003: A Circulating Genetic Signature in Psoriasis Associates With Future Cardiovascular Events." Circulation 146, Suppl_1 (November 8, 2022). http://dx.doi.org/10.1161/circ.146.suppl_1.15003.
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Introduction: Psoriasis (PsO) is an inflammatory skin disease associated with cardiovascular (CV) disease (CVD). Multiple biomarkers are proposed to enhance risk assessment in PsO, yet the overlap between biomarkers of PsO and CV risk are incompletely understood. We therefore investigated the whole blood transcriptome in PsO, and prevalence and future risk of a CV event. Methods: PsO patients (n=37), without CV disease and 11 age-, sex-matched controls underwent whole blood RNA sequencing. The upregulated genetic signature in PsO vs controls was then evaluated in CVD cohorts: Group 1) women referred for cardiac catheterization for (n=26, median age 61 [IQR; 54 - 70] years) vs without (n=41, median age 62 [IQR; 58 - 69] years) an active myocardial infarction (MI), group 2) patients with peripheral artery disease followed longitudinally for major adverse CV or limb events (MACLE; n=106, median age 66 [IQR; 60 - 72] years, 74% male, median follow-up 2.5 years). Results: In the PsO cohort, median age was 44 (IQR; 34 - 51) years, 49% male, and ACC/AHA ASCVD Risk Score of 1.0% (0.6 - 3.4) with no significant difference vs controls. The median psoriasis area and severity index score (PASI) was 4.0 (IQR 2.9 - 8.2), PsO duration 15 (IQR; 9 - 25) years, with 36% on biologic therapy. Overall, 247 genes were upregulated and 228 downregulated in PsO vs controls (Figure 1A, p<0.05), and 1,302 genes positively and 1,244 genes negatively associated with PASI (Figure 1B, p<0.05). Seventy-three genes overlapped between these two comparisons (Figure 1C); key cytokine regulators were IL-6, IL-1β, and IFN gamma (Figure 1D). In the CVD cohorts, 50 out of 73 genes (68%, group 1) significantly associated with prevalent MI, and 29 (40%, group 2) with incident MACLE (Figure 1E). Conclusions: A whole blood transcriptomic signature of PsO diagnosis and severity was associated with prevalent MI and incident MACLE. These data have implications for understanding the link between PsO, systemic inflammation, and CVD.
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Grivas, Alexandros, Maria Grigoriou, Nikos Malissovas, George Sentis, Anastasia Filia, Sofia Flouda, Pelagia Katsimpri, Panayotis Verginis, and Dimitrios T. Boumpas. "Combined – whole blood and skin fibroblasts- transcriptomic analysis in Psoriatic Arthritis reveals molecular signatures of activity, resistance and early response to treatment." Frontiers in Immunology 13 (September 8, 2022). http://dx.doi.org/10.3389/fimmu.2022.964274.
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BackgroundAn interplay between immune cells and resident skin and joint stromal cells is implicated in psoriatic arthritis (PsA), yet the mechanisms remain elusive with a paucity of molecular biomarkers for activity and response. Combined transcriptomic and immunophenotypic analysis of whole blood and skin fibroblasts could provide further insights.MethodsWhole blood RNA-seq was performed longitudinally in 30 subjects with PsA at the beginning, one and six months after treatment, with response defined at six months. As control groups, 10 healthy individuals and 10 subjects with rheumatoid arthritis (RA) were recruited combined with public datasets from patients with psoriasis (PsO) and systemic lupus erythematous (SLE). Differential expression analysis and weighted gene co-expression network analysis were performed to identify gene expression signatures, while deconvolution and flow cytometry to characterize the peripheral blood immune cell profile. In a subset of affected and healthy individuals, RNA-seq of skin fibroblasts was performed and subjected to CellChat analysis to identify the blood-skin fibroblast interaction network.ResultsPsA demonstrated a distinct “activity” gene signature in the peripheral blood dominated by TNF- and IFN-driven inflammation, deregulated cholesterol and fatty acid metabolism and expansion of pro-inflammatory non-classical monocytes. Comparison with the blood transcriptome of RA, PsO, and SLE revealed a “PsA-specific signature” enriched in extracellular matrix remodeling. This was further supported by the skin fibroblast gene expression profile, displaying an activated, proliferating phenotype, and by skin-blood interactome analysis revealing interactions with circulating immune cells through WNT, PDGF and immune-related semaphorins. Of note, resistance to treatment was associated with upregulation of genes involved in TGFβ signaling and angiogenesis and persistent increase of non-classical monocytes. Differentially expressed genes related to platelet activation and hippo signaling discriminated responders and non-responders as early as one month after treatment initiation.ConclusionTranscriptome analysis of peripheral blood and skin fibroblasts in PsA reveals a distinct disease activity signature and supports the involvement of skin fibroblasts through their activation and interaction with circulating immune cells. Aberrant TGFβ signaling and persistently increased non-classical monocytes characterize treatment-resistant PsA, with pro-inflammatory pathways related to platelet activation and Hippo signaling predicting early response to treatment.
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Broser, Philip, Ursula von Mengershausen, Katrin Heldt, Deborah Bartholdi, Dominique Braun, Christine Wolf, and Min Ae Lee-Kirsch. "Precision treatment of Singleton Merten syndrome with ruxolitinib: a case report." Pediatric Rheumatology 20, no. 1 (April 11, 2022). http://dx.doi.org/10.1186/s12969-022-00686-7.
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Abstract Background Singleton-Merten syndrome 1 (SGMRT1) is a rare type I interferonopathy caused by heterozygous mutations in the IFIH1 gene. IFIH1 encodes the pattern recognition receptor MDA5 which senses viral dsRNA and activates antiviral type I interferon (IFN) signaling. In SGMRT1, IFIH1 mutations confer a gain-of-function which causes overactivation of type I interferon (IFN) signaling leading to autoinflammation. Case presentation We report the case of a nine year old child who initially presented with a slowly progressive decline of gross motor skill development and muscular weakness. At the age of five years, he developed osteoporosis, acro-osteolysis, alveolar bone loss and severe psoriasis. Whole exome sequencing revealed a pathogenic de novo IFIH1 mutation, confirming the diagnosis of SGMRT1. Consistent with constitutive type I interferon activation, patient blood cells exhibited a strong IFN signature as shown by marked up-regulation of IFN-stimulated genes. The patient was started on the Janus kinase (JAK) inhibitor, ruxolitinib, which inhibits signaling at the IFN-α/β receptor. Within days of treatment, psoriatic skin lesions resolved completely and the IFN signature normalized. Therapeutic efficacy was sustained and over the course muscular weakness, osteopenia and growth also improved. Conclusions JAK inhibition represents a valuable therapeutic option for patients with SGMRT1. Our findings also highlight the potential of a patient-tailored therapeutic approach based on pathogenetic insight.
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Tengvall, Katarina, Elisabeth Sundström, Chao Wang, Kerstin Bergvall, Ola Wallerman, Eric Pederson, Åsa Karlsson, et al. "Bayesian model and selection signature analyses reveal risk factors for canine atopic dermatitis." Communications Biology 5, no. 1 (December 8, 2022). http://dx.doi.org/10.1038/s42003-022-04279-8.
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AbstractCanine atopic dermatitis is an inflammatory skin disease with clinical similarities to human atopic dermatitis. Several dog breeds are at increased risk for developing this disease but previous genetic associations are poorly defined. To identify additional genetic risk factors for canine atopic dermatitis, we here apply a Bayesian mixture model adapted for mapping complex traits and a cross-population extended haplotype test to search for disease-associated loci and selective sweeps in four dog breeds at risk for atopic dermatitis. We define 15 associated loci and eight candidate regions under selection by comparing cases with controls. One associated locus is syntenic to the major genetic risk locus (Filaggrin locus) in human atopic dermatitis. One selection signal in common type Labrador retriever cases positions across the TBC1D1 gene (body weight) and one signal of selection in working type German shepherd controls overlaps the LRP1B gene (brain), near the KYNU gene (psoriasis). In conclusion, we identify candidate genes, including genes belonging to the same biological pathways across multiple loci, with potential relevance to the pathogenesis of canine atopic dermatitis. The results show genetic similarities between dog and human atopic dermatitis, and future across-species genetic comparisons are hereby further motivated.
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Al-Janabi, Ali, Paul Martin, Adnan Khan, Amy Foulkes, Catherine Smith, Christopher Griffiths, Andrew Morris, Steve Eyre, and Richard Warren. "P38 Integrating proteomics and genomics to investigate the mechanisms of paradoxical eczema developing in patients with psoriasis treated with biologics: a UK multicentre, longitudinal, cohort study." British Journal of Dermatology 188, Supplement_4 (June 2023). http://dx.doi.org/10.1093/bjd/ljad113.066.
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Abstract Few studies have explored the immunology and genetic risk of paradoxical eczema occurring in patients with psoriasis treated with biologics. This study aims to describe the systemic inflammatory signature of paradoxical eczema using proteomics and explore whether it is genetically mediated. Participants were adults treated with biologics for plaque psoriasis, who were corecruited to the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) and Biomarkers of Systemic Treatment Outcomes in Psoriasis (BSTOP) studies. To identify differentially expressed proteins and enriched gene sets, we used the Olink Target 96 Inflammation panel on 256 serum samples from BSTOP for 71 cases with paradoxical eczema and 75 controls. Paradoxical eczema was defined as eczema, atopic eczema or atopic dermatitis occurring during biologic exposure. Case samples across three time points [T1: prebiologic (n = 42); T2, postbiologic (n = 45); T3, postparadoxical eczema (n = 41)] were matched 1 : 1 with control samples. Case samples at T2 and T3 were taken during exposure to the same biologic that caused paradoxical eczema. Genes contributing to proteomic signatures were selected, and single-nucleotide polymorphisms (SNPs) that were nonsynonymous or associated with significant expression quantitative trait loci were used to create polygenic risk scores (PRS) in a genotyped cohort of 88 paradoxical eczema cases and 3124 psoriasis controls. Signal transducing adapter molecule 1-binding protein expression was lower in cases at T1 than in controls (log-fold change −0.44, adjusted P = 0.022); no other proteins achieved statistical significance at equivalent time points. Eleven gene sets, including cytokine and chemokine pathways, were enriched in cases at T2 and 10 at T3. Of the 39 proteins contributing to enriched gene sets, 21 are elevated in the sera of patients with atopic dermatitis. A PRS including 38 SNPs linked to enriched gene sets was associated with paradoxical eczema (adjusted P = 0.046). We subdivided the SNPs into those linked to specific gene sets, such as chemokine, cytokine and interleukin (IL)-10 signalling, to generate 10 partitioned PRS. Seven were associated with paradoxical eczema (adjusted P < 0.05). These SNPs do not map to known atopic loci. The paradoxical eczema systemic inflammatory proteome trends toward atopic dermatitis at a gene set level and is detectable before the onset of the phenotype. This signature may be mediated genetically by SNPs associated with these gene sets. Further studies are needed to explore the role of specific pathways (such as IL-10 signalling) in paradoxical eczema and define the inflammatory profile in the skin.
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Liu, Shougang, Xiuqing Yuan, Hang Su, Fanghua Liu, Zhe Zhuang, and Yongfeng Chen. "ZNF384: A Potential Therapeutic Target for Psoriasis and Alzheimer’s Disease Through Inflammation and Metabolism." Frontiers in Immunology 13 (May 20, 2022). http://dx.doi.org/10.3389/fimmu.2022.892368.
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BackgroundPsoriasis is an immune-related skin disease notable for its chronic inflammation of the entire system. Alzheimer’s disease (AD) is more prevalent in psoriasis than in the general population. Immune-mediated pathophysiologic processes may link these two diseases, but the mechanism is still unclear. This article aimed to explore potential molecular mechanisms in psoriasis and AD.MethodsGene expression profiling data of psoriasis and AD were acquired in the Gene Expression Omnibus (GEO) database. Gene Set Enrichment Analysis (GSEA) and single-sample GSEA (ssGSEA) were first applied in two datasets. Differentially expressed genes (DEGs) of two diseases were identified, and common DEGs were selected. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed to explore common biological pathways. Signature transcription factors (STFs) were identified and their diagnostic values was calculated by receiver operating characteristic (ROC) curve analysis in the exploration cohort and verified in the validation cohort. The expression levels of STFs were further investigated in the validation cohort and the GTEx Portal Database. Additionally, four kinds of interaction analysis were performed: correlation analysis among STFs, gene-gene, chemical-protein, and protein-ligand interaction analyses. In the end, we predicted the transcription factor that potentially regulates STFs.ResultsBiosynthesis and metabolic pathways were enriched in GSEA analysis. In ssGSEA analysis, most immunoreaction gene lists exhibited differential enrichment in psoriasis cases, whereas three receptor-related gene lists did in AD. The KEGG analysis of common DEGs redetermined inflammatory and metabolic pathways essential in both diseases. 5 STFs (PPARG, ZFPM2, ZNF415, HLX, and ANHX) were screened from common DEGs. The ROC analysis indicated that all STFs have diagnostic values in two diseases, especially ZFPM2. The correlation analysis, gene-gene, chemical-protein, and protein-ligand interaction analyses suggested that STFs interplay and involve inflammation and aberrant metabolism. Eventually, ZNF384 was the predicted transcription factor regulating PPARG, ZNF415, HLX, and ANHX.ConclusionsThe STFs (PPARG, ZFPM2, ZNF415, HLX, and ANHX) may increase the morbidity rate of AD in psoriasis by initiating a positive feedback loop of excessive inflammation and metabolic disorders. ZNF384 is a potential therapeutic target for psoriasis and AD by regulating PPARG, ZNF415, HLX, and ANHX.
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Dai, Xiuju, Masamoto Murakami, Ken Shiraishi, Jun Muto, Mikiko Tohyama, Hideki Mori, Ryo Utsunomiya, and Koji Sayama. "EGFR ligands synergistically increase IL‐17A‐induced expression of psoriasis signature genes in human keratinocytes via IκBζ and Bcl3." European Journal of Immunology, April 12, 2022. http://dx.doi.org/10.1002/eji.202149706.
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