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1دورية أكاديمية
المؤلفون: Coomans de Brachène, Alexandra, Alvelos, Maria Ines, Szymczak, Florian, Zimath, Priscila L., Castela, Angela, Marmontel de Souza, Bianca, Roca Rivada, Arturo, Marín-Cañas, Sandra, Yi, Xiaoyan, Op de Beeck, Anne, Morgan, Noel G., Sonntag, Sebastian, Jawurek, Sayro, Title, Alexandra C., Yesildag, Burcak, Pattou, François, Kerr-Conte, Julie, Montanya, Eduard, Nacher, Montserrat, Marselli, Lorella
المصدر: Diabetologia; May2024, Vol. 67 Issue 5, p908-927, 20p
مستخلص: Aims/hypothesis: The proinflammatory cytokines IFN-α, IFN-γ, IL-1β and TNF-α may contribute to innate and adaptive immune responses during insulitis in type 1 diabetes and therefore represent attractive therapeutic targets to protect beta cells. However, the specific role of each of these cytokines individually on pancreatic beta cells remains unknown. Methods: We used deep RNA-seq analysis, followed by extensive confirmation experiments based on reverse transcription-quantitative PCR (RT-qPCR), western blot, histology and use of siRNAs, to characterise the response of human pancreatic beta cells to each cytokine individually and compared the signatures obtained with those present in islets of individuals affected by type 1 diabetes. Results: IFN-α and IFN-γ had a greater impact on the beta cell transcriptome when compared with IL-1β and TNF-α. The IFN-induced gene signatures have a strong correlation with those observed in beta cells from individuals with type 1 diabetes, and the level of expression of specific IFN-stimulated genes is positively correlated with proteins present in islets of these individuals, regulating beta cell responses to 'danger signals' such as viral infections. Zinc finger NFX1-type containing 1 (ZNFX1), a double-stranded RNA sensor, was identified as highly induced by IFNs and shown to play a key role in the antiviral response in beta cells. Conclusions/interpretation: These data suggest that IFN-α and IFN-γ are key cytokines at the islet level in human type 1 diabetes, contributing to the triggering and amplification of autoimmunity. [ABSTRACT FROM AUTHOR]
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2دورية أكاديمية
المؤلفون: Szymczak, Florian, Alvelos, Maria Inês, Marin Canas, Sandra, Oliveira Castela, Angela Sofia, Demine, Stéphane, Colli, Maikel Luis, Op De Beeck, Anne, Thomaidou, Sofia, Marselli, L., Zaldumbide, Arnaud AZ, Marchetti, Piero, Eizirik, Décio L
المصدر: Science advances, 8 (37
مصطلحات موضوعية: Biologie
الوصف: IFNα is a key regulator of the dialogue between pancreatic β cells and the immune system in early type 1 diabetes (T1D). IFNα up-regulates HLA class I expression in human β cells, fostering autoantigen presentation to the immune system. We observed by bulk and single-cell RNA sequencing that exposure of human induced pluripotent-derived islet-like cells to IFNα induces expression of HLA class I and of other genes involved in antigen presentation, including the transcriptional activator NLRC5. We next evaluated the global role of NLRC5 in human insulin-producing EndoC-βH1 and human islet cells by RNA sequencing and targeted gene/protein determination. NLRC5 regulates expression of HLA class I, antigen presentation–related genes, and chemokines. NLRC5 also mediates the effects of IFNα on alternative splicing, a generator of β cell neoantigens, suggesting that it is a central player of the effects of IFNα on β cells that contribute to trigger and amplify autoimmunity in T1D. ; SCOPUS: ar.j ; info:eu-repo/semantics/published
وصف الملف: 1 full-text file(s): application/pdf
العلاقة: uri/info:doi/10.1126/sciadv.abn5732; uri/info:pmid/36103539; uri/info:scp/85138448750; https://dipot.ulb.ac.be/dspace/bitstream/2013/352916/3/sciadv.abn5732-1.pdfTest; http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/352916Test
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3دورية أكاديمية
المؤلفون: Szymczak, Florian, Cohen-Fultheim, Roni, Thomaidou, Sofia, Coomans De Brachene, Alexandra, Oliveira Castela, Angela Sofia, Colli, Maikel Luis, Marchetti, Piero, Levanon, Erez, Eizirik, Decio L., Zaldumbide, Arnaud AZ
المصدر: Frontiers in endocrinology, 13
مصطلحات موضوعية: Biologie
الوصف: Introduction Enterovirus infection has long been suspected as a possible trigger for type 1 diabetes. Upon infection, viral double-stranded RNA (dsRNA) is recognized by membrane and cytosolic sensors that orchestrate type I interferon signaling and the recruitment of innate immune cells to the pancreatic islets. In this context, adenosine deaminase acting on RNA 1 (ADAR1) editing plays an important role in dampening the immune response by inducing adenosine mispairing, destabilizing the RNA duplexes and thus preventing excessive immune activation. Methods Using high-throughput RNA sequencing data from human islets and EndoC-βH1 cells exposed to IFNα or IFNγ/IL1β, we evaluated the role of ADAR1 in human pancreatic β cells and determined the impact of the type 1 diabetes pathophysiological environment on ADAR1-dependent RNA editing. Results We show that both IFNα and IFNγ/IL1β stimulation promote ADAR1 expression and increase the A-to-I RNA editing of Alu-Containing mRNAs in EndoC-βH1 cells as well as in primary human islets. Discussion We demonstrate that ADAR1 overexpression inhibits type I interferon response signaling, while ADAR1 silencing potentiates IFNα effects. In addition, ADAR1 overexpression triggers the generation of alternatively spliced mRNAs, highlighting a novel role for ADAR1 as a regulator of the β cell transcriptome under inflammatory conditions. ; SCOPUS: ar.j ; info:eu-repo/semantics/published
وصف الملف: 1 full-text file(s): application/pdf
العلاقة: uri/info:doi/10.3389/fendo.2022.1058345; uri/info:scp/85144067862; https://dipot.ulb.ac.be/dspace/bitstream/2013/352879/1/doi_336523.pdfTest; http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/352879Test
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4دورية أكاديمية
المؤلفون: Coomans De Brachene, Alexandra, Scoubeau, Corentin, Musuaya, Anyishaï, Costa-Junior, Jose Maria, Oliveira Castela, Angela Sofia, Carpentier, Julie, Faoro, Vitalie, Klass, Malgorzata, Cnop, Miriam, Eizirik, Décio L
المصدر: Diabetologia
مصطلحات موضوعية: Enseignement des sciences bio-médicales et agricoles, Humans, Male, Female, Infant, Insulin-Secreting Cells -- metabolism, Diabetes Mellitus, Type 2 -- therapy -- metabolism, Clusterin -- metabolism -- pharmacology, Pandemics, COVID-19, Apoptosis -- physiology, Endoplasmic Reticulum Stress, Apoptosis, Exercise, Human pancreatic beta cells, Type 1 diabetes, Type 2 diabetes
الوصف: Diabetes is characterised by progressive loss of functional pancreatic beta cells. None of the therapeutic agents used to treat diabetes arrest this process; preventing beta cell loss remains a major unmet need. We have previously shown that serum from eight young healthy male participants who exercised for 8 weeks protected human islets and insulin-producing EndoC-βH1 cells from apoptosis induced by proinflammatory cytokines or the endoplasmic reticulum (ER) stressor thapsigargin. Whether this protective effect is influenced by sex, age, training modality, ancestry or diabetes is unknown. ; IF 2021 (update 2022) :10.46 ; SCOPUS: ar.j ; info:eu-repo/semantics/published
وصف الملف: 2 full-text file(s): application/pdf | application/pdf
العلاقة: uri/info:doi/10.1007/s00125-022-05837-9; uri/info:pii/10.1007/s00125-022-05837-9; uri/info:pmid/36401627; uri/info:scp/85142138280; uri/info:pmcid/PMC9676790; https://dipot.ulb.ac.be/dspace/bitstream/2013/353309/1/PMC9676790.pdfTest; https://dipot.ulb.ac.be/dspace/bitstream/2013/353309/4/doi_336953.pdfTest; http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/353309Test
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5تقرير
المؤلفون: Syed, Farooq, Ballew, Olivia, Lee, Chih-Chun, Rana, Jyoti, Krishnan, Preethi, Castela, Angela, Weaver, Staci A, Chalasani, Namratha Shivani, Thomaidou, Sofia F, Demine, Stephane, Chang, Garrick, Coomans de Brachène, Alexandra, Alvelos, Maria Ines, Marselli, Lorella, Orr, Kara, Felton, Jamie L, Liu, Jing, Marchetti, Piero, Zaldumbide, Arnaud, Scheuner, Donalyn, Eizirik, Decio L, Evans-Molina, Carmella
المصدر: bioRxiv
مصطلحات موضوعية: T cell, Type 1 diabetes, interferon-α, islets of Langerhans, tyrosine protein-kinase 2 (TYK2), β cell
الوصف: Tyrosine protein-kinase 2 (TYK2), a member of the Janus kinase family, mediates inflammatory signaling through multiple cytokines, including interferon-α (IFNα), interleukin (IL)-12, and IL-23. Missense mutations in TYK2 are associated with protection against type 1 diabetes (T1D), and inhibition of TYK2 shows promise in the management of other autoimmune conditions. Here, we evaluated the effects of specific TYK2 inhibitors (TYK2is) in pre-clinical models of T1D. First, human β cells, cadaveric donor islets, and iPSC-derived islets were treated in vitro with IFNα in combination with a small molecule TYK2i (BMS-986165 or a related molecule BMS-986202). TYK2 inhibition prevented IFNα-induced β cell HLA class I up-regulation, endoplasmic reticulum stress, and chemokine production. In co-culture studies, pre-treatment of β cells with a TYK2i prevented IFNα-induced activation of T cells targeting an epitope of insulin. In vivo administration of BMS-986202 in two mouse models of T1D (RIP-LCMV-GP mice and NOD mice) reduced systemic and tissue-localized inflammation, prevented β cell death, and delayed T1D onset. Transcriptional phenotyping of pancreatic islets, pancreatic lymph nodes (PLN), and spleen during early disease pathogenesis highlighted a role for TYK2 inhibition in modulating signaling pathways associated with inflammation, translational control, stress signaling, secretory function, immunity, and diabetes. Additionally, TYK2i treatment changed the composition of innate and adaptive immune cell populations in the blood and disease target tissues, resulting in an immune phenotype with a diminished capacity for β cell destruction. Overall, these findings indicate that TYK2i has beneficial effects in both the immune and endocrine compartments in models of T1D, thus supporting a path forward for testing TYK2 inhibitors in human T1D.
العلاقة: https://doi.org/10.1101/2024.03.20.585925Test; https://pubmed.ncbi.nlm.nih.gov/38766166Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11100605Test/
الإتاحة: https://doi.org/10.1101/2024.03.20.585925Test
https://pubmed.ncbi.nlm.nih.gov/38766166Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11100605Test/ -
6دورية أكاديمية
المؤلفون: Coomans De Brachene, Alexandra, Castela, Angela, Musuaya, Anyishaï, Marselli, L, Marchetti, P., Eizirik, Decio L.
المصدر: Auto- immunity highlights, 12 (1
مصطلحات موضوعية: Sciences bio-médicales et agricoles, Human pancreatic beta cells, Mitochondrial dsRNA, PNPT1, Type 1 diabetes, Type I interferon
الوصف: Type 1 diabetes (T1D) is an autoimmune disease characterized by the progressive destruction of pancreatic beta cells. Interferon-α (IFNα), an antiviral cytokine, is expressed in the pancreatic islets in early T1D, which may be secondary to viral infections. However, not all patients harboring a type I IFN signature present signals of viral infection, suggesting that this response might be initiated by other "danger signals". Accumulation of mitochondrial double-stranded RNA (mtdsRNA; a danger signal), secondary to silencing of members of the mitochondrial degradosome, PNPT1 and SUV3, has been described to activate the innate immune response. ; SCOPUS: ar.j ; info:eu-repo/semantics/published
وصف الملف: 1 full-text file(s): application/pdf
العلاقة: uri/info:doi/10.1186/s13317-021-00148-2; uri/info:pii/10.1186/s13317-021-00148-2; uri/info:pmid/33773604; uri/info:scp/85103276805; uri/info:pmcid/PMC8005246; https://dipot.ulb.ac.be/dspace/bitstream/2013/341151/1/doi_324795.pdfTest; http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/341151Test
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7دورية أكاديمية
المؤلفون: Alvelos, Maria Inês, Szymczak, Florian, Castela, Angela, Marin Canas, Sandra, Marmontel De Souza, Bianca, Gkantounas, Yannis, Colli, Maikel Luis, Fantuzzi, Federica, Cosentino, Cristina, Igoillo Esteve, Mariana, Marselli, Lorella, Marchetti, Piero, Cnop, Miriam, Eizirik, Decio L.
المصدر: Islets
مصطلحات موضوعية: Sciences bio-médicales et agricoles
الوصف: info:eu-repo/semantics/published
وصف الملف: 2 full-text file(s): application/pdf | application/pdf
العلاقة: https://dipot.ulb.ac.be/dspace/bitstream/2013/326386/3/Alvelospreprint.pdfTest; https://dipot.ulb.ac.be/dspace/bitstream/2013/326386/4/islets_paper.pdfTest; http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/326386Test
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8دورية أكاديمية
المؤلفون: Alvelos, Maria Inês, Szymczak, Florian, Castela, Ângela, Marín-Cañas, Sandra, de Souza, Bianca Marmontel, Gkantounas, Ioannis, Colli, Maikel, Fantuzzi, Federica, Cosentino, Cristina, Igoillo-Esteve, Mariana, Marselli, Lorella, Marchetti, Piero, Cnop, Miriam, Eizirik, Décio L.
المساهمون: Fonds De La Recherche Scientifique - FNRS, Innoviris, Innovative Medicines Initiative 2 Joint Undertaking, Walloon Region SPW-EERWin2Wal, Indiana Biosciences Research Institute, Dutch Diabetes Research Foundation, Welbio/FRFS
المصدر: Islets ; volume 13, issue 3-4, page 51-65 ; ISSN 1938-2014 1938-2022
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9دورية أكاديمية
المؤلفون: Colli, Maikel Luis, Ramos-Rodríguez, Mireia, Nakayasu, Ernesto Satoshi, Alvelos, Maria Inês, Lopes, Miguel, Hill, Jessica L E, Turatsinze, Jean Valéry, Coomans De Brachene, Alexandra, Russell, Mark M.A., Raurell-Vila, Helena, Castela, Angela, Juan-Mateu, Jonàs, Webb-Robertson, Bobbie-Jo M., Krogvold, Lars, Dahl-Jorgensen, Knut, Marselli, L, Marchetti, P., Richardson, Sarah J, Morgan, Noel G, Metz, Thomas O., Pasquali, Lorenzo, Eizirik, Decio L.
المصدر: Nature communications, 11 (1
مصطلحات موضوعية: Sciences bio-médicales et agricoles, Alternative Splicing -- drug effects, Cells, Cultured, Chromatin -- drug effects -- metabolism, Data Mining, Diabetes Mellitus, Type 1 -- genetics, Gene Expression Regulation -- drug effects, Gene Regulatory Networks, Humans, Insulin-Secreting Cells -- drug effects -- physiology, Interferon-alpha -- metabolism -- pharmacology, Protein Interaction Maps, Proteomics, Transcription Factors -- genetics -- metabolism, Transcription Initiation Site
الوصف: Interferon-α (IFNα), a type I interferon, is expressed in the islets of type 1 diabetic individuals, and its expression and signaling are regulated by T1D genetic risk variants and viral infections associated with T1D. We presently characterize human beta cell responses to IFNα by combining ATAC-seq, RNA-seq and proteomics assays. The initial response to IFNα is characterized by chromatin remodeling, followed by changes in transcriptional and translational regulation. IFNα induces changes in alternative splicing (AS) and first exon usage, increasing the diversity of transcripts expressed by the beta cells. This, combined with changes observed on protein modification/degradation, ER stress and MHC class I, may expand antigens presented by beta cells to the immune system. Beta cells also up-regulate the checkpoint proteins PDL1 and HLA-E that may exert a protective role against the autoimmune assault. Data mining of the present multi-omics analysis identifies two compound classes that antagonize IFNα effects on human beta cells. ; SCOPUS: ar.j ; info:eu-repo/semantics/published
وصف الملف: 1 full-text file(s): application/pdf
العلاقة: uri/info:doi/10.1038/s41467-020-16327-0; uri/info:pii/10.1038/s41467-020-16327-0; uri/info:pmid/32444635; uri/info:scp/85085264347; uri/info:pmcid/PMC7244579; https://dipot.ulb.ac.be/dspace/bitstream/2013/341152/1/doi_324796.pdfTest; http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/341152Test
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10دورية أكاديمية
المؤلفون: Coomans De Brachene, Alexandra, Castela, Angela, Op De Beeck, Anne, Mirmira, Raghavendra R.G., Marselli, Lorella, Marchetti, Piero, Masse, Craig, Miao, Wenyan, Leit, Silvana, Evans-Molina, Carmella, Eizirik, Decio L.
المصدر: Diabetes, obesity and metabolism
مصطلحات موضوعية: Sciences bio-médicales et agricoles
الوصف: Aim: Type 1 diabetes (T1D) is a chronic autoimmune disease leading to progressive loss of pancreatic beta cells. Interferon (IFN)-α plays a critical role in the crosstalk between pancreatic beta cells and the immune system in early insulitis. In human beta cells IFNα signals through JAK1 and TYK2, leading to endoplasmic reticulum stress, inflammation and HLA class I overexpression. IFNα, acting synergistically with IL-1β, induces apoptosis. Polymorphisms in TYK2 that decrease its activity are associated with protection against T1D, and we hypothesized that pharmacological inhibitors that specifically target TYK2 could protect human beta cells against the deleterious effects of IFNα. Materials and Methods: Two TYK2 inhibitors provided by Nimbus Lakshmi were tested in human insulin-producing EndoC-βH1 cells and human islets to evaluate their effect on IFNα signalling, beta-cell function and susceptibility to viral infection using RT-qPCR, western blot, immunofluorescence, ELISA and nuclear dyes. Results: The two TYK2 inhibitors tested prevented IFNα-induced human beta-cell gene expression in a dose-dependent manner. They also protected human islets against IFNα + IL-1β-induced apoptosis. Importantly, these inhibitors did not modify beta-cell function or their survival following infection with the potential diabetogenic coxsackieviruses CVB1 and CVB5. Conclusions: The two TYK2 inhibitors tested inhibit the IFNα signalling pathway in human beta cells, decreasing its pro-inflammatory and pro-apoptotic effects without sensitizing the cells to viral infection. The preclinical findings could pave the way for future clinical trials with TYK2 inhibitors for the prevention and treatment of type 1 diabetes. ; SCOPUS: ar.j ; info:eu-repo/semantics/published
وصف الملف: 1 full-text file(s): application/pdf
العلاقة: uri/info:doi/10.1111/dom.14104; uri/info:pmid/32476252; uri/info:scp/85087436986; https://dipot.ulb.ac.be/dspace/bitstream/2013/308093/3/dom.14104.pdfTest; http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/308093Test
