المؤلفون: Lisa Zimmer, Bastian Schilling, Yinghong Wang, Georgina V Long, Jennifer McQuade, Ana Arance, Douglas B Johnson, Nadia Yousaf, Kazi J Nahar, Matteo S Carlino, Kate Young, Joanna Lee, Liselotte Tas, Serigne N Lo, Christian Blank, Alexander Maxwell Menzies, Catriona Harvey, Janet McKeown, Sheima Farag, Aafke Meerveld-Eggink, Austin Thomas, Roberto Martín Huertas

المصدر: Journal for ImmunoTherapy of Cancer, Vol 12, Iss 1 (2024)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Background Immune checkpoint inhibitor (ICI) gastrointestinal toxicity (gastritis, enteritis, colitis) is a major cause of morbidity and treatment-related death. Guidelines agree steroid-refractory cases warrant infliximab, however best management of infliximab-refractory ICI gastrointestinal toxicity (IRIGItox) is unknown.Methods We conducted an international multicenter retrospective case series. IRIGItox was defined as failure of symptom resolution ≤grade 1 (Common Terminology Criteria for Adverse Events V.5.0) following ≥2 infliximab doses or failure of symptom resolution ≤grade 2 after one dose. Data were extracted regarding demographics, steroid use, response to treatment, and survival outcomes. Toxicity was graded at symptom onset and time of infliximab failure. Efficacy of infliximab refractory therapy was assessed by symptom resolution, time to resolution and steroid wean duration. Survival outcomes were examined based on immunosuppressive therapy received.Results 78 patients were identified: median age 60 years; 56% men; majority melanoma (N=70, 90%); 60 (77%) received anti-cytotoxic T-lymphocyte-associated protein 4 alone or in combination with anti-programmed cell death protein-1 and most had colitis (N=74, 95%). 106 post-infliximab treatments were given: 31 calcineurin inhibitors (CNIs); 27 antimetabolites (mycophenolate, azathioprine); 16 non-systemic immunomodulatory agents (eg, mesalazine or budesonide); 15 vedolizumab; 5 other biologics (anti-interleukin-12/23, 16, Janus kinase inhibitors) and 7 interventional procedures (including colectomy); 5 did not receive post-infliximab therapy. Symptom resolution was achieved in most (N=23/31, 74%) patients treated with CNIs; 12/27 (44%) with antimetabolites; 7/16 (44%) with non-systemic immunomodulation, 8/15 (53%) with vedolizumab and 5/7 (71%) with interventional procedures. No non-vedolizumab biologics resulted in toxicity resolution. CNIs had the shortest time to symptom resolution (12 days) and steroid wean (43 days); however, were associated with poorer event-free survival (6.3 months) and overall survival (26.8 months) than other agents. Conversely, vedolizumab had the longest time to toxicity resolution and steroid wean, 66 and 124 days, but most favorable survival data: EFS 24.5 months; median OS not reached. Six death occurred (three due to IRIGItox or management of toxicity; three with persisting IRIGItox and progressive disease).Conclusions IRIGItox causes major morbidity and mortality. Management is heterogeneous. CNIs appear most likely to result in toxicity resolution in the shortest time period, however, are associated with poorer oncological outcomes in contrast to vedolizumab.

وصف الملف: electronic resource

العلاقة: https://jitc.bmj.com/content/12/1/e008232.fullTest; https://doaj.org/toc/2051-1426Test

الوصول الحر: https://doaj.org/article/fd4c46a2bc33417a85a04b53c7be5d49Test

المؤلفون: Sjoerd H van der Burg, Ilina Ehsan, Mariette I E van Poelgeest, Dana A M Mustafa, Helena C van Doorn, Kim E Kortekaas, Saskia J Santegoets, Liselotte Tas, Pornpimol Charoentong

المصدر: Journal for ImmunoTherapy of Cancer, Vol 9, Iss 10 (2021)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

وصف الملف: electronic resource

العلاقة: https://jitc.bmj.com/content/9/10/e003671.fullTest; https://doaj.org/toc/2051-1426Test

الوصول الحر: https://doaj.org/article/a1025a5a3f4948c98a290b15cf047a5eTest

المؤلفون: Iris L. A. Bodewes, Peter J. van der Spek, Leticia G. Leon, Annemarie J. M. Wijkhuijs, Cornelia G. van Helden-Meeuwsen, Liselotte Tas, Marco W. J. Schreurs, Paul L. A. van Daele, Peter D. Katsikis, Marjan A. Versnel

المصدر: Frontiers in Immunology, Vol 10 (2019)

مصطلحات موضوعية: Sjögren's syndrome, fatigue, interferon, proteomics, SOMAscan, Immunologic diseases. Allergy, RC581-607

الوصف: Background: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease, where patients often suffer from fatigue. Biological pathways underlying fatigue are unknown. In this study aptamer-based SOMAscan technology is used to identify potential biomarkers and treatment targets for fatigue in pSS.Methods: SOMAscan® Assay 1.3k was performed on serum samples of healthy controls (HCs) and pSS patients characterized for interferon upregulation and fatigue. Differentially expressed proteins (DEPs) between pSS patients and HC or fatigued and non-fatigued pSS patients were validated and discriminatory capacity of markers was tested using independent technology.Results: Serum concentrations of over 1,300 proteins were compared between 63 pSS patients and 20 HCs resulting in 58 upregulated and 46 downregulated proteins. Additionally, serum concentrations of 30 interferon positive (IFNpos) and 30 interferon negative (IFNneg) pSS patients were compared resulting in 25 upregulated and 13 downregulated proteins. ELISAs were performed for several DEPs between pSS patients and HCs or IFNpos and IFNneg all showing a good correlation between protein levels measured by ELISA and relative fluorescence units (RFU) measured by the SOMAscan. Comparing 22 fatigued and 23 non-fatigued pSS patients, 16 serum proteins were differentially expressed, of which 14 were upregulated and 2 were downregulated. Top upregulated DEPs included neuroactive synaptosomal-associated protein 25 (SNAP-25), alpha-enolase (ENO1) and ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1). Furthermore, the proinflammatory mediator IL36a and several complement factors were upregulated in fatigued compared to non-fatigued pSS patients. ROC analysis indicated that DEPs showed good capacity to discriminate fatigued and non-fatigued pSS patients.Conclusion: In this study we validated the use of aptamer-based proteomics and identified a novel set of proteins which were able to distinguish fatigued from non-fatigued pSS patients and identified a so-called “fatigue signature.”

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/article/10.3389/fimmu.2019.00312/fullTest; https://doaj.org/toc/1664-3224Test

الوصول الحر: https://doaj.org/article/46734dad477b4401b0089d6c67ed3791Test

المؤلفون: Liselotte Tas, Inge Jedema, John B.A.G. Haanen

المصدر: Current opinion in oncology.

مصطلحات موضوعية: Cancer Research, Oncology

الوصف: Treatment with tumor-infiltrating lymphocytes (TILs) has shown remarkable clinical responses in patients with advanced solid tumors. Although the TIL production process is very robust, the original protocol stems from the early nineties and lacks effective selection for tumor-reactivity and functional activity. In this review we highlight the limitations of the current production process and give an overview of improvements that can be made to increase TIL efficacy.With the recent advances in single cell sequencing technologies, our understanding of the composition and phenotype of TILs in the tumor micro environment has majorly increased, which forms the basis for the development of new strategies to improve the TIL production process. Strategies involve selection for neoantigen-reactive TILs by cell sorting or selective expansion strategies. Furthermore, gene editing strategies like Clustered regularly interspaced short palindromic repeats-Cas (CRISPR-Cas9) can be used to increase TIL functionality.Although combining all the possible improvements into a next generation TIL product might be challenging, it is highly likely that those techniques will increase the clinical value of TIL therapy in the coming years.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3a4db8c7325f2d357e09d9cdb321a3cdTest
https://pubmed.ncbi.nlm.nih.gov/36607824Test

المؤلفون: Saskia J. A. M. Santegoets, Kim E. Kortekaas, Pornpimol Charoentong, Sjoerd H. van der Burg, Helena C. van Doorn, Liselotte Tas, Mariette I.E. van Poelgeest, Dana A M Mustafa, Ilina Ehsan

المساهمون: Gynecological Oncology, Pathology

المصدر: Journal for Immunotherapy of Cancer
Journal for ImmunoTherapy of Cancer, 9(10). BMJ PUBLISHING GROUP
Journal for ImmunoTherapy of Cancer, Vol 9, Iss 10 (2021)
Journal for ImmunoTherapy of Cancer, 9(10):e003671. BioMed Central Ltd.

مصطلحات موضوعية: Adult, Cancer Research, endocrine system, Myeloid, Lymphocyte, T cell, medicine.medical_treatment, T-Lymphocytes, Immunology, Biology, B7-H1 Antigen, Immune system, SDG 3 - Good Health and Well-being, PD-L1, medicine, gene expression profiling, Immunology and Allergy, Cytotoxic T cell, tumor microenvironment, Humans, RC254-282, Aged, Pharmacology, Aged, 80 and over, Tumor microenvironment, Vulvar Neoplasms, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Basic Tumor Immunology, Immunotherapy, Middle Aged, medicine.anatomical_structure, Oncology, Cancer research, biology.protein, Carcinoma, Squamous Cell, Molecular Medicine, Female

الوصف: BackgroundA profound insight into the immune landscape of vulvar squamous cell carcinoma (VSCC) is lacking. Here, an in-depth interrogation of T cell infiltration, local immune contexture, signaling pathways and checkpoint molecule expression was performed in early-stage and late-stage VSCC.MethodsThe type, location, and infiltration pattern of T cells were studied in 109 patients with primary VSCC FIGO stage I–III. RNA expression of genes involved in immune oncology and oncogenic signaling pathways was analyzed in 40 VSCC, matched for prognostic clinicopathological variables, analyzed for HPV and p53 status, and selected based on T cell infiltration.ResultsHigh intraepithelial infiltration with CD4 or CD8 T cells was associated with longer overall and recurrence-free survival and formed an independent prognostic factor, outperforming molecular subtype and stage of the disease. Strong T cell infiltrated VSCC displayed a coordinated immune response reflected by a positive association between T cells and different lymphocyte and myeloid cell subsets. The expression of genes involved in the migration of T cells and myeloid cells, T cell activation and costimulation, interferon (IFN)-γ signaling, cytotoxicity and apoptosis was higher than in low infiltrated tumors. An active immune signaling profile was observed in all inflamed, part of the altered-excluded and not in altered-immunosuppressed or deserted VSCC. While several checkpoint molecules were overexpressed, only PD-L1 expression displayed discriminatory ability and clinical usefulness. High PD-L1 expression was detected in all inflamed and ~60% of the altered-excluded VSCC.ConclusionAn active immune signaling profile is present in 35% of primary FIGO I–III VSCCs, suggesting potential responsiveness to neoadjuvant PD-1/PD-L1 immunotherapy.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4f229dd19735830c6208417869a7f683Test
https://hdl.handle.net/1887/3264398Test

المؤلفون: Iris L A Bodewes, Sylvia Kamphuis, P. Martin van Hagen, Erika Huijser, Marjan A. Versnel, Cornelia G van Helden-Meeuwsen, Ruth Huizinga, Liselotte Tas, Paul L A van Daele, Virgil A. S. H. Dalm, Noortje Groot

المساهمون: Immunology, Internal Medicine, Cardiology, Pediatrics

المصدر: Journal of Autoimmunity, 91, 97-102. Academic Press

مصطلحات موضوعية: Myxovirus Resistance Proteins, 0301 basic medicine, Neutrophils, Interferon Regulatory Factor-7, Immunology, Thiophenes, Protein Serine-Threonine Kinases, Peripheral blood mononuclear cell, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Interferon, Humans, Lupus Erythematosus, Systemic, Immunology and Allergy, Medicine, STAT1, Antigens, Phosphorylation, skin and connective tissue diseases, Receptor, Cells, Cultured, Adaptor Proteins, Signal Transducing, 030203 arthritis & rheumatology, Scleroderma, Systemic, biology, business.industry, Intracellular Signaling Peptides and Proteins, RNA-Binding Proteins, virus diseases, TLR7, Cytoskeletal Proteins, Pyrimidines, STAT1 Transcription Factor, Sjogren's Syndrome, 030104 developmental biology, Gene Expression Regulation, Toll-Like Receptor 7, Interferon Type I, biology.protein, IRF7, Interferon Regulatory Factor-3, Carrier Proteins, business, IRF3, Signal Transduction, medicine.drug

الوصف: Objective Upregulation of type I interferons (IFN-I) is a hallmark of systemic autoimmune diseases like primary Sjogren's syndrome (pSS), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). Expression of IFN-I is induced by three different receptor families: Toll-like receptors (TLRs), RIG-like receptors (RLRs) and DNA-sensing receptors (DSRs). TANK-binding kinase (TBK1) is an important signaling hub downstream of RLRs and DSRs. TBK1 activates IRF3 and IRF7, leading to IFN-I production and subsequent induction of interferon stimulated genes (ISGs). The objective of this study was to explore the potential of BX795, an inhibitor of TBK1, to downregulate IFN-I activation in pSS, SLE and SSc. Methods TBK1, IRF3, IRF7 and STAT1 were determined by RT-PCR in PAXgene samples and phosphorylated-TBK1 (pTBK1) was analyzed by flowcytometry in plasmacytoid dendritic cells (pDCs) from IFN-I positive (IFNpos) patients. Peripheral blood mononuclear cells (PBMCs) of pSS, SLE and SSc patients and TLR7 stimulated PBMCs of healthy controls (HCs) were cultured with the TBK1 inhibitor BX795, followed by analysis of ISGs. Results Increased gene expression of TBK1, IRF3, IRF7 and STAT1 in whole blood and pTBK1 in pDCs was observed in IFNpos pSS, SLE and SSc patients compared to HCs. Upon treatment with BX795, PBMCs from IFNpos pSS, SLE, SSc and TLR7-stimulated HCs downregulated the expression of the ISGs MxA, IFI44, IFI44L, IFIT1 and IFIT3. Conclusions TBK1 inhibition reduced expression of ISGs in PBMCs from IFNpos patients with systemic autoimmune diseases indicating TBK1 as a potential treatment target.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::37cab9dde920682f560ce7c093fdac24Test
https://doi.org/10.1016/j.jaut.2018.02.001Test

المؤلفون: Iris L. A. Bodewes, Peter J. van der Spek, Leticia G. Leon, Annemarie J. M. Wijkhuijs, Cornelia G. van Helden-Meeuwsen, Liselotte Tas, Marco W. J. Schreurs, Paul L. A. van Daele, Peter D. Katsikis, Marjan A. Versnel

مصطلحات موضوعية: Immunology, Applied Immunology (incl. Antibody Engineering, Xenotransplantation and T-cell Therapies), Autoimmunity, Cellular Immunology, Humoural Immunology and Immunochemistry, Immunogenetics (incl. Genetic Immunology), Innate Immunity, Transplantation Immunology, Tumour Immunology, Immunology not elsewhere classified, Genetic Immunology, Animal Immunology, Veterinary Immunology, Sjögren's syndrome, fatigue, interferon, proteomics, SOMAscan

الوصف: Background: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease, where patients often suffer from fatigue. Biological pathways underlying fatigue are unknown. In this study aptamer-based SOMAscan technology is used to identify potential biomarkers and treatment targets for fatigue in pSS. Methods: SOMAscan® Assay 1.3k was performed on serum samples of healthy controls (HCs) and pSS patients characterized for interferon upregulation and fatigue. Differentially expressed proteins (DEPs) between pSS patients and HC or fatigued and non-fatigued pSS patients were validated and discriminatory capacity of markers was tested using independent technology. Results: Serum concentrations of over 1,300 proteins were compared between 63 pSS patients and 20 HCs resulting in 58 upregulated and 46 downregulated proteins. Additionally, serum concentrations of 30 interferon positive (IFNpos) and 30 interferon negative (IFNneg) pSS patients were compared resulting in 25 upregulated and 13 downregulated proteins. ELISAs were performed for several DEPs between pSS patients and HCs or IFNpos and IFNneg all showing a good correlation between protein levels measured by ELISA and relative fluorescence units (RFU) measured by the SOMAscan. Comparing 22 fatigued and 23 non-fatigued pSS patients, 16 serum proteins were differentially expressed, of which 14 were upregulated and 2 were downregulated. Top upregulated DEPs included neuroactive synaptosomal-associated protein 25 (SNAP-25), alpha-enolase (ENO1) and ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1). Furthermore, the proinflammatory mediator IL36a and several complement factors were upregulated in fatigued compared to non-fatigued pSS patients. ROC analysis indicated that DEPs showed good capacity to discriminate fatigued and non-fatigued pSS patients. Conclusion: In this study we validated the use of aptamer-based proteomics and identified a novel set of proteins which were able to distinguish fatigued from non-fatigued pSS patients and identified a so-called ...

العلاقة: https://figshare.com/articles/figure/Image_1_Fatigue_in_Sj_gren_s_Syndrome_A_Search_for_Biomarkers_and_Treatment_Targets_JPEG/7769117Test

الإتاحة: https://doi.org/10.3389/fimmu.2019.00312.s001Test
https://figshare.com/articles/figure/Image_1_Fatigue_in_Sj_gren_s_Syndrome_A_Search_for_Biomarkers_and_Treatment_Targets_JPEG/7769117Test

المؤلفون: Iris L. A. Bodewes, Peter J. van der Spek, Leticia G. Leon, Annemarie J. M. Wijkhuijs, Cornelia G. van Helden-Meeuwsen, Liselotte Tas, Marco W. J. Schreurs, Paul L. A. van Daele, Peter D. Katsikis, Marjan A. Versnel

مصطلحات موضوعية: Immunology, Applied Immunology (incl. Antibody Engineering, Xenotransplantation and T-cell Therapies), Autoimmunity, Cellular Immunology, Humoural Immunology and Immunochemistry, Immunogenetics (incl. Genetic Immunology), Innate Immunity, Transplantation Immunology, Tumour Immunology, Immunology not elsewhere classified, Genetic Immunology, Animal Immunology, Veterinary Immunology, Sjögren's syndrome, fatigue, interferon, proteomics, SOMAscan

الوصف: Background: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease, where patients often suffer from fatigue. Biological pathways underlying fatigue are unknown. In this study aptamer-based SOMAscan technology is used to identify potential biomarkers and treatment targets for fatigue in pSS. Methods: SOMAscan® Assay 1.3k was performed on serum samples of healthy controls (HCs) and pSS patients characterized for interferon upregulation and fatigue. Differentially expressed proteins (DEPs) between pSS patients and HC or fatigued and non-fatigued pSS patients were validated and discriminatory capacity of markers was tested using independent technology. Results: Serum concentrations of over 1,300 proteins were compared between 63 pSS patients and 20 HCs resulting in 58 upregulated and 46 downregulated proteins. Additionally, serum concentrations of 30 interferon positive (IFNpos) and 30 interferon negative (IFNneg) pSS patients were compared resulting in 25 upregulated and 13 downregulated proteins. ELISAs were performed for several DEPs between pSS patients and HCs or IFNpos and IFNneg all showing a good correlation between protein levels measured by ELISA and relative fluorescence units (RFU) measured by the SOMAscan. Comparing 22 fatigued and 23 non-fatigued pSS patients, 16 serum proteins were differentially expressed, of which 14 were upregulated and 2 were downregulated. Top upregulated DEPs included neuroactive synaptosomal-associated protein 25 (SNAP-25), alpha-enolase (ENO1) and ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1). Furthermore, the proinflammatory mediator IL36a and several complement factors were upregulated in fatigued compared to non-fatigued pSS patients. ROC analysis indicated that DEPs showed good capacity to discriminate fatigued and non-fatigued pSS patients. Conclusion: In this study we validated the use of aptamer-based proteomics and identified a novel set of proteins which were able to distinguish fatigued from non-fatigued pSS patients and identified a so-called ...

العلاقة: https://figshare.com/articles/dataset/Table_1_Fatigue_in_Sj_gren_s_Syndrome_A_Search_for_Biomarkers_and_Treatment_Targets_DOCX/7769123Test

الإتاحة: https://doi.org/10.3389/fimmu.2019.00312.s003Test
https://figshare.com/articles/dataset/Table_1_Fatigue_in_Sj_gren_s_Syndrome_A_Search_for_Biomarkers_and_Treatment_Targets_DOCX/7769123Test

المؤلفون: Liselotte Tas, Sylvia Kamphuis, Virgil A. S. H. Dalm, P L A van Daele, Erika Huijser, I. Bodewes, N. Groot, M. Versnel, M. van Hagen, C.G. van Helden-Meeuwsen, Ruth Huizinga

المصدر: FRIDAY, 15 JUNE 2018.

مصطلحات موضوعية: biology, business.industry, Kinase, CD14, CD19, Downregulation and upregulation, Interferon, Gene expression, Cancer research, medicine, biology.protein, Receptor, business, Interferon type I, medicine.drug

الوصف: Background Type I interferon (IFN-I) upregulation is a hallmark of systemic autoimmune diseases like primary Sjogren’s syndrome (pSS). Expression of IFN-I is induced by three different receptor families: Toll-like receptors (TLRs), RIG-like receptors (RLRs) and DNA-sensing receptors (DSRs). Previously we have shown increased mRNA levels of TLRs and RLRs in plasmacytoid dendritic cells (pDC) and CD14 +monocytes of IFN-I positive (IFNpos) pSS patients.1 TANK-binding kinase (TBK1), is an important signalling hub downstream of RLRs and DSRs and leads to production of IFN-I and subsequent induction of interferon-stimulated genes (ISGs). Objectives Study RLRs and DSRs in pSS and explore the potential of a TBK1 inhibitor to downregulate IFN-I activation. Methods Expression of RLRs and DSRs was assessed by RQ-PCR and flowcytometry in CD14 +monocytes, BDCA4 +CD123+pDC and CD19 +B cells from IFNpos pSS patients. pDCs from IFNpos pSS patients were analysed by flowcytometry for phosphorylated-TBK1 (pTBK1). PBMCs of pSS patients were cultured with a TBK1 inhibitor, BX795, followed by analysis of IFN-I production and expression of ISGs. Results In addition to upregulated mRNA levels of RLRs IFIH1 (encoding for MDA5) and DDX58 (encoding for RIG-I), which we previously observed in pDC and monocytes of IFNpos pSS patients, gene expression of IFIH1 and DDX58 was also upregulated in B cells. Upregulation of mRNA levels of the DSRs IFI16 and ZBP1 was observed in monocytes and B cells from IFNpos patients. In pDC protein expression of MDA5, ZBP-1, IFI16 was increased in IFNpos pSS, while there were no differences in RIG-I. In monocytes protein expression of MDA5 was increased and a trend was visible for RIG-I and IFI16. B cells showed increased protein expression of MDA5 and a trend was observed for RIG-I, ZBP-1 and IFI16. These data indicate upregulation of RLRs and DSRs particularly in pDC of IFNpos pSS patients. To further look into the signalling of RLRs and DSRs, phosphorylation of TBK was studied in pDC, the main IFN-I producers, of pSS patients. Increased expression of pTBK1 was observed in pDCs from IFNpos pSS. Upon treatment with BX795, PBMCs from IFNpos pSS downregulated the production of IFN-I and mRNA expression of the ISGs MxA, IFI44, IFI44L, IFIT1 and IFIT3. Conclusions RLRs and DSRs are upregulated in IFNpos pSS. Signalling of these receptors could be blocked using a TBK1 inhibitor, which reduced IFN-I protein production and expression of ISGs in PBMCs of IFNpos pSS patients. As patented pharmacological inhibitors, amongst others a small molecule inhibitor, are available TBK1 inhibition is indicated as a potential future treatment target for IFNpos pSS. Reference [1] Maria, et al. ARD2016. Acknowledgements The research for this manuscript was (partly) performed within the framework of the Erasmus Postgraduate School Molecular Medicine. The authors thank patients and healthy volunteers for taking part in this study. Disclosure of Interest I. Bodewes: None declared, E. Huijser: None declared, C. van Helden-Meeuwsen: None declared, L. Tas: None declared, R. Huizinga: None declared, V. Dalm: None declared, M. van Hagen: None declared, N. Groot: None declared, S. Kamphuis: None declared, P. van Daele: None declared, M. Versnel Grant/research support from: Research funding Domainex

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::30c43b769c0505d58bc0080a90d8b6fbTest
https://doi.org/10.1136/annrheumdis-2018-eular.4641Test

المؤلفون: C.G. van Helden-Meeuwsen, Ruth Huizinga, Virgil A. S. H. Dalm, M. van Hagen, Liselotte Tas, N. Groot, Erika Huijser, M. Versnel, I. Bodewes, P L A van Daele, Sylvia Kamphuis

المصدر: Innate immunity in rheumatic diseases.

مصطلحات موضوعية: biology, business.industry, virus diseases, Molecular medicine, Peripheral blood mononuclear cell, Downregulation and upregulation, Interferon, Immunology, medicine, biology.protein, IRF7, STAT1, skin and connective tissue diseases, IRF3, business, Receptor, medicine.drug

الوصف: Background Upregulation of type I interferons (IFN-I) is a hallmark of systemic autoimmune diseases like systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). Three different receptor families are implicated in the induction of IFN-I production: Toll-like receptors (TLRs), RIG-like receptors (RLRs) and DNA-sensing receptors (DSRs). TANK-binding kinase (TBK1), is an important signalling hub downstream of RLRs and DSRs. TBK1 activates IRF3 and IRF7, leading to IFN-I production and subsequent induction of interferon-stimulated genes (ISGs). Objectives To explore the potential of TBK1 inhibitors to downregulate IFN-I activation in SLE and SSc. Methods TBK1, IRF3, IRF7 and STAT1 were determined by qPCR in PAXgene samples and phosphorylated-TBK1 (pTBK1) was analysed by flowcytometry in plasmacytoid dendritic cells (pDCs) from IFN-I positive (IFNpos) patients. Peripheral blood mononuclear cells (PBMCs) from SLE and SSc patients and TLR7-stimulated PBMCs from healthy controls (HCs) were cultured with the TBK1 inhibitors BX795 followed by analysis of ISGs. Results Increased expression of TBK1, IRF3, IRF7 and STAT1 in whole blood and pTBK1 in pDCs was observed in IFNpos pSS, SLE and SSc patients compared to HCs. Upon treatment with BX795, PBMCs from IFNpos pSS, SLE, SSc and TLR7-stimulated HCs downregulated the expression of the ISGs MxA, IFI44, IFI44L, IFIT1 and IFIT3. The TBK1 inhibitor inhibited the secretion of IFN-I by TLR7-stimulated PBMCs from HCs. Conclusions TBK1 inhibition reduced expression of ISGs in PBMCs from IFNpos SLE and SSc patients patients indicating TBK1 as a potential treatment target. Acknowledgements The research for this manuscript was (partly) performed within the framework of the Erasmus Postgraduate School Molecular Medicine. The authors thank patients and healthy volunteers for taking part in this study. Disclosure of Interest E. Huijser: None declared, I. Bodewes: None declared, C. van Helden-Meeuwsen: None declared, L. Tas: None declared, R. Huizinga: None declared, V. Dalm: None declared, M. van Hagen: None declared, N. Groot: None declared, S. Kamphuis: None declared, P. van Daele: None declared, M. Versnel Grant/research support from: Research funding Domainex

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::1af96553c6dd47e449cfe9c8b5ccc737Test
https://doi.org/10.1136/annrheumdis-2018-eular.6367Test