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1. N6-methyladenosine promotes TNF mRNA degradation in CD4+ T lymphocytes.

Author

Vroonhoven, Ellen C N van, Picavet, Lucas W, Scholman, Rianne C, Sijbers, Lyanne J P M, Kievit, Corlinda R E, Dungen, Noortje A M van den, Mokry, Michal, Evers, Anouk, Lebbink, Robert J, Mocholi, Enric, Coffer, Paul J, Calis, Jorg J A, Vastert, Sebastiaan J, and Loosdregt, Jorg van

Subjects
RNA modification & restriction, TUMOR necrosis factors, T cells, RNA methylation, LYMPHOCYTE transformation
Abstract

N6-methyladenosine (m6A) is a RNA modification that can regulate post-transcriptional processes including RNA stability, translation, splicing, and nuclear export. In CD4+ lymphocytes, m6A modifications have been demonstrated to play a role in early differentiation processes. The role of m6A in CD4+ T cell activation and effector function remains incompletely understood. To assess the role of m6A in CD4+ T lymphocyte activation and function, we assessed the transcriptome-wide m6A landscape of human primary CD4+ T cells by methylated RNA immunoprecipitation sequencing. Stimulation of the T cells impacted the m6A pattern of hundreds of transcripts including tumor necrosis factor (TNF). m6A methylation was increased on TNF messenger RNA (mRNA) after activation, predominantly in the 3′ untranslated region of the transcript. Manipulation of m6A levels in primary human T cells, the directly affected the expression of TNF. Furthermore, we identified that the m6A reader protein YTHDF2 binds m6A-methylated TNF mRNA, and promotes its degradation. Taken together, this study demonstrates that TNF expression in CD4+ T lymphocytes is regulated via m6A and YTHDF2, thereby providing novel insight into the regulation of T cell effector functions. [ABSTRACT FROM AUTHOR]

Published
2024
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2. m6A Reader YTHDC1 Impairs Respiratory Syncytial Virus Infection by Downregulating Membrane CX3CR1 Expression

Author

Picavet, Lucas W., primary, van Vroonhoven, Ellen C. N., additional, Scholman, Rianne C., additional, Smits, Yesper T. H., additional, Banerjee, Rupa, additional, Besteman, Sjanna B., additional, Viveen, Mattheus C., additional, van der Vlist, Michiel M., additional, Tanenbaum, Marvin E., additional, Lebbink, Robert J., additional, Vastert, Sebastiaan J., additional, and van Loosdregt, Jorg, additional

Published
2024
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3. N6-methyladenosine promotes TNF mRNA degradation in CD4+T lymphocytes

Author

van Vroonhoven, Ellen C N, Picavet, Lucas W, Scholman, Rianne C, Sijbers, Lyanne J P M, Kievit, Corlinda R E, van den Dungen, Noortje A M, Mokry, Michal, Evers, Anouk, Lebbink, Robert J, Mocholi, Enric, Coffer, Paul J, Calis, Jorg J A, Vastert, Sebastiaan J, and van Loosdregt, Jorg

Abstract

N6-methyladenosine (m6A) is a RNA modification that can regulate post-transcriptional processes including RNA stability, translation, splicing, and nuclear export. In CD4+lymphocytes, m6A modifications have been demonstrated to play a role in early differentiation processes. The role of m6A in CD4+T cell activation and effector function remains incompletely understood. To assess the role of m6A in CD4+T lymphocyte activation and function, we assessed the transcriptome-wide m6A landscape of human primary CD4+T cells by methylated RNA immunoprecipitation sequencing. Stimulation of the T cells impacted the m6A pattern of hundreds of transcripts including tumor necrosis factor (TNF). m6A methylation was increased on TNFmessenger RNA (mRNA) after activation, predominantly in the 3′ untranslated region of the transcript. Manipulation of m6A levels in primary human T cells, the directly affected the expression of TNF. Furthermore, we identified that the m6A reader protein YTHDF2 binds m6A-methylated TNFmRNA, and promotes its degradation. Taken together, this study demonstrates that TNF expression in CD4+T lymphocytes is regulated via m6A and YTHDF2, thereby providing novel insight into the regulation of T cell effector functions.This study demonstrates that tumor necrosis factor expression in CD4+ T lymphocytes is regulated via N6-methyladenosine and YTHDF2, thereby providing novel insight into the regulation of T cell effector functions.T helper cells are immune cells of the adaptive immune system. These cells are activated by antigen presenting cells that have engulfed invading pathogens. When the T helper cell is activated, it will produce and excrete signaling molecules (cytokines) that activate other immune cells in order to eradicate these pathogens. Cytokines are formed after translation of RNA molecules that encode for these cytokines. In this study it was found that a modification (N6-methyladenosine) on RNA molecules is involved in the regulation of the life cycle of these RNA molecules. It was found that the degradation of RNA encoding for cytokine tumor necrosis factor (TNF) was mediated through N6-methyladenosine and its “reader” protein YTHDF2 in activated T helper cells. As TNF promotes inflammation, reduction of TNF production through this mechanism dampens the immune response and therefore prevents chronic inflammation.

Published
2024
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4. m6A Reader YTHDC1 Impairs Respiratory Syncytial Virus Infection by Downregulating Membrane CX3CR1 Expression

Author

CTI, Immuno/reuma onderzoek 3 (Loosdregt), Infection & Immunity, CTI Lab support, Arts-assistenten Kinderen, MMB Research line 2, CTI Van der Vlist, MMB Research line 3a, CTI Van Loosdregt, Immuno/reuma onderzoek 1 (Vastert), Immunologie/Reumatologie, Child Health, CTI Research, Picavet, Lucas W., van Vroonhoven, Ellen C.N., Scholman, Rianne C., Smits, Yesper T.H., Banerjee, Rupa, Besteman, Sjanna B., Viveen, Mattheus C., van der Vlist, Michiel M., Tanenbaum, Marvin E., Lebbink, Robert J., Vastert, Sebastiaan J., van Loosdregt, Jorg, CTI, Immuno/reuma onderzoek 3 (Loosdregt), Infection & Immunity, CTI Lab support, Arts-assistenten Kinderen, MMB Research line 2, CTI Van der Vlist, MMB Research line 3a, CTI Van Loosdregt, Immuno/reuma onderzoek 1 (Vastert), Immunologie/Reumatologie, Child Health, CTI Research, Picavet, Lucas W., van Vroonhoven, Ellen C.N., Scholman, Rianne C., Smits, Yesper T.H., Banerjee, Rupa, Besteman, Sjanna B., Viveen, Mattheus C., van der Vlist, Michiel M., Tanenbaum, Marvin E., Lebbink, Robert J., Vastert, Sebastiaan J., and van Loosdregt, Jorg

Published
2024

5. CBP/P300 Inhibition Impairs CD4+ T Cell Activation: Implications for Autoimmune Disorders

Author

Immuno/reuma onderzoek 3 (Loosdregt), Infection & Immunity, CTI Van Loosdregt, Immuno/reuma onderzoek 1 (Vastert), CTI Lab support, CDL Onderzoek Pasterkamp, Experimentele Afd. Cardiologie 1, Child Health, Circulatory Health, Immunologie/Reumatologie, CTI Research, Picavet, Lucas Wilhelmus, Samat, Anoushka A K, Calis, Jorg, Nijhuis, Lotte, Scholman, Rianne, Mokry, Michal, Tough, David F, Prinjha, Rabinder K, Vastert, Sebastiaan J, van Loosdregt, Jorg, Immuno/reuma onderzoek 3 (Loosdregt), Infection & Immunity, CTI Van Loosdregt, Immuno/reuma onderzoek 1 (Vastert), CTI Lab support, CDL Onderzoek Pasterkamp, Experimentele Afd. Cardiologie 1, Child Health, Circulatory Health, Immunologie/Reumatologie, CTI Research, Picavet, Lucas Wilhelmus, Samat, Anoushka A K, Calis, Jorg, Nijhuis, Lotte, Scholman, Rianne, Mokry, Michal, Tough, David F, Prinjha, Rabinder K, Vastert, Sebastiaan J, and van Loosdregt, Jorg

Published
2024

6. Recombinant Interleukin-1 Receptor antagonist is an effective first-line treatment strategy in new-onset systemic Juvenile Idiopathic Arthritis, irrespective of HLA-DRB1 background and IL1RN variants

Author

Immuno/reuma onderzoek 1 (Vastert), Infection & Immunity, Immuno/reuma onderzoek 5 (Vastert2), Child Health, CTI Vastert, Genetica Sectie Genoomdiagnostiek, Cancer, Genetica Medische Informatica, CTI Van Loosdregt, Immuno/reuma patientenzorg, CTI Research, Immuno/reuma onderzoek 3 (Loosdregt), Immunologie/Reumatologie, Erkens, Remco G A, Calis, Jorg J A, Verwoerd, Anouk, De Roock, Sytze, Ter Haar, Nienke M, Den Engelsman, Gerda, Van der Veken, Lars T, Ernst, Robert F, Van Deutekom, Hanneke W M, Pickering, Alex, Scholman, Rianne C, Jansen, Marc H A, Swart, Joost F, Sinha, Rashmi, Roth, Johannes, Schulert, Grant S, Grom, Alexei A, Van Loosdregt, Jorg, Vastert, Sebastiaan J, Immuno/reuma onderzoek 1 (Vastert), Infection & Immunity, Immuno/reuma onderzoek 5 (Vastert2), Child Health, CTI Vastert, Genetica Sectie Genoomdiagnostiek, Cancer, Genetica Medische Informatica, CTI Van Loosdregt, Immuno/reuma patientenzorg, CTI Research, Immuno/reuma onderzoek 3 (Loosdregt), Immunologie/Reumatologie, Erkens, Remco G A, Calis, Jorg J A, Verwoerd, Anouk, De Roock, Sytze, Ter Haar, Nienke M, Den Engelsman, Gerda, Van der Veken, Lars T, Ernst, Robert F, Van Deutekom, Hanneke W M, Pickering, Alex, Scholman, Rianne C, Jansen, Marc H A, Swart, Joost F, Sinha, Rashmi, Roth, Johannes, Schulert, Grant S, Grom, Alexei A, Van Loosdregt, Jorg, and Vastert, Sebastiaan J

Published
2024

7. CBP/P300 Inhibition Impairs CD4+ T Cell Activation: Implications for Autoimmune Disorders.

Author

Picavet, Lucas Wilhelmus, Samat, Anoushka A. K., Calis, Jorg, Nijhuis, Lotte, Scholman, Rianne, Mokry, Michal, Tough, David F., Prinjha, Rabinder K., Vastert, Sebastiaan J., and van Loosdregt, Jorg

Subjects
T cells, AUTOIMMUNE diseases, JUVENILE idiopathic arthritis, CD4 antigen, CREB protein, LYSINE
Abstract

T cell activation is critical for an effective immune response against pathogens. However, dysregulation contributes to the pathogenesis of autoimmune diseases, including Juvenile Idiopathic Arthritis (JIA). The molecular mechanisms underlying T cell activation are still incompletely understood. T cell activation promotes the acetylation of histone 3 at Lysine 27 (H3K27ac) at enhancer and promoter regions of proinflammatory cytokines, thereby increasing the expression of these genes which is essential for T cell function. Co-activators E1A binding protein P300 (P300) and CREB binding protein (CBP), collectively known as P300/CBP, are essential to facilitate H3K27 acetylation. Presently, the role of P300/CBP in human CD4+ T cells activation remains incompletely understood. To assess the function of P300/CBP in T cell activation and autoimmune disease, we utilized iCBP112, a selective inhibitor of P300/CBP, in T cells obtained from healthy controls and JIA patients. Treatment with iCBP112 suppressed T cell activation and cytokine signaling pathways, leading to reduced expression of many proinflammatory cytokines, including IL-2, IFN-γ, IL-4, and IL-17A. Moreover, P300/CBP inhibition in T cells derived from the inflamed synovium of JIA patients resulted in decreased expression of similar pathways and preferentially suppressed the expression of disease-associated genes. This study underscores the regulatory role of P300/CBP in regulating gene expression during T cell activation while offering potential insights into the pathogenesis of autoimmune diseases. Our findings indicate that P300/CBP inhibition could potentially be leveraged for the treatment of autoimmune diseases such as JIA in the future. [ABSTRACT FROM AUTHOR]

Published
2024
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8. Conserved human effector Treg cell transcriptomic and epigenetic signature in arthritic joint inflammation

Author

Mijnheer, Gerdien, Lutter, Lisanne, Mokry, Michal, van der Wal, Marlot, Scholman, Rianne, Fleskens, Veerle, Pandit, Aridaman, Tao, Weiyang, Wekking, Mark, Vervoort, Stephin, Roberts, Ceri, Petrelli, Alessandra, Peeters, Janneke G. C., Knijff, Marthe, de Roock, Sytze, Vastert, Sebastiaan, Taams, Leonie S., van Loosdregt, Jorg, and van Wijk, Femke

Published
2021
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9. m 6 A Reader YTHDC1 Impairs Respiratory Syncytial Virus Infection by Downregulating Membrane CX3CR1 Expression.

Author

Picavet, Lucas W., van Vroonhoven, Ellen C. N., Scholman, Rianne C., Smits, Yesper T. H., Banerjee, Rupa, Besteman, Sjanna B., Viveen, Mattheus C., van der Vlist, Michiel M., Tanenbaum, Marvin E., Lebbink, Robert J., Vastert, Sebastiaan J., and van Loosdregt, Jorg

Subjects
RESPIRATORY syncytial virus infections, PARAINFLUENZA viruses, CHEMOKINE receptors, RNA methylation, RESPIRATORY infections in children, RESPIRATORY syncytial virus infection vaccines, LIFE cycles (Biology)
Abstract

Respiratory syncytial virus (RSV) is the most prevalent cause of acute lower respiratory infection in young children. Currently, the first RSV vaccines are approved by the FDA. Recently, N6-methyladenosine (m6A) RNA methylation has been implicated in the regulation of the viral life cycle and replication of many viruses, including RSV. m6A methylation of RSV RNA has been demonstrated to promote replication and prevent anti-viral immune responses by the host. Whether m6A is also involved in viral entry and whether m6A can also affect RSV infection via different mechanisms than methylation of viral RNA is poorly understood. Here, we identify m6A reader YTH domain-containing protein 1 (YTHDC1) as a novel negative regulator of RSV infection. We demonstrate that YTHDC1 abrogates RSV infection by reducing the expression of RSV entry receptor CX3C motif chemokine receptor 1 (CX3CR1) on the cell surface of lung epithelial cells. Altogether, these data reveal a novel role for m6A methylation and YTHDC1 in the viral entry of RSV. These findings may contribute to the development of novel treatment options to control RSV infection. [ABSTRACT FROM AUTHOR]

Published
2024
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10. Recombinant Interleukin‐1 Receptor antagonist is an effective first‐line treatment strategy in new‐onset systemic Juvenile Idiopathic Arthritis, irrespective of HLA‐DRB1 background and IL1RN variants

Author

Erkens, Remco G. A., primary, Calis, Jorg J. A., additional, Verwoerd, Anouk, additional, De Roock, Sytze, additional, Ter Haar, Nienke M., additional, Den Engelsman, Gerda, additional, Van der Veken, Lars T., additional, Ernst, Robert F., additional, Van Deutekom, Hanneke W. M., additional, Pickering, Alex, additional, Scholman, Rianne C., additional, Jansen, Marc H. A., additional, Swart, Joost F., additional, Sinha, Rashmi, additional, Roth, Johannes, additional, Schulert, Grant S., additional, Grom, Alexei A., additional, Van Loosdregt, Jorg, additional, and Vastert, Sebastiaan J., additional

Published
2023
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11. N6-Methyladenosine Directly Regulates CD40L Expression in CD4+ T Lymphocytes

Author

van Vroonhoven, Ellen C. N., primary, Picavet, Lucas W., additional, Scholman, Rianne C., additional, van den Dungen, Noortje A. M., additional, Mokry, Michal, additional, Evers, Anouk, additional, Lebbink, Robert J., additional, Calis, Jorg J. A., additional, Vastert, Sebastiaan J., additional, and van Loosdregt, Jorg, additional

Published
2023
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12. Recombinant Interleukin‐1 Receptor Antagonist Is an Effective First‐Line Treatment Strategy in New‐Onset Systemic Juvenile Idiopathic Arthritis, Irrespective of HLA‐DRB1 Background and IL1RN Variants.

Author

Erkens, Remco G. A., Calis, Jorg J. A., Verwoerd, Anouk, De Roock, Sytze, Ter Haar, Nienke M., Den Engelsman, Gerda, Van der Veken, Lars T., Ernst, Robert F., Van Deutekom, Hanneke W. M., Pickering, Alex, Scholman, Rianne C., Jansen, Marc H. A., Swart, Joost F., Sinha, Rashmi, Roth, Johannes, Schulert, Grant S., Grom, Alexei A., Van Loosdregt, Jorg, and Vastert, Sebastiaan J.

Subjects
THERAPEUTIC use of cytokines, HLA-B27 antigen, SEQUENCE analysis, BIOLOGICAL products, INTERLEUKIN-1, CELL receptors, JUVENILE idiopathic arthritis, INTERSTITIAL lung diseases, ALLELES, EOSINOPHILIA, DESCRIPTIVE statistics, RECOMBINANT proteins, LONGITUDINAL method, DISEASE remission
Abstract

Objective: Human leukocyte antigen (HLA)‐DRB1*15:01 has been recently associated with interstitial lung disease (LD), eosinophilia, and drug reactions in systemic juvenile idiopathic arthritis (sJIA). Additionally, genetic variants in IL1RN have been linked to poor response to anakinra. We sought to reproduce these findings in a prospective cohort study of patients with new‐onset sJIA treated with anakinra as first‐line therapy. Methods: HLA and IL1RN risk alleles were identified via whole‐genome sequencing. Treatment responses and complications were compared between carriers versus noncarriers. Results: Seventeen of 65 patients (26%) carried HLA‐DRB1*15:01, comparable with the general population, and there was enrichment for HLA‐DRB1*11:01, a known risk locus for sJIA. The rates of clinical inactive disease (CID) at 6 months, 1 year, and 2 years were generally high, irrespective of HLA‐DRB1 or IL1RN variants, but significantly lower in carriers of an HLA‐DRB1*11:01 allele. One patient, an HLA‐DRB1*15:01 carrier, developed sJIA‐LD. Of the three patients with severe drug reactions to biologics, one carried HLA‐DRB1*15:01. The prevalence of eosinophilia did not significantly differ between HLA‐DRB1*15:01 carriers and noncarriers at disease onset (6.2% vs 14.9%, P = 0.67) nor after the start of anakinra (35.3% vs 37.5% in the first 2 years of disease). Conclusion: We observed high rates of CID using anakinra as first‐line treatment irrespective of HLA‐DRB1 or IL1RN variants. Only one of the 17 HLA‐DRB1*15:01 carriers developed sJIA‐LD, and of the three patients with drug reactions to biologics, only one carried HLA‐DRB1*15:01. Although thorough monitoring for the development of drug hypersensitivity and refractory disease courses in sJIA, including sJIA‐LD, remains important, our data support the early start of biologic therapy in patients with new‐onset sJIA irrespective of HLA‐DRB1 background or IL1RN variants. [ABSTRACT FROM AUTHOR]

Published
2024
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13. N6-Methyladenosine Directly Regulates CD40L Expression in CD4+ T Lymphocytes

Author

CTI Eijkelkamp, CTI Van Loosdregt, Infection & Immunity, Experimentele Afdeling Longziekten 2, CDL Research analisten, Cancer, CDL Onderzoek Pasterkamp, Experimentele Afd. Cardiologie 1, Child Health, Circulatory Health, MMB Research line 3a, Immuno/reuma onderzoek 1 (Vastert), Immunologie/Reumatologie, CTI Research, Immuno/reuma onderzoek 3 (Loosdregt), van Vroonhoven, Ellen C.N., Picavet, Lucas W., Scholman, Rianne C., van den Dungen, Noortje A.M., Mokry, Michal, Evers, Anouk, Lebbink, Robert J., Calis, Jorg J.A., Vastert, Sebastiaan J., van Loosdregt, Jorg, CTI Eijkelkamp, CTI Van Loosdregt, Infection & Immunity, Experimentele Afdeling Longziekten 2, CDL Research analisten, Cancer, CDL Onderzoek Pasterkamp, Experimentele Afd. Cardiologie 1, Child Health, Circulatory Health, MMB Research line 3a, Immuno/reuma onderzoek 1 (Vastert), Immunologie/Reumatologie, CTI Research, Immuno/reuma onderzoek 3 (Loosdregt), van Vroonhoven, Ellen C.N., Picavet, Lucas W., Scholman, Rianne C., van den Dungen, Noortje A.M., Mokry, Michal, Evers, Anouk, Lebbink, Robert J., Calis, Jorg J.A., Vastert, Sebastiaan J., and van Loosdregt, Jorg

Published
2023

14. Epigenetic changes in inflammatory arthritis monocytes contribute to disease and can be targeted by JAK inhibition

Author

CMM Groep Coffer, CDL Cluster Onderzoek en Onderwijs, CTI Van Loosdregt, CMM Sectie Stem Cells, Onderzoek, Cancer, Infection & Immunity, Regenerative Medicine and Stem Cells, CDL Onderzoek Pasterkamp, Experimentele Afd. Cardiologie 1, Child Health, Circulatory Health, Immuno/reuma onderzoek 1 (Vastert), Immunologie/Reumatologie, CTI Van Wijk, CTI Research, Immuno/reuma onderzoek 3 (Loosdregt), Peeters, Janneke G C, Boltjes, Arjan, Scholman, Rianne C, Vervoort, Stephin J, Coffer, Paul J, Mokry, Michal, Vastert, Sebastiaan J, van Wijk, Femke, van Loosdregt, Jorg, CMM Groep Coffer, CDL Cluster Onderzoek en Onderwijs, CTI Van Loosdregt, CMM Sectie Stem Cells, Onderzoek, Cancer, Infection & Immunity, Regenerative Medicine and Stem Cells, CDL Onderzoek Pasterkamp, Experimentele Afd. Cardiologie 1, Child Health, Circulatory Health, Immuno/reuma onderzoek 1 (Vastert), Immunologie/Reumatologie, CTI Van Wijk, CTI Research, Immuno/reuma onderzoek 3 (Loosdregt), Peeters, Janneke G C, Boltjes, Arjan, Scholman, Rianne C, Vervoort, Stephin J, Coffer, Paul J, Mokry, Michal, Vastert, Sebastiaan J, van Wijk, Femke, and van Loosdregt, Jorg

Published
2023

18. N 6 -Methyladenosine Directly Regulates CD40L Expression in CD4 + T Lymphocytes.

Author

van Vroonhoven, Ellen C. N., Picavet, Lucas W., Scholman, Rianne C., van den Dungen, Noortje A. M., Mokry, Michal, Evers, Anouk, Lebbink, Robert J., Calis, Jorg J. A., Vastert, Sebastiaan J., and van Loosdregt, Jorg

Subjects
GENE expression, T cells, RNA-binding proteins, GENETIC regulation, T cell differentiation, CYTOKINE receptors, T cell receptors
Abstract

Simple Summary: The tight regulation of the expression of cytokines, surface receptors and co-stimulatory and co-inhibitory molecules is necessary for a well-functioning immune system. There are various cellular processes that regulate the expression of these immune regulatory proteins, for instance at the RNA transcript level. Epitranscriptomic regulation, involving RNA binding proteins and modifications, can determine the turnover and translation of mRNA transcripts. N6-methyladenosine (m6A) is the most abundant RNA modification in eukaryotic cells and it was demonstrated that m6A is involved in the early differentiation of CD4+ T lymphocytes. However, the function of m6A in CD4+ T cell activation and function is still incompletely understood. Here, we demonstrate that m6A regulates the activation of CD4+ T lymphocytes via the regulation of CD40 ligand expression, a key co-stimulatory molecule expressed on the cell surface of CD4+ T cells. The discovery of this novel function of m6A and its regulatory proteins contributes to our general understanding of CD4+ T cell activation, gene expression regulation and autoimmune disease pathogenesis. T cell activation is a highly regulated process, modulated via the expression of various immune regulatory proteins including cytokines, surface receptors and co-stimulatory proteins. N6-methyladenosine (m6A) is an RNA modification that can directly regulate RNA expression levels and it is associated with various biological processes. However, the function of m6A in T cell activation remains incompletely understood. We identify m6A as a novel regulator of the expression of the CD40 ligand (CD40L) in human CD4+ lymphocytes. Manipulation of the m6A 'eraser' fat mass and obesity-associated protein (FTO) and m6A 'writer' protein methyltransferase-like 3 (METTL3) directly affects the expression of CD40L. The m6A 'reader' protein YT521-B homology domain family-2 (YTHDF2) is hypothesized to be able to recognize and bind m6A specific sequences on the CD40L mRNA and promotes its degradation. This study demonstrates that CD40L expression in human primary CD4+ T lymphocytes is regulated via m6A modifications, elucidating a new regulatory mechanism in CD4+ T cell activation that could possibly be leveraged in the future to modulate T cell responses in patients with immune-related diseases. [ABSTRACT FROM AUTHOR]

Published
2023
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24. Conserved human effector Treg cell transcriptomic and epigenetic signature in arthritic joint inflammation

Author

Infection & Immunity, MMB Research line 1, CTI Van Wijk, Onderzoek Precision medicine, Child Health, Circulatory Health, CTI Van Loosdregt, CTI Pandit, Lab Reumatologie/Klinische Immunologie, CTI Research, CMM Groep Coffer, Immuno/reuma onderzoek 1 (Vastert), Immuno/reuma onderzoek 5 (Vastert2), Immuno/reuma onderzoek 3 (Loosdregt), Mijnheer, Gerdien, Lutter, Lisanne, Mokry, Michal, van der Wal, Marlot, Scholman, Rianne, Fleskens, Veerle, Pandit, Aridaman, Tao, Weiyang, Wekking, Mark, Vervoort, Stephin, Roberts, Ceri, Petrelli, Alessandra, Peeters, Janneke G C, Knijff, Marthe, de Roock, Sytze, Vastert, Sebastiaan, Taams, Leonie S, van Loosdregt, Jorg, van Wijk, Femke, Infection & Immunity, MMB Research line 1, CTI Van Wijk, Onderzoek Precision medicine, Child Health, Circulatory Health, CTI Van Loosdregt, CTI Pandit, Lab Reumatologie/Klinische Immunologie, CTI Research, CMM Groep Coffer, Immuno/reuma onderzoek 1 (Vastert), Immuno/reuma onderzoek 5 (Vastert2), Immuno/reuma onderzoek 3 (Loosdregt), Mijnheer, Gerdien, Lutter, Lisanne, Mokry, Michal, van der Wal, Marlot, Scholman, Rianne, Fleskens, Veerle, Pandit, Aridaman, Tao, Weiyang, Wekking, Mark, Vervoort, Stephin, Roberts, Ceri, Petrelli, Alessandra, Peeters, Janneke G C, Knijff, Marthe, de Roock, Sytze, Vastert, Sebastiaan, Taams, Leonie S, van Loosdregt, Jorg, and van Wijk, Femke

Published
2021

25. Human Tregs at the materno-fetal interface show site-specific adaptation reminiscent of tumor Tregs

Author

CTI Van Wijk, Arts-assistenten DV&B, Onderzoek Precision medicine, Child Health, Circulatory Health, CTI Van Loosdregt, Pathologie Pathologen staf, Cancer, MS Verloskunde, Infection & Immunity, Wienke, Judith, Brouwers, Laura, van der Burg, Leone M, Mokry, Michal, Scholman, Rianne C, Nikkels, Peter G J, van Rijn, Bas B, van Wijk, Femke, CTI Van Wijk, Arts-assistenten DV&B, Onderzoek Precision medicine, Child Health, Circulatory Health, CTI Van Loosdregt, Pathologie Pathologen staf, Cancer, MS Verloskunde, Infection & Immunity, Wienke, Judith, Brouwers, Laura, van der Burg, Leone M, Mokry, Michal, Scholman, Rianne C, Nikkels, Peter G J, van Rijn, Bas B, and van Wijk, Femke

Published
2020

26. Conserved human effector Treg signature is reflected in transcriptomic and epigenetic landscape

Author

Mijnheer, Gerdien, primary, Lutter, Lisanne, additional, Mokry, Michal, additional, van der Wal, Marlot, additional, Fleskens, Veerle, additional, Scholman, Rianne, additional, Pandit, Aridaman, additional, Tao, Weiyang, additional, Wekking, Mark, additional, Vervoort, Stephin, additional, Roberts, Ceri, additional, Petrelli, Alessandra, additional, Peeters, Janneke G.C., additional, Knijff, Marthe, additional, de Roock, Sytze, additional, Vastert, Sebastiaan, additional, Taams, Leonie S., additional, van Loosdregt, Jorg, additional, and van Wijk, Femke, additional

Published
2020
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31. Effect of anticoagulants on 162 circulating immune related proteins in healthy subjects

Author

Lab Dermatologie/Allergologie, Infection & Immunity, Immuno/reuma patientenzorg, Reumatologie onderzoek 2, Child Health, Circulatory Health, CTI, Onderzoek, Scholman, Rianne C, Giovannone, Barbara, Hiddingh, Sanne, Meerding, Jenny M, Malvar Fernandez, Beatriz, van Dijk, Mariska E A, Tempelman, Mariëlle J, Prakken, Berent J, de Jager, Wilco, Lab Dermatologie/Allergologie, Infection & Immunity, Immuno/reuma patientenzorg, Reumatologie onderzoek 2, Child Health, Circulatory Health, CTI, Onderzoek, Scholman, Rianne C, Giovannone, Barbara, Hiddingh, Sanne, Meerding, Jenny M, Malvar Fernandez, Beatriz, van Dijk, Mariska E A, Tempelman, Mariëlle J, Prakken, Berent J, and de Jager, Wilco

Published
2018

33. Reversal of Sepsis-Like Features of Neutrophils by Interleukin-1 Blockade in Patients With Systemic-Onset Juvenile Idiopathic Arthritis

Author

ter Haar, Nienke M., primary, Tak, Tamar, additional, Mokry, Michal, additional, Scholman, Rianne C., additional, Meerding, Jenny M., additional, de Jager, Wilco, additional, Verwoerd, Anouk, additional, Foell, Dirk, additional, Vogl, Thomas, additional, Roth, Johannes, additional, Leliefeld, Pieter H. C., additional, van Loosdregt, Jorg, additional, Koenderman, Leo, additional, Vastert, Sebastiaan J., additional, and de Roock, Sytze, additional

Published
2018
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34. Differential adipokine receptor expression on circulating leukocyte subsets in lean and obese children

Author

Keustermans, Genoveva, Van Der Heijden, Laila B., Boer, Berlinda, Scholman, Rianne, Nuboer, Roos, Pasterkamp, Gerard, Prakken, Berent, De Jager, Wilco, Kalkhoven, Eric, Janse, Arieke J, Schipper, Henk S., Keustermans, Genoveva, Van Der Heijden, Laila B., Boer, Berlinda, Scholman, Rianne, Nuboer, Roos, Pasterkamp, Gerard, Prakken, Berent, De Jager, Wilco, Kalkhoven, Eric, Janse, Arieke J, and Schipper, Henk S.

Published
2017

35. Differential adipokine receptor expression on circulating leukocyte subsets in lean and obese children

Author

CDL unit HLA, Infection & Immunity, Child Health, MS Algemene Pediatrie Onderzoek 2, Arts-assistenten Kinderen, CDL Cluster Onderzoek en Onderwijs, Immuno/reuma patientenzorg, Circulatory Health, Reumatologie onderzoek 2, CTI, CTI Boes, Keustermans, Genoveva, Van Der Heijden, Laila B., Boer, Berlinda, Scholman, Rianne, Nuboer, Roos, Pasterkamp, Gerard, Prakken, Berent, De Jager, Wilco, Kalkhoven, Eric, Janse, Arieke J, Schipper, Henk S., CDL unit HLA, Infection & Immunity, Child Health, MS Algemene Pediatrie Onderzoek 2, Arts-assistenten Kinderen, CDL Cluster Onderzoek en Onderwijs, Immuno/reuma patientenzorg, Circulatory Health, Reumatologie onderzoek 2, CTI, CTI Boes, Keustermans, Genoveva, Van Der Heijden, Laila B., Boer, Berlinda, Scholman, Rianne, Nuboer, Roos, Pasterkamp, Gerard, Prakken, Berent, De Jager, Wilco, Kalkhoven, Eric, Janse, Arieke J, and Schipper, Henk S.

Published
2017

38. A novel human STAT3 mutation presents with autoimmunity involving Th17 hyperactivation

Author

Wienke, Judith, Janssen, Willemijn, Scholman, Rianne, Spits, Hilde, Gijn, Marielle van, Boes, Marianne, van Montfrans, Joris, Moes, Nicolette, de Roock, Sytze, Wienke, Judith, Janssen, Willemijn, Scholman, Rianne, Spits, Hilde, Gijn, Marielle van, Boes, Marianne, van Montfrans, Joris, Moes, Nicolette, and de Roock, Sytze

Published
2015

39. Methotrexate treatment affects effector but not regulatory T cells in juvenile idiopathic arthritis

Author

Immuno/reuma onderzoek 1 (Vastert), Unit Opleiding Aios, Reumatologie patientenzorg, Infection & Immunity, Child Health, Reumatologie, Cluster B, Immuno/reuma patientenzorg, Circulatory Health, CTI Vastert, Bulatovic-Calasan, Maja, Vastert, Sebastiaan J., Scholman, Rianne C., Verweij, Frederik, Klein, Mark, Wulffraat, Nico W., Prakken, Berent J., van Wijk, Femke, Immuno/reuma onderzoek 1 (Vastert), Unit Opleiding Aios, Reumatologie patientenzorg, Infection & Immunity, Child Health, Reumatologie, Cluster B, Immuno/reuma patientenzorg, Circulatory Health, CTI Vastert, Bulatovic-Calasan, Maja, Vastert, Sebastiaan J., Scholman, Rianne C., Verweij, Frederik, Klein, Mark, Wulffraat, Nico W., Prakken, Berent J., and van Wijk, Femke

Published
2015

40. Cytokine profiling at disease onset: support for classification of young antinuclear antibody-positive patients as a separate category of juvenile idiopathic arthritis

Author

Child Health, MMB opleiding Arts microbioloog, Infection & Immunity, CDL Celdiagnostiek, Reumatologie patientenzorg, Circulatory Health, CTI Vastert, van den Broek, Theo, Hoppenreijs, Esther, Meerding, Jenny, Scholman, Rianne, Otten, Henny G, Swart, Joost F, Martini, Alberto, Prakken, Berent, de Jager, Wilco, Child Health, MMB opleiding Arts microbioloog, Infection & Immunity, CDL Celdiagnostiek, Reumatologie patientenzorg, Circulatory Health, CTI Vastert, van den Broek, Theo, Hoppenreijs, Esther, Meerding, Jenny, Scholman, Rianne, Otten, Henny G, Swart, Joost F, Martini, Alberto, Prakken, Berent, and de Jager, Wilco

Published
2015

41. A novel human STAT3 mutation presents with autoimmunity involving Th17 hyperactivation

Author

CTI Van Loosdregt, CTI Boes, Infection & Immunity, Genetica Sectie Genoomdiagnostiek, Immuno/reuma onderzoek 2 (Boes), Child Health, Immuno/reuma patientenzorg, Wienke, Judith, Janssen, Willemijn, Scholman, Rianne, Spits, Hilde, Gijn, Marielle van, Boes, Marianne, van Montfrans, Joris, Moes, Nicolette, de Roock, Sytze, CTI Van Loosdregt, CTI Boes, Infection & Immunity, Genetica Sectie Genoomdiagnostiek, Immuno/reuma onderzoek 2 (Boes), Child Health, Immuno/reuma patientenzorg, Wienke, Judith, Janssen, Willemijn, Scholman, Rianne, Spits, Hilde, Gijn, Marielle van, Boes, Marianne, van Montfrans, Joris, Moes, Nicolette, and de Roock, Sytze

Published
2015

43. T cell recognition of naturally presented epitopes of self-heat shock protein 70

Author

LS Immunologie, I&I RATIA-SIB, Risk Assessment of Toxic and Immunomodulatory Agents, Strategic Infection Biology, De Jong, Huib, Koffeman, Eva C., Meerding, Jennifer M., Scholman, Rianne C., Wieten, Lotte, De Jager, Wilco, Klein, Mark, Otten, Henny, Van Wijk, Femke, Van Der Zee, Ruurd, Bijlsma, Johannes W J, Broere, Femke, Van Eden, Willem, Prakken, Berent J., LS Immunologie, I&I RATIA-SIB, Risk Assessment of Toxic and Immunomodulatory Agents, Strategic Infection Biology, De Jong, Huib, Koffeman, Eva C., Meerding, Jennifer M., Scholman, Rianne C., Wieten, Lotte, De Jager, Wilco, Klein, Mark, Otten, Henny, Van Wijk, Femke, Van Der Zee, Ruurd, Bijlsma, Johannes W J, Broere, Femke, Van Eden, Willem, and Prakken, Berent J.

Published
2014

46. Increased Presence of FOXP3+ Regulatory T Cells in Inflamed Muscle of Patients with Active Juvenile Dermatomyositis Compared to Peripheral Blood

Author

Vercoulen, Yvonne, primary, Bellutti Enders, Felicitas, additional, Meerding, Jenny, additional, Plantinga, Maud, additional, Elst, Elisabeth F., additional, Varsani, Hemlata, additional, van Schieveen, Christa, additional, Bakker, Mette H., additional, Klein, Mark, additional, Scholman, Rianne C., additional, Spliet, Wim, additional, Ricotti, Valeria, additional, Koenen, Hans J. P. M., additional, de Weger, Roel A., additional, Wedderburn, Lucy R., additional, van Royen-Kerkhof, Annet, additional, and Prakken, Berent J., additional

Published
2014
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47. Increased Presence of FOXP3+ Regulatory T Cells in Inflamed Muscle of Patients with Active Juvenile Dermatomyositis Compared to Peripheral Blood.

Author

Vercoulen, Yvonne, Bellutti Enders, Felicitas, Meerding, Jenny, Plantinga, Maud, Elst, Elisabeth F., Varsani, Hemlata, van Schieveen, Christa, Bakker, Mette H., Klein, Mark, Scholman, Rianne C., Spliet, Wim, Ricotti, Valeria, Koenen, Hans J. P. M., de Weger, Roel A., Wedderburn, Lucy R., van Royen-Kerkhof, Annet, and Prakken, Berent J.

Subjects
MYOSITIS, T cells, DERMATOMYOSITIS, BLOOD cells, SKIN physiology, MUSCULAR dystrophy
Abstract

Juvenile dermatomyositis (JDM) is an immune-mediated inflammatory disease affecting the microvasculature of skin and muscle. CD4+CD25+FOXP3+ regulatory T cells (Tregs) are key regulators of immune homeostasis. A role for Tregs in JDM pathogenesis has not yet been established. Here, we explored Treg presence and function in peripheral blood and muscle of JDM patients. We analyzed number, phenotype and function of Tregs in blood from JDM patients by flow cytometry and in vitro suppression assays, in comparison to healthy controls and disease controls (Duchenne’s Muscular Dystrophy). Presence of Tregs in muscle was analyzed by immunohistochemistry. Overall, Treg percentages in peripheral blood of JDM patients were similar compared to both control groups. Muscle biopsies of new onset JDM patients showed increased infiltration of numbers of T cells compared to Duchenne’s muscular dystrophy. Both in JDM and Duchenne’s muscular dystrophy the proportion of FOXP3+ T cells in muscles were increased compared to JDM peripheral blood. Interestingly, JDM is not a self-remitting disease, suggesting that the high proportion of Tregs in inflamed muscle do not suppress inflammation. In line with this, peripheral blood Tregs of active JDM patients were less capable of suppressing effector T cell activation in vitro, compared to Tregs of JDM in clinical remission. These data show a functional impairment of Tregs in a proportion of patients with active disease, and suggest a regulatory role for Tregs in JDM inflammation. [ABSTRACT FROM AUTHOR]

Published
2014
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50. Lymphocyte-Dependent and -Independent Regulation of Cxcl8 Expression in Zebrafish Intestines.

Author

Brugman, Sylvia, Witte, Merlijn, Scholman, Rianne C., Klein, Mark R., Boes, Marianne, and Nieuwenhuis, Edward E. S.

Subjects
*LYMPHOCYTES, *ZEBRA danio, *NEUTROPHIL immunology, *ENTEROCOLITIS, *T cells
Abstract

CXCL8 is a potent neutrophil recruiting chemokine. CXCL8 is produced by several innate immune cells, including neutrophils, macrophages, as well as epithelial cells. Although previously considered only to be produced as a result of TLR signaling in these cells, recent reports show that T cell-derived cytokines also induce CXCL8 in epithelial cells. Likewise, we observed that T cell inhibition diminished intestinal production of functional mouse homologs of CXCL8 in the early phase of enterocolitis. In this study, we specifically investigated whether adaptive cells contribute to innate cxcl8 expression in the intestines. To this end, we used the zebrafish as our model system. Unlike murine models that lack CXCL8, zebrafish have two CXCL8 chemokines that are both elevated after an acute inflammatory stimulus and recruit neutrophils. Furthermore, zebrafish develop innate and adaptive immunity sequentially, enabling analysis of intestinal cxcl8 expression in the absence (<3 wk of age) and presence (>3 wk of age) of adaptive immunity. In this study, we show that intestinal cxcl8-l1 but not cxcl8-l2 expression is regulated by T lymphocytes under homeostatic conditions. In contrast, during intestinal inflammation especially, cxcl8-l1 expression is upregulated independent of T lymphocyte presence. Furthermore, we show that human CXCL8 is able to induce intestinal zebrafish neutrophil recruitment and cxcl8-l1 expression, demonstrating that zebrafish can be used as a model to study CXCL8 function and regulation. In conclusion, these data provide evidence that Cxcl8-l1 and Cxcl8-l2 are differentially regulated via T lymphocyte-dependent and -independent mechanisms during homeostasis and inflammation. [ABSTRACT FROM AUTHOR]

Published
2014
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