9 results on '"Steenwijk EC"'
Search Results
2. BRAF V600E is associated with higher incidence of second cancers in adults with Langerhans cell histiocytosis.
- Author
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Acosta-Medina AA, Kemps PG, Zondag TCE, Abeykoon JP, Forma-Borst J, Steenwijk EC, Feijen EAM, Teepen JC, Bennani NN, Schram SM, Shah MV, Davidge-Pitts C, Koster MJ, Ryu JH, Vassallo R, Tobin WO, Young JR, Dasari S, Rech K, Ravindran A, Cleven AHG, Verdijk RM, van Noesel CJM, Balgobind BV, Bouma GJ, Saeed P, Bramer JAM, de Groen RAL, Vermaat JSP, van de Sande MAJ, Smit EF, Langerak AW, van Wezel T, Tonino SH, van den Bos C, van Laar JAM, Go RS, Goyal G, and van Halteren AGS
- Subjects
- Humans, Adult, Proto-Oncogene Proteins B-raf genetics, Retrospective Studies, Incidence, Mutation, Neoplasms, Second Primary epidemiology, Neoplasms, Second Primary genetics, Histiocytosis, Langerhans-Cell epidemiology, Histiocytosis, Langerhans-Cell genetics, Histiocytosis, Langerhans-Cell pathology
- Abstract
In this retrospective study, BRAF mutation status did not correlate with disease extent or (event-free) survival in 156 adults with Langerhans cell histiocytosis. BRAFV600E was associated with an increased incidence of second malignancies, often comprising hematological cancers, which may be clonally related., (© 2023 by The American Society of Hematology.)
- Published
- 2023
- Full Text
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3. Clinicogenomic associations in childhood Langerhans cell histiocytosis: an international cohort study.
- Author
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Kemps PG, Zondag TCE, Arnardóttir HB, Solleveld-Westerink N, Borst J, Steenwijk EC, van Egmond D, Swennenhuis JF, Stelloo E, Trambusti I, Verdijk RM, van Noesel CJM, Cleven AHG, Scheijde-Vermeulen MA, Koudijs MJ, Krsková L, Hawkins C, Egeler RM, Brok J, von Bahr Greenwood T, Svojgr K, Beishuizen A, van Laar JAM, Pötschger U, Hutter C, Sieni E, Minkov M, Abla O, van Wezel T, van den Bos C, and van Halteren AGS
- Subjects
- Humans, Cohort Studies, Proto-Oncogene Proteins B-raf genetics, Mutation, Histiocytosis, Langerhans-Cell genetics, Neoplasms
- Abstract
Langerhans cell histiocytosis (LCH) is a rare neoplastic disorder caused by somatic genetic alterations in hematopoietic precursor cells differentiating into CD1a+/CD207+ histiocytes. LCH clinical manifestation is highly heterogeneous. BRAF and MAP2K1 mutations account for ∼80% of genetic driver alterations in neoplastic LCH cells. However, their clinical associations remain incompletely understood. Here, we present an international clinicogenomic study of childhood LCH, investigating 377 patients genotyped for at least BRAFV600E. MAPK pathway gene alterations were detected in 300 (79.6%) patients, including 191 (50.7%) with BRAFV600E, 54 with MAP2K1 mutations, 39 with BRAF exon 12 mutations, 13 with rare BRAF alterations, and 3 with ARAF or KRAS mutations. Our results confirm that BRAFV600E associates with lower age at diagnosis and higher prevalence of multisystem LCH, high-risk disease, and skin involvement. Furthermore, BRAFV600E appeared to correlate with a higher prevalence of central nervous system (CNS)-risk bone lesions. In contrast, MAP2K1 mutations associated with a higher prevalence of single-system (SS)-bone LCH, and BRAF exon 12 deletions seemed to correlate with more lung involvement. Although BRAFV600E correlated with reduced event-free survival in the overall cohort, neither BRAF nor MAP2K1 mutations associated with event-free survival when patients were stratified by disease extent. Thus, the correlation of BRAFV600E with inferior clinical outcome is (primarily) driven by its association with disease extents known for high rates of progression or relapse, including multisystem LCH. These findings advance our understanding of factors underlying the remarkable clinical heterogeneity of LCH but also question the independent prognostic value of lesional BRAFV600E status., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2023
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4. Apparent Lack of BRAF V600E Derived HLA Class I Presented Neoantigens Hampers Neoplastic Cell Targeting by CD8 + T Cells in Langerhans Cell Histiocytosis.
- Author
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Kemps PG, Zondag TC, Steenwijk EC, Andriessen Q, Borst J, Vloemans S, Roelen DL, Voortman LM, Verdijk RM, van Noesel CJM, Cleven AHG, Hawkins C, Lang V, de Ru AH, Janssen GMC, Haasnoot GW, Franken KLMC, van Eijk R, Solleveld-Westerink N, van Wezel T, Egeler RM, Beishuizen A, van Laar JAM, Abla O, van den Bos C, van Veelen PA, and van Halteren AGS
- Subjects
- Adult, Cell Line, Tumor, Child, Female, Humans, Male, Mutation immunology, Antigens, Neoplasm immunology, CD8-Positive T-Lymphocytes immunology, HLA-A Antigens immunology, Histiocytosis, Langerhans-Cell immunology, Neoplasms immunology, Proto-Oncogene Proteins B-raf immunology
- Abstract
Langerhans Cell Histiocytosis (LCH) is a neoplastic disorder of hematopoietic origin characterized by inflammatory lesions containing clonal histiocytes (LCH-cells) intermixed with various immune cells, including T cells. In 50-60% of LCH-patients, the somatic BRAF
V600E driver mutation, which is common in many cancers, is detected in these LCH-cells in an otherwise quiet genomic landscape. Non-synonymous mutations like BRAFV600E can be a source of neoantigens capable of eliciting effective antitumor CD8+ T cell responses. This requires neopeptides to be stably presented by Human Leukocyte Antigen (HLA) class I molecules and sufficient numbers of CD8+ T cells at tumor sites. Here, we demonstrate substantial heterogeneity in CD8+ T cell density in n = 101 LCH-lesions, with BRAFV600E mutated lesions displaying significantly lower CD8+ T cell:CD1a+ LCH-cell ratios ( p = 0.01) than BRAF wildtype lesions. Because LCH-lesional CD8+ T cell density had no significant impact on event-free survival, we investigated whether the intracellularly expressed BRAFV600E protein is degraded into neopeptides that are naturally processed and presented by cell surface HLA class I molecules. Epitope prediction tools revealed a single HLA class I binding BRAFV600E derived neopeptide (KIGDFGLAT E K), which indeed displayed strong to intermediate binding capacity to HLA-A* 03:01 and HLA-A* 11:01 in an in vitro peptide-HLA binding assay. Mass spectrometry-based targeted peptidomics was used to investigate the presence of this neopeptide in HLA class I presented peptides isolated from several BRAFV600E expressing cell lines with various HLA genotypes. While the HLA-A* 02:01 binding BRAF wildtype peptide KIGDFGLATV was traced in peptides isolated from all five cell lines expressing this HLA subtype, KIGDFGLAT E K was not detected in the HLA class I peptidomes of two distinct BRAFV600E transduced cell lines with confirmed expression of HLA-A* 03:01 or HLA-A* 11:01. These data indicate that the in silico predicted HLA class I binding and proteasome-generated neopeptides derived from the BRAFV600E protein are not presented by HLA class I molecules. Given that the BRAFV600E mutation is highly prevalent in chemotherapy refractory LCH-patients who may qualify for immunotherapy, this study therefore questions the efficacy of immune checkpoint inhibitor therapy in LCH., (Copyright © 2020 Kemps, Zondag, Steenwijk, Andriessen, Borst, Vloemans, Roelen, Voortman, Verdijk, van Noesel, Cleven, Hawkins, Lang, de Ru, Janssen, Haasnoot, Franken, van Eijk, Solleveld-Westerink, van Wezel, Egeler, Beishuizen, van Laar, Abla, van den Bos, van Veelen and van Halteren.)- Published
- 2020
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5. Systemic interferon type I and type II signatures in primary Sjögren's syndrome reveal differences in biological disease activity.
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Bodewes ILA, Al-Ali S, van Helden-Meeuwsen CG, Maria NI, Tarn J, Lendrem DW, Schreurs MWJ, Steenwijk EC, van Daele PLA, Both T, Bowman SJ, Griffiths B, Ng WF, and Versnel MA
- Subjects
- Adult, Female, Humans, Interferon Type I biosynthesis, Interferon-gamma biosynthesis, Male, Middle Aged, Reverse Transcriptase Polymerase Chain Reaction, Severity of Illness Index, Sjogren's Syndrome diagnosis, Sjogren's Syndrome metabolism, Gene Expression Regulation, Interferon Type I genetics, Interferon-gamma genetics, RNA genetics, Sjogren's Syndrome genetics
- Abstract
Objective: To assess the relationships between systemic IFN type I (IFN-I) and II (IFN-II) activity and disease manifestations in primary SS (pSS)., Methods: RT-PCR of multiple IFN-induced genes followed by principal component analysis of whole blood RNA of 50 pSS patients was used to identify indicator genes of systemic IFN-I and IFN-II activities. Systemic IFN activation levels were analysed in two independent European cohorts (n = 86 and 55, respectively) and their relationships with clinical features were analysed., Results: Three groups could be stratified according to systemic IFN activity: IFN inactive (19-47%), IFN-I (53-81%) and IFN-I + II (35-55%). No patient had isolated IFN-II activation. IgG levels were highest in patients with IFN-I + II, followed by IFN-I and IFN inactive patients. The prevalence of anti-SSA and anti-SSB was higher among those with IFN activation. There was no difference in total-EULAR SS Disease Activity Index (ESSDAI) or ClinESSDAI between the three subject groups. For individual ESSDAI domains, only the biological domain scores differed between the three groups (higher among the IFN active groups). For patient reported outcomes, there were no differences in EULAR Sjögren's syndrome patient reported index (ESSPRI), fatigue or dryness between groups, but pain scores were lower in the IFN active groups. Systemic IFN-I but not IFN-I + II activity appeared to be relatively stable over time., Conclusions: Systemic IFN activation is associated with higher activity only in the ESSDAI biological domain but not in other domains or the total score. Our data raise the possibility that the ESSDAI biological domain score may be a more sensitive endpoint for trials targeting either IFN pathway.
- Published
- 2018
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6. Type I IFN signature in childhood-onset systemic lupus erythematosus: a conspiracy of DNA- and RNA-sensing receptors?
- Author
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Wahadat MJ, Bodewes ILA, Maria NI, van Helden-Meeuwsen CG, van Dijk-Hummelman A, Steenwijk EC, Kamphuis S, and Versnel MA
- Subjects
- Adolescent, Adult, Child, Child, Preschool, DEAD Box Protein 58 genetics, DEAD Box Protein 58 metabolism, DNA genetics, DNA metabolism, Female, Humans, Interferon Type I metabolism, Lupus Erythematosus, Systemic metabolism, Male, RNA genetics, RNA metabolism, Toll-Like Receptor 7 genetics, Toll-Like Receptor 7 metabolism, Young Adult, Gene Expression Profiling, Interferon Type I genetics, Lupus Erythematosus, Systemic genetics, Monocytes metabolism
- Abstract
Background: Childhood-onset systemic lupus erythematosus (cSLE) is an incurable multi-systemic autoimmune disease. Interferon type I (IFN-I) plays a pivotal role in the pathogenesis of SLE. The objective of this study was to assess the prevalence of the IFN-I signature and the contribution of cytosolic nucleic acid receptors to IFN-I activation in a cohort of primarily white cSLE patients., Methods: The IFN-I score (positive or negative), as a measure of IFN-I activation, was assessed using real-time quantitative PCR (RT-PCR) expression values of IFN-I signature genes (IFI44, IFI44L, IFIT1, Ly6e, MxA, IFITM1) in CD14+ monocytes of cSLE patients and healthy controls (HCs). Innate immune receptor expression was determined by RT-PCR and flow cytometry. To clarify the contribution of RNA-binding RIG-like receptors (RLRs) and DNA-binding receptors (DBRs) to IFN-I activation, peripheral blood mononuclear cells (PBMCs) from patients were treated with BX795, a TANK-binding kinase 1 (TBK1) inhibitor blocking RLR and DBR pathways., Results: The IFN-I signature was positive in 57% of cSLE patients and 15% of the HCs. Upregulated gene expression of TLR7, RLRs (IFIH1, DDX58, DDX60, DHX58) and DBRs (ZBP-1, IFI16) was observed in CD14+ monocytes of the IFN-I-positive cSLE patients. Additionally, RIG-I and ZBP-1 protein expression was upregulated in these cells. Spontaneous IFN-I stimulated gene (ISG) expression in PBMCs from cSLE patients was inhibited by a TBK1-blocker., Conclusions: IFN-I activation, assessed as ISG expression, in cSLE is associated with increased expression of TLR7, and RNA and DNA binding receptors, and these receptors contribute to IFN-I activation via TBK1 signaling. TBK1-blockers may therefore be a promising treatment target for SLE.
- Published
- 2018
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7. Contrasting expression pattern of RNA-sensing receptors TLR7, RIG-I and MDA5 in interferon-positive and interferon-negative patients with primary Sjögren's syndrome.
- Author
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Maria NI, Steenwijk EC, IJpma AS, van Helden-Meeuwsen CG, Vogelsang P, Beumer W, Brkic Z, van Daele PL, van Hagen PM, van der Spek PJ, Drexhage HA, and Versnel MA
- Subjects
- Adult, Aged, Cells, Cultured, DEAD Box Protein 58 analysis, DEAD Box Protein 58 genetics, DEAD Box Protein 58 metabolism, Dendritic Cells, Female, Humans, Interferon Regulatory Factor-7 analysis, Interferon Regulatory Factor-7 genetics, Interferon Regulatory Factor-7 metabolism, Interferon-Induced Helicase, IFIH1 analysis, Interferon-Induced Helicase, IFIH1 genetics, Interferon-Induced Helicase, IFIH1 metabolism, Male, Middle Aged, Monocytes metabolism, Myeloid Differentiation Factor 88 genetics, Oligonucleotide Array Sequence Analysis, Oxidoreductases Acting on CH-CH Group Donors, Phosphorylation, Proteins genetics, Receptors, Immunologic, Salivary Glands chemistry, Sjogren's Syndrome metabolism, Toll-Like Receptor 7 analysis, Toll-Like Receptor 7 metabolism, Up-Regulation, Interferon Type I blood, RNA, Messenger analysis, Signal Transduction, Sjogren's Syndrome blood, Sjogren's Syndrome genetics, Toll-Like Receptor 7 genetics
- Abstract
Objective: The interferon (IFN) type I signature is present in over half of patients with primary Sjögren's syndrome (pSS) and associated with higher disease-activity and autoantibody presence. Plasmacytoid dendritic cells (pDCs) are considered as the main source of enhanced IFN type I expression. The objective of this study was to unravel the molecular pathways underlying IFN type I bioactivity in pDCs of patients with pSS., Methods: Blood samples from 42 healthy controls (HC) and 115 patients with pSS were stratified according to their IFN type I signature. CD123
+ BDCA4+ pDCs and CD14+ monocytes were isolated from peripheral blood mononuclear cells (PBMCs). Genome-wide microarray analysis was conducted on sorted pDCs in a small sample set, followed by validation of differentially expressed genes of interest in pDCs and monocytes., Results: We found an upregulation of endosomal toll-like receptor (TLR) 7, but not TLR9, in IFN-positive (IFNpos) pDCs (p<0.05) and monocytes (p=0.024). Additionally, the downstream signalling molecules MyD88, RSAD2 and IRF7 were upregulated, as were the cytoplasmic RNA-sensing receptors DDX58/retinoic acid inducible gene-I (RIG-I) and IFIH1/melanoma differentiation associated gene-5 (MDA5). In vitro triggering of the TLR7-pathway in HC PBMCs induced upregulation of DDX58/RIG-I and IFIH1/MDA5, and downregulated TLR9. The upregulation of TLR7, its downstream signalling pathway, DDX58/RIG-I and IFIH1/MDA5 were confined to patients with IFN-positive pSS. IFN-negative patients had a contrasting expression pattern-TLR7 normal, and decreased TLR9, RIG-I and MDA5., Conclusions: Here we conclude a contrasting expression pattern of the RNA-sensing receptors TLR7, RIG-I and MDA5 in pDCs and monocytes of patients with IFNpos pSS. This profile could explain the pathogenic IFN production and might reveal novel therapeutic targets in these patients., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)- Published
- 2017
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8. Association of Increased Treg Cell Levels With Elevated Indoleamine 2,3-Dioxygenase Activity and an Imbalanced Kynurenine Pathway in Interferon-Positive Primary Sjögren's Syndrome.
- Author
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Maria NI, van Helden-Meeuwsen CG, Brkic Z, Paulissen SM, Steenwijk EC, Dalm VA, van Daele PL, Martin van Hagen P, Kroese FG, van Roon JA, Harkin A, Dik WA, Drexhage HA, Lubberts E, and Versnel MA
- Subjects
- Female, Humans, Male, Middle Aged, Signal Transduction, Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism, Interferons blood, Kynurenine physiology, Sjogren's Syndrome blood, Sjogren's Syndrome immunology, T-Lymphocytes, Regulatory enzymology
- Abstract
Objective: Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme that converts tryptophan to kynurenine, is driven in part by type I and type II interferons (IFNs). Naive T cells are polarized into FoxP3+ Treg cells upon exposure to either IDO+ cells or kynurenine. Recent studies have suggested that the kynurenine pathway reflects a crucial interface between the immune and nervous system. The aims of the present study were to evaluate whether Treg cell levels are elevated, in conjunction with increased IDO activity, in patients with primary Sjögren's syndrome (SS) who are positive for the IFN gene expression signature, and to investigate the downstream kynurenine pathway in these patients., Methods: Serum from 71 healthy controls, 58 IFN-negative patients with primary SS, and 66 IFN-positive patients with primary SS was analyzed using high-performance liquid chromatography to measure the levels of tryptophan and kynurenine. Expression levels of messenger RNA (mRNA) for IDO and downstream enzymes in the kynurenine pathway were assessed in CD14+ monocytes using real-time quantitative polymerase chain reaction. CD4+CD45RO+ T helper memory cell populations were analyzed by flow cytometry., Results: Significantly increased levels of IDO activity (assessed as the kynurenine:tryptophan ratio) (P = 0.0054) and percentages of CD25(high) FoxP3+ Treg cells (P = 0.039) were observed in the serum from IFN-positive patients with primary SS, and these parameters were significantly correlated with one another (r = 0.511, P = 0.002). In circulating monocytes from IFN-positive patients with primary SS, the expression of IDO1 mRNA was up-regulated (P < 0.0001), and this was correlated with the IFN gene expression score (r = 0.816, P < 0.0001). Interestingly, the proapoptotic and neurotoxic downstream enzyme kynurenine 3-monooxygenase was up-regulated (P = 0.0057), whereas kynurenine aminotransferase I (KATI) (P = 0.0003), KATIII (P = 0.016), and KATIV (P = 0.04) were down-regulated in IFN-positive patients with primary SS compared to healthy controls., Conclusion: These findings demonstrate enhanced IDO activity in conjunction with increased percentages of CD25(high) FoxP3+ Treg cells in primary SS patients who carry the IFN signature. In addition, IFN-positive patients with primary SS exhibit an imbalanced kynurenine pathway, with evidence of a shift toward potentially more proapoptotic and neurotoxic metabolites. Intervening in these IFN- and IDO-induced immune system imbalances may offer a new array of possibilities for therapeutic interventions in patients with primary SS., (© 2016, American College of Rheumatology.)
- Published
- 2016
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9. Tertiary lymphoid structures are confined to patients presenting with unifocal Langerhans Cell Histiocytosis.
- Author
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Quispel WT, Steenwijk EC, van Unen V, Santos SJ, Koens L, Mebius R, Egeler RM, and van Halteren AG
- Abstract
Langerhans cell histiocytosis (LCH) is a neoplastic myeloid disorder with a thus far poorly understood immune component. Tertiary lymphoid structures (TLS) are lymph node-like entities which create an immune-promoting microenvironment at tumor sites. We analyzed the presence and clinical relevance of TLS in n = 104 H&E-stained, therapy-naive LCH lesions of non-lymphoid origin and applied immunohistochemistry to a smaller series. Lymphoid-follicular aggregates were detected in 34/104 (33%) lesions. In line with the lymphocyte recruitment capacity of MECA-79(+) high endothelial venules (HEVs), MECA-79(+)-expressing-LCH lesions (37/77, 48%) contained the most CD3(+) T-lymphocytes (p = 0.003). TLS were identified in 8/15 lesions and contained T-and B-lymphocytes, Follicular Dendritic Cells (FDC), HEVs and the chemokines CXCL13 and CCL21 representing key cellular components and TLS-inducing factors in conventional lymph nodes (LN). Lymphoid-follicular aggregates were most frequently detected in patients presenting with unifocal LCH (24/70, 34%) as compared to patients with poly-ostotic or multi-system LCH (7/30, 23%, p = 0.03). In addition, patients with lymphoid-follicular aggregates-containing lesions had the lowest risk to develop new LCH lesions (p = 0.04). The identification of various stages of TLS formation within LCH lesions may indicate a key role for the immune system in controlling aberrant histiocytes which arise in peripheral tissues.
- Published
- 2016
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