291 results on '"Hendriks RW"'
Search Results
2. Modified Vaccinia Virus Ankara Preferentially Targets Antigen Presenting Cells In Vitro, Ex Vivo and In Vivo
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Altenburg, AF, van de Sandt, CE, Li, BWS, MacLoughlin, RJ, Fouchier, RAM, van Amerongen, G, Volz, A, Hendriks, RW, de Swart, RL, Sutter, G, Rimmelzwaan, GF, de Vries, RD, Altenburg, AF, van de Sandt, CE, Li, BWS, MacLoughlin, RJ, Fouchier, RAM, van Amerongen, G, Volz, A, Hendriks, RW, de Swart, RL, Sutter, G, Rimmelzwaan, GF, and de Vries, RD
- Abstract
Modified Vaccinia virus Ankara (MVA) is a promising vaccine vector with an excellent safety profile. However, despite extensive pre-clinical and clinical testing, surprisingly little is known about the cellular tropism of MVA, especially in relevant animal species. Here, we performed in vitro, ex vivo and in vivo experiments with recombinant MVA expressing green fluorescent protein (rMVA-GFP). In both human peripheral blood mononuclear cells and mouse lung explants, rMVA-GFP predominantly infected antigen presenting cells. Subsequent in vivo experiments performed in mice, ferrets and non-human primates indicated that preferential targeting of dendritic cells and alveolar macrophages was observed after respiratory administration, although subtle differences were observed between the respective animal species. Following intramuscular injection, rMVA-GFP was detected in interdigitating cells between myocytes, but also in myocytes themselves. These data are important in advancing our understanding of the basis for the immunogenicity of MVA-based vaccines and aid rational vaccine design and delivery strategies.
- Published
- 2017
3. Essential, dose-dependent role for the transcription factor Gata3 in the development of IL-5+ and IL
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Klein Wolterink RG, Serafini N, van Nimwegen M, Vosshenrich CA, de Bruijn MJ, Fonseca Pereira D, Veiga Fernandes H, Hendriks RW, and Di Santo JP (2013)
- Published
- 2013
4. A3.1 1.25(OH)2D3Inhibits Th17 Polarisation and RORγt Expression through GATA3-Dependent and -Independent Mechanisms
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Dankers, W, primary, Hamburg, JP van, additional, Mus, AMC, additional, Asmawidjaja, PS, additional, Corneth, OBJ, additional, Luk, F, additional, Leeuwen, JPTM van, additional, Hendriks, RW, additional, Boon, L, additional, Colin, EM, additional, and Lubberts, E, additional
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- 2013
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5. BLNK (B-cell linker)
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Yuvaraj, S, primary and Hendriks, RW, additional
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- 2013
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6. Impaired survival of regulatory T cells in pulmonary sarcoidosis patients
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Broos, CE, primary, Van Nimwegen, M, additional, KleinJan, A, additional, Ten Berge, B, additional, Muskens, F, additional, In 't Veen, JCCM, additional, Hoogsteden, HC, additional, Hendriks, RW, additional, Lambrecht, BN, additional, Kool, M, additional, and van den Blink, B, additional
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- 2012
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7. BTK (Bruton agammaglobulinemia tyrosine kinase)
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Hendriks, RW, primary and van, Loo PF, additional
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- 2011
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8. SLE-Like Syndrome with Pulmonary Involvement in Mice Overexpressing Bruton's Tyrosine Kinase in Mature B Lymphocytes.
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Hendriks, RW, primary, Kil, LP, additional, Dingjan, GM, additional, De Bruijn, M, additional, and Van Loo, PF, additional
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- 2009
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9. GATA-3 protects against severe joint inflammation and bone erosion and reduces differentiation of Th17 cells during experimental arthritis.
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van Hamburg JP, Mus AM, de Bruijn MJ, de Vogel L, Boon L, Cornelissen F, Asmawidjaja P, Hendriks RW, and Lubberts E
- Abstract
OBJECTIVE: Rheumatoid arthritis is associated with the infiltration of T helper cells into the joints. It is unclear whether interferon-gamma (IFNgamma)-producing Th1 cells or the novel T helper subset, interleukin-17 (IL-17)-producing Th17 cells, are the pathogenic mediators of joint inflammation in chronic nonautoimmune arthritis. Therefore, this study was aimed at examining whether the Th2-specific transcription factor GATA-3 can regulate arthritis, in an experimental murine model, by modulating Th1 and/or Th17 cell polarization. METHODS: Arthritis was induced with methylated bovine serum albumin (mBSA) in both wild-type and CD2 T cell-specific GATA-3 (CD2-GATA-3)-transgenic mice. At days 1 and 7 after the induction of arthritis, knee joints were scored macroscopically for arthritis severity and for histologic changes. Single-cell suspensions were generated from the spleens, lymph nodes, and inflamed knee joints. Cytokine expression by CD4+ T cells was determined using flow cytometry, and IL-17 expression in the inflamed knee joints was determined by enzyme-linked immunosorbent assay. Analyses of gene expression were performed for Th17-associated factors. RESULTS: Wild-type mice developed severe joint inflammation, including massive inflammatory cell infiltration and bone erosion that increased significantly over time, reaching maximal arthritis scores at day 7. In contrast, only mild joint inflammation was observed in CD2-GATA-3-transgenic mice. This mild effect was further accompanied by systemic and local reductions in the numbers of IL-17+IFNgamma- and IL-17+IFNgamma+, but not IL-17-IFNgamma+, CD4+ T cells, and by induction of Th2 cytokine expression. Moreover, GATA-3 overexpression resulted in reduced gene expression of the Th17-associated transcription factor retinoic acid-related orphan receptor gammat. CONCLUSION: These results indicate that enforced GATA-3 expression protects against severe joint inflammation and bone erosion in mice, accompanied by reduced differentiation of Th17 cells, but not Th1 cells, during mBSA-induced arthritis. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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10. Epigenomic partitioning of a polygenic risk score for asthma reveals distinct genetically driven disease pathways.
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Stikker B, Trap L, Sedaghati-Khayat B, de Bruijn MJW, van Ijcken WFJ, de Roos E, Ikram A, Hendriks RW, Brusselle G, van Rooij J, and Stadhouders R
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- Humans, Female, Male, Netherlands, Middle Aged, Prospective Studies, Aged, Adult, Risk Factors, Child, Age of Onset, Risk Assessment, Genetic Risk Score, Asthma genetics, Genome-Wide Association Study, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Multifactorial Inheritance, Epigenomics
- Abstract
Background: Individual differences in susceptibility to developing asthma, a heterogeneous chronic inflammatory lung disease, are poorly understood. Whether genetics can predict asthma risk and how genetic variants modulate the complex pathophysiology of asthma are still debated., Aim: To build polygenic risk scores for asthma risk prediction and epigenomically link predictive genetic variants to pathophysiological mechanisms., Methods: Restricted polygenic risk scores were constructed using single nucleotide variants derived from genome-wide association studies and validated using data generated in the Rotterdam Study, a Dutch prospective cohort of 14 926 individuals. Outcomes used were asthma, childhood-onset asthma, adulthood-onset asthma, eosinophilic asthma and asthma exacerbations. Genome-wide chromatin analysis data from 19 disease-relevant cell types were used for epigenomic polygenic risk score partitioning., Results: The polygenic risk scores obtained predicted asthma and related outcomes, with the strongest associations observed for childhood-onset asthma (2.55 odds ratios per polygenic risk score standard deviation, area under the curve of 0.760). Polygenic risk scores allowed for the classification of individuals into high-risk and low-risk groups. Polygenic risk score partitioning using epigenomic profiles identified five clusters of variants within putative gene regulatory regions linked to specific asthma-relevant cells, genes and biological pathways., Conclusions: Polygenic risk scores were associated with asthma(-related traits) in a Dutch prospective cohort, with substantially higher predictive power observed for childhood-onset than adult-onset asthma. Importantly, polygenic risk score variants could be epigenomically partitioned into clusters of regulatory variants with different pathophysiological association patterns and effect estimates, which likely represent distinct genetically driven disease pathways. Our findings have potential implications for personalised risk mitigation and treatment strategies., Competing Interests: Conflict of interest: G. Brusselle has received fees for lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis and Sanofi Regeneron; and honoraria for participating on advisory boards from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merck Sharp & Dohme, Novartis and Sanofi Regeneron. The remaining authors declare no conflicts of interest., (Copyright ©The authors 2024.)
- Published
- 2024
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11. Airway epithelial cell response to RSV is mostly impaired in goblet and multiciliated cells in asthma.
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Gay ACA, Banchero M, Carpaij O, Kole TM, Apperloo L, van Gosliga D, Fajar PA, Koppelman GH, Bont L, Hendriks RW, van den Berge M, and Nawijn MC
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- Humans, Male, Female, Respiratory Mucosa virology, Respiratory Mucosa metabolism, Adult, Bronchi, Middle Aged, Cells, Cultured, Respiratory Syncytial Viruses, Cilia pathology, Case-Control Studies, Intercellular Adhesion Molecule-1, Asthma immunology, Respiratory Syncytial Virus Infections immunology, Goblet Cells pathology, Epithelial Cells virology, Epithelial Cells metabolism
- Abstract
Background: In patients with asthma, respiratory syncytial virus (RSV) infections can cause disease exacerbation by infecting the epithelial layer of the airways, inducing subsequent immune response. The type I interferon antiviral response of epithelial cells upon RSV infection is found to be reduced in asthma in most-but not all-studies. Moreover, the molecular mechanisms causing the differences in the asthmatic bronchial epithelium in response to viral infection are poorly understood., Methods: Here, we investigated the transcriptional response to RSV infection of primary bronchial epithelial cells (pBECs) from patients with asthma (n=8) and healthy donors (n=8). The pBECs obtained from bronchial brushes were differentiated in air-liquid interface conditions and infected with RSV. After 3 days, cells were processed for single-cell RNA sequencing., Results: A strong antiviral response to RSV was observed for all cell types, for all samples (p<1e-48). Most (1045) differentially regulated genes following RSV infection were found in cells transitioning to secretory cells. Goblet cells from patients with asthma showed lower expression of genes involved in the interferon response (false discovery rate <0.05), including OASL , ICAM1 and TNFAIP3 . In multiciliated cells, an impairment of the signalling pathways involved in the response to RSV in asthma was observed., Conclusion: Our results highlight that the response to RSV infection of the bronchial epithelium in asthma and healthy airways was largely similar. However, in asthma, the response of goblet and multiciliated cells is impaired, highlighting the need for studying airway epithelial cells at high resolution in the context of asthma exacerbation., Competing Interests: Competing interests: GHK, MCN and MvdB received project funding from GlaxoSmithKline. GHK and MvdB received funding from AstraZeneca. MvdB received funding from Novartis, Genentech and Roche., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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12. Increased proportions of circulating PD-1 + CD4 + memory T cells and PD-1 + regulatory T cells associate with good response to prednisone in pulmonary sarcoidosis.
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Miedema JR, de Jong LJ, Kahlmann V, Bergen IM, Broos CE, Wijsenbeek MS, Hendriks RW, and Corneth OBJ
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- Humans, Male, Female, Middle Aged, Adult, Treatment Outcome, Memory T Cells drug effects, Memory T Cells immunology, Memory T Cells metabolism, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Glucocorticoids therapeutic use, Vital Capacity drug effects, Aged, Sarcoidosis, Pulmonary drug therapy, Sarcoidosis, Pulmonary blood, Sarcoidosis, Pulmonary immunology, Sarcoidosis, Pulmonary diagnosis, Programmed Cell Death 1 Receptor, Prednisone therapeutic use, T-Lymphocytes, Regulatory drug effects, T-Lymphocytes, Regulatory immunology
- Abstract
Background: The treatment response to corticosteroids in patients with sarcoidosis is highly variable. CD4
+ T cells are central in sarcoid pathogenesis and their phenotype in peripheral blood (PB) associates with disease course. We hypothesized that the phenotype of circulating T cells in patients with sarcoidosis may correlate with the response to prednisone treatment. Therefore, we aimed to correlate frequencies and phenotypes of circulating T cells at baseline with the pulmonary function response at 3 and 12 months during prednisone treatment in patients with pulmonary sarcoidosis., Methods: We used multi-color flow cytometry to quantify activation marker expression on PB T cell populations in 22 treatment-naïve patients and 21 healthy controls (HCs). Pulmonary function tests at baseline, 3 and 12 months were used to measure treatment effect., Results: Patients with sarcoidosis showed an absolute forced vital capacity (FVC) increase of 14.2% predicted (± 10.6, p < 0.0001) between baseline and 3 months. Good response to prednisone (defined as absolute FVC increase of ≥ 10% predicted) was observed in 12 patients. CD4+ memory T cells and regulatory T cells from patients with sarcoidosis displayed an aberrant phenotype at baseline, compared to HCs. Good responders at 3 months had significantly increased baseline proportions of PD-1+ CD4+ memory T cells and PD-1+ regulatory T cells, compared to poor responders and HCs. Moreover, decreased fractions of CD25+ cells and increased fractions of PD-1+ cells within the CD4+ memory T cell population correlated with ≥ 10% FVC increase at 12 months. During treatment, the aberrantly activated phenotype of memory and regulatory T cells reversed., Conclusions: Increased proportions of circulating PD-1+ CD4+ memory T cells and PD-1+ regulatory T cells and decreased proportions of CD25+ CD4+ memory T cells associate with good FVC response to prednisone in pulmonary sarcoidosis, representing promising new blood biomarkers for prednisone efficacy., Trial Registration: NL44805.078.13., (© 2024. The Author(s).)- Published
- 2024
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13. Measuring burden of disease in both asthma and COPD by merging the ACQ and CCQ: less is more?
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Cuperus LJA, van Zelst CM, Kerstjens HAM, Hendriks RW, Rutten-van Molken MPMH, Muilwijk-Kroes JB, Braunstahl GJ, and In 't Veen JCCM
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- Humans, Male, Female, Surveys and Questionnaires, Middle Aged, Aged, Adult, Primary Health Care statistics & numerical data, Asthma epidemiology, Pulmonary Disease, Chronic Obstructive physiopathology, Pulmonary Disease, Chronic Obstructive epidemiology, Cost of Illness
- Abstract
Symptoms of asthma and COPD often overlap, and both diseases can co-exist in one patient. The asthma control questionnaire (ACQ) and clinical COPD questionnaire (CCQ) were developed to assess disease burden in respectively asthma or COPD. This study explores the possibility of creating a new questionnaire to assess disease burden in all obstructive lung diseases by integrating and reducing questions of the ACQ and CCQ. Data of patients with asthma, COPD and asthma-COPD overlap (ACO) were collected from a primary and secondary care center. Patients completed ACQ and CCQ on the same day. Linear regression tested correlations. Principal Component Analysis (PCA) was used for item reduction. The secondary cohort with asthma and COPD patients was used for initial question selection (development cohort). These results were reproduced in the primary care cohort and secondary cohort of patients with ACO. The development cohort comprised 252 patients with asthma and 96 with COPD. Correlation between ACQ and CCQ in asthma was R = 0.82, and in COPD R = 0.83. PCA determined a selection of 9 questions. Reproduction in primary care data (asthma n = 1110, COPD n = 1041, ACO = 355) and secondary care data of ACO patients (n = 53) resulted in similar correlations and PCA-derived selection of questions. In conclusion, PCA determined a selection of nine questions of the ACQ and CCQ: working title 'the Obstructive Lung Disease Questionnaire'. These results suggest that this pragmatic set of questions might be sufficient to assess disease burden in obstructive lung disease in both primary as secondary care., (© 2024. The Author(s).)
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- 2024
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14. Aberrant characteristics of peripheral blood innate lymphoid cells in COPD, independent of smoking history.
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van Zelst CM, In 't Veen JCCM, Krabbendam L, de Boer GM, de Bruijn MJW, van Nimwegen M, van der Ploeg EK, van Uden D, Stadhouders R, Tramper-Stranders GA, Hendriks RW, and Braunstahl GJ
- Abstract
Background: Distinguishing asthma and COPD can pose challenges in clinical practice. Increased group 1 innate lymphoid cells (ILC1s) have been found in the lungs and peripheral blood of COPD patients, while asthma is associated with elevated levels of ILC2s. However, it is unclear whether the inflammatory characteristics of ILC1s and ILC2s differ between COPD and asthma. This study aims to compare peripheral blood ILC subsets and their expression of inflammatory markers in COPD patients, asthma patients and controls., Methods: The study utilised multi-colour flow cytometry to analyse peripheral blood ILC populations in clinically stable COPD patients (n=38), asthma patients (n=37), and smoking (n=19) and non-smoking (n=16) controls., Results: Proportions of peripheral blood inflammatory CD4
+ ILC1s were significantly higher in COPD patients than in asthma. Proportions of CD4- ILC1s were increased in COPD patients compared to asthma patients and smoking controls. Frequencies of CD117- ILC2s were significantly reduced in COPD patients compared with asthma patients. In contrast, the fraction of inflammatory CD45RO+ cells within the CD117- ILC2 population was significantly increased. Principal component analyses showed that combined features of the circulating ILC compartment separated COPD patients from asthma patients and both control groups., Conclusion: Our in-depth characterisation of ILC1 and ILC2 populations in peripheral blood revealed significant differences in their phenotypes between COPD and asthma patients and smoking or non-smoking controls. These findings suggest a role for both ILC subsets in COPD disease pathology, independent of smoking history, and may have implications for patient stratification and therapy development., Competing Interests: Conflict of interest: All authors declare that they have no conflicts of interest related to the topic., (Copyright ©The authors 2024.)- Published
- 2024
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15. Aberrant B cell receptor signaling in circulating naïve and IgA + memory B cells from newly-diagnosed autoantibody-positive rheumatoid arthritis patients.
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Neys SFH, Heutz JW, van Hulst JAC, Vink M, Bergen IM, de Jong PHP, Lubberts E, Hendriks RW, and Corneth OBJ
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- Humans, Memory B Cells, Immunoglobulin Isotypes, Receptors, Antigen, B-Cell, Immunoglobulin A, Autoantibodies, Arthritis, Rheumatoid
- Abstract
Objective: Altered B cell receptor (BCR) signaling has been implicated in the pathogenesis of rheumatoid arthritis (RA). Here we aimed to identify signaling aberrations in autoantibody-positive and autoantibody-negative RA patients by performing a comprehensive analysis of the BCR signaling cascade in different B cell subsets., Methods: We first optimized phosphoflow cytometry for an in-depth analysis of BCR signaling across immunoglobulin isotypes in healthy donors. Subsequently, we compared BCR signaling in circulating B cell subsets from treatment-naïve, newly-diagnosed autoantibody-positive RA and autoantibody-negative RA patients and healthy controls (HCs)., Results: We observed subset-specific phosphorylation patterns of the BCR signalosome in circulating B cells from healthy donors. Compared with HCs, autoantibody-positive RA patients displayed enhanced responses to BCR stimulation for multiple signaling proteins, specifically in naïve and IgA
+ memory B cells. Whereas in unstimulated healthy donor B cells, the phosphorylation status of individual signaling proteins showed only limited correlation, BCR stimulation enhanced the interconnectivity in phosphorylation within the BCR signalosome. However, this strong interconnectivity within the BCR signalosome in stimulated B cells from HCs was lost in RA, especially in autoantibody-positive RA patients. Finally, we observed strong correlations between SYK and BTK protein expression, and IgA and IgG anti-citrullinated protein antibody concentrations in serum from autoantibody-positive RA patients., Conclusion: Collectively, the isotype-specific analysis of multiple key components of the BCR signalosome identified aberrant BCR signaling responses in treatment-naïve autoantibody-positive RA patients, particularly in naïve B cells and IgA+ memory B cells. Our findings support differential involvement of dysregulated BCR signaling in the pathogenesis of autoantibody-positive and autoantibody-negative RA., (Copyright © 2024. Published by Elsevier Ltd.)- Published
- 2024
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16. Atypical B cells (CD21-CD27-IgD-) correlate with lack of response to checkpoint inhibitor therapy in NSCLC.
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Belderbos RA, Corneth OBJ, Dumoulin D, Hendriks RW, Aerts JGJV, and Willemsen M
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- Humans, B-Lymphocytes, Phenotype, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms pathology, Mesothelioma pathology
- Abstract
Introduction: Checkpoint inhibitor (CI) therapy has revolutionized treatment for non-small cell lung cancer (NSCLC). However, a proportion of patients do not respond to CI therapy for unknown reasons. Although the current paradigm in anti-tumor immunity evolves around T cells, the presence of tertiary lymphoid structures and memory B cells has been positively correlated with response to CI therapy in NSCLC. In addition, double negative (DN) (CD27
- IgD- ) B cells have been shown to be abundant in NSCLC compared to healthy lung tissue and inversely correlate with the intratumoral presence of memory B cells. Nonetheless, no study has correlated DN B cells to survival in NSCLC., Methods: In this study, we evaluated the presence and phenotype of B cells in peripheral blood with flow cytometry of patients with NSCLC and mesothelioma before receiving CI therapy and correlated these with clinical outcome., Results: Non-responding patients showed decreased frequencies of B cells, yet increased frequencies of antigen-experienced CD21- DN (Atypical) B cells compared to responding patients and HC, which was confirmed in patients with mesothelioma treated with CI therapy., Conclusions: These data show that the frequency of CD21- DN B cells correlates with lack of response to CI therapy in thoracic malignancies. The mechanism by which CD21- DN B cells hamper CI therapy remains unknown. Our findings support the hypothesis that CD21- DN B cells resemble phenotypically identical exhausted B cells that are seen in chronic infection or function as antigen presenting cells that induce regulatory T cells., Competing Interests: Declaration of Competing Interest Daphne Dumoulin reports personal fees from Roche, BMS, MSD, Pfizer, Astra Zeneca and Novartis outside the submitted work. Joachim Aerts reports personal fees and nonfinancial support from MSD, personal fees from BMS, Boehringer Ingelheim, Amphera, Eli-Lilly, Takeda, Bayer, Roche, Astra Zeneca outside the submitted work; in addition, Joachim Aerts has a patent allogenic tumor cell lysate licensed to Amphera, a patent combination immunotherapy in cancer pending, and a patent biomarker for immunotherapy pending; Joachim Aerts served as an unpaid editorial board member of Translational Lung Cancer Research from September 2019 to September 2021. The other authors do not have a conflict of interest to disclose., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2024
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17. The European B cell network.
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van Spriel AB and Hendriks RW
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- Europe, B-Lymphocytes
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- 2023
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18. Interleukin-10 multitasking in allergic airway inflammation.
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Hendriks RW
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- Humans, Inflammation, Lung, Interleukin-33, Interleukin-10, Asthma
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- 2023
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19. FastCAR: fast correction for ambient RNA to facilitate differential gene expression analysis in single-cell RNA-sequencing datasets.
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Berg M, Petoukhov I, van den Ende I, Meyer KB, Guryev V, Vonk JM, Carpaij O, Banchero M, Hendriks RW, van den Berge M, and Nawijn MC
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- Humans, Sequence Analysis, RNA methods, Transcriptome, Research Design, Single-Cell Analysis methods, RNA metabolism, Gene Expression Profiling methods
- Abstract
Cell type-specific differential gene expression analyses based on single-cell transcriptome datasets are sensitive to the presence of cell-free mRNA in the droplets containing single cells. This so-called ambient RNA contamination may differ between samples obtained from patients and healthy controls. Current ambient RNA correction methods were not developed specifically for single-cell differential gene expression (sc-DGE) analyses and might therefore not sufficiently correct for ambient RNA-derived signals. Here, we show that ambient RNA levels are highly sample-specific. We found that without ambient RNA correction, sc-DGE analyses erroneously identify transcripts originating from ambient RNA as cell type-specific disease-associated genes. We therefore developed a computationally lean and intuitive correction method, Fast Correction for Ambient RNA (FastCAR), optimized for sc-DGE analysis of scRNA-Seq datasets generated by droplet-based methods including the 10XGenomics Chromium platform. FastCAR uses the profile of transcripts observed in libraries that likely represent empty droplets to determine the level of ambient RNA in each individual sample, and then corrects for these ambient RNA gene expression values. FastCAR can be applied as part of the data pre-processing and QC in sc-DGE workflows comparing scRNA-Seq data in a health versus disease experimental design. We compared FastCAR with two methods previously developed to remove ambient RNA, SoupX and CellBender. All three methods identified additional genes in sc-DGE analyses that were not identified in the absence of ambient RNA correction. However, we show that FastCAR performs better at correcting gene expression values attributed to ambient RNA, resulting in a lower frequency of false-positive observations. Moreover, the use of FastCAR in a sc-DGE workflow increases the cell-type specificity of sc-DGE analyses across disease conditions., (© 2023. The Author(s).)
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- 2023
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20. Editorial: Emerging talents in B cell biology: 2022.
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Zemlin M, Hendriks RW, and Schroeder HW Jr
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- B-Lymphocytes, Interleukin-10
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
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- 2023
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21. Circulating T cells in sarcoidosis have an aberrantly activated phenotype that correlates with disease outcome.
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Miedema JR, de Jong LJ, van Uden D, Bergen IM, Kool M, Broos CE, Kahlmann V, Wijsenbeek MS, Hendriks RW, and Corneth OBJ
- Abstract
Rationale: Disease course in sarcoidosis is highly variable. Bronchoalveolar lavage fluid and mediastinal lymph nodes show accumulation of activated T cells with a T-helper (Th)17.1 signature, which correlates with non-resolving sarcoidosis. We hypothesize that the peripheral blood (PB) T cell phenotype may correlate with outcome., Objectives: To compare frequencies, phenotypes and function of circulating T cell populations in sarcoidosis patients with healthy controls (HCs) and correlate these parameters with outcome., Methods: We used multi-color flow cytometry to quantify activation marker expression on PB T cell subsets in treatment-naïve patients and HCs. The disease course was determined after 2-year follow-up. Cytokine production was measured after T cell stimulation in vitro., Measurements and Main Results: We observed significant differences between patients and HCs in several T cell populations, including CD8
+ and CD4+ T cells, Th1/Th17 subsets, CD4+ T memory stem cells, regulatory T cells (Tregs) and γδ T cells. Decreased frequencies of CD4+ T cells and increased frequencies of Tregs and CD8+ γδ T cells correlated with worse outcome. Naïve CD4+ T cells displayed an activated phenotype with increased CD25 expression in patients with active chronic disease at 2-year follow-up. A distinctive Treg phenotype with increased expression of CD25, CTLA4, CD69, PD-1 and CD95 correlated with chronic sarcoidosis. Upon stimulation, both naïve and memory T cells displayed a different cytokine profile in sarcoidosis compared to HCs., Conclusions: Circulating T cell subpopulations of sarcoidosis patients display phenotypic abnormalities that correlate with disease outcome, supporting a critical role of aberrant T cell activation in sarcoidosis pathogenesis., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2023
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22. Immunological profiling in long COVID: overall low grade inflammation and T-lymphocyte senescence and increased monocyte activation correlating with increasing fatigue severity.
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Berentschot JC, Drexhage HA, Aynekulu Mersha DG, Wijkhuijs AJM, GeurtsvanKessel CH, Koopmans MPG, Voermans JJC, Hendriks RW, Nagtzaam NMA, de Bie M, Heijenbrok-Kal MH, Bek LM, Ribbers GM, van den Berg-Emons RJG, Aerts JGJV, Dik WA, and Hellemons ME
- Subjects
- Humans, Monocytes, Post-Acute COVID-19 Syndrome, Aftercare, SARS-CoV-2, Patient Discharge, Fatigue, Cytokines, Inflammation complications, T-Lymphocytes, COVID-19 complications
- Abstract
Background: Many patients with SARS-CoV-2 infection develop long COVID with fatigue as one of the most disabling symptoms. We performed clinical and immune profiling of fatigued and non-fatigued long COVID patients and age- and sex-matched healthy controls (HCs)., Methods: Long COVID symptoms were assessed using patient-reported outcome measures, including the fatigue assessment scale (FAS, scores ≥22 denote fatigue), and followed up to one year after hospital discharge. We assessed inflammation-related genes in circulating monocytes, serum levels of inflammation-regulating cytokines, and leukocyte and lymphocyte subsets, including major monocyte subsets and senescent T-lymphocytes, at 3-6 months post-discharge., Results: We included 37 fatigued and 36 non-fatigued long COVID patients and 42 HCs. Fatigued long COVID patients represented a more severe clinical profile than non-fatigued patients, with many concurrent symptoms (median 9 [IQR 5.0-10.0] vs 3 [1.0-5.0] symptoms, p<0.001), and signs of cognitive failure (41%) and depression (>24%). Immune abnormalities that were found in the entire group of long COVID patients were low grade inflammation (increased inflammatory gene expression in monocytes, increased serum pro-inflammatory cytokines) and signs of T-lymphocyte senescence (increased exhausted CD8
+ TEMRA -lymphocytes). Immune profiles did not significantly differ between fatigued and non-fatigued long COVID groups. However, the severity of fatigue (total FAS score) significantly correlated with increases of intermediate and non-classical monocytes, upregulated gene levels of CCL2, CCL7, and SERPINB2 in monocytes, increases in serum Galectin-9, and higher CD8+ T-lymphocyte counts., Conclusion: Long COVID with fatigue is associated with many concurrent and persistent symptoms lasting up to one year after hospitalization. Increased fatigue severity associated with stronger signs of monocyte activation in long COVID patients and potentially point in the direction of monocyte-endothelial interaction. These abnormalities were present against a background of immune abnormalities common to the entire group of long COVID patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Berentschot, Drexhage, Aynekulu Mersha, Wijkhuijs, GeurtsvanKessel, Koopmans, Voermans, Hendriks, Nagtzaam, de Bie, Heijenbrok-Kal, Bek, Ribbers, van den Berg-Emons, Aerts, Dik and Hellemons.)- Published
- 2023
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23. Overcoming immune checkpoint blockade resistance in solid tumors with intermittent ITK inhibition.
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Zhao M, Li L, Kiernan CH, Castro Eiro MD, Dammeijer F, van Meurs M, Brouwers-Haspels I, Wilmsen MEP, Grashof DGB, van de Werken HJG, Hendriks RW, Aerts JG, Mueller YM, and Katsikis PD
- Subjects
- Humans, Immune Checkpoint Inhibitors, Protein-Tyrosine Kinases, Pancreatic Neoplasms, Mesothelioma
- Abstract
Cytotoxic CD8 + T cell (CTL) exhaustion is driven by chronic antigen stimulation. Reversing CTL exhaustion with immune checkpoint blockade (ICB) has provided clinical benefits in different types of cancer. We, therefore, investigated whether modulating chronic antigen stimulation and T-cell receptor (TCR) signaling with an IL2-inducible T-cell kinase (ITK) inhibitor, could confer ICB responsiveness to ICB resistant solid tumors. In vivo intermittent treatment of 3 ICB-resistant solid tumor (melanoma, mesothelioma or pancreatic cancer) with ITK inhibitor significantly improved ICB therapy. ITK inhibition directly reinvigorate exhausted CTL in vitro as it enhanced cytokine production, decreased inhibitory receptor expression, and downregulated the transcription factor TOX. Our study demonstrates that intermittent ITK inhibition can be used to directly ameliorate CTL exhaustion and enhance immunotherapies even in solid tumors that are ICB resistant., (© 2023. Springer Nature Limited.)
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- 2023
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24. Ibrutinib directly reduces CD8+T cell exhaustion independent of BTK.
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Li L, Zhao M, Kiernan CH, Castro Eiro MD, van Meurs M, Brouwers-Haspels I, Wilmsen MEP, Grashof DGB, van de Werken HJG, Hendriks RW, Mueller YM, and Katsikis PD
- Abstract
Introduction: Cytotoxic CD8+ T cell (CTL) exhaustion is a dysfunctional state of T cells triggered by persistent antigen stimulation, with the characteristics of increased inhibitory receptors, impaired cytokine production and a distinct transcriptional profile. Evidence from immune checkpoint blockade therapy supports that reversing T cell exhaustion is a promising strategy in cancer treatment. Ibrutinib, is a potent inhibitor of BTK, which has been approved for the treatment of chronic lymphocytic leukemia. Previous studies have reported improved function of T cells in ibrutinib long-term treated patients but the mechanism remains unclear. We investigated whether ibrutinib directly acts on CD8+ T cells and reinvigorates exhausted CTLs., Methods: We used an established in vitro CTL exhaustion system to examine whether ibrutinib can directly ameliorate T cell exhaustion. Changes in inhibitory receptors, transcription factors, cytokine production and killing capacity of ibrutinib-treated exhausted CTLs were detected by flow cytometry. RNA-seq was performed to study transcriptional changes in these cells. Btk deficient mice were used to confirm that the effect of ibrutinib was independent of BTK expression., Results: We found that ibrutinib reduced exhaustion-related features of CTLs in an in vitro CTL exhaustion system. These changes included decreased inhibitory receptor expression, enhanced cytokine production, and downregulation of the transcription factor TOX with upregulation of TCF1. RNA-seq further confirmed that ibrutinib directly reduced the exhaustion-related transcriptional profile of these cells. Importantly, using btk deficient mice we showed the effect of ibrutinib was independent of BTK expression, and therefore mediated by one of its other targets., Discussion: Our study demonstrates that ibrutinib directly ameliorates CTL exhaustion, and provides evidence for its synergistic use with cancer immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Zhao, Kiernan, Castro Eiro, van Meurs, Brouwers-Haspels, Wilmsen, Grashof, van de Werken, Hendriks, Mueller and Katsikis.)
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- 2023
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25. Correction: Inflammatory and tolerogenic myeloid cells determine outcome following human allergen challenge.
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Voskamp AL, Tak T, Gerdes ML, Menafra R, Duijster E, Jochems SP, Kielbasa SM, Kormelink TG, Stam KA, van Hengel ORJ, de Jong NW, Hendriks RW, Kloet SL, Yazdanbakhsh M, de Jong EC, Gerth van Wijk R, and Smits HH
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- 2023
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26. Inflammatory and tolerogenic myeloid cells determine outcome following human allergen challenge.
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Voskamp AL, Tak T, Gerdes ML, Menafra R, Duijster E, Jochems SP, Kielbasa SM, Kormelink TG, Stam KA, van Hengel ORJ, de Jong NW, Hendriks RW, Kloet SL, Yazdanbakhsh M, de Jong EC, Gerth van Wijk R, and Smits HH
- Subjects
- Humans, Nasal Mucosa, Myeloid Cells pathology, Inflammation pathology, Allergens, Rhinitis, Allergic, Perennial pathology
- Abstract
Innate mononuclear phagocytic system (MPS) cells preserve mucosal immune homeostasis. We investigated their role at nasal mucosa following allergen challenge with house dust mite. We combined single-cell proteome and transcriptome profiling on nasal immune cells from nasal biopsies cells from 30 allergic rhinitis and 27 non-allergic subjects before and after repeated nasal allergen challenge. Biopsies of patients showed infiltrating inflammatory HLA-DRhi/CD14+ and CD16+ monocytes and proallergic transcriptional changes in resident CD1C+/CD1A+ conventional dendritic cells (cDC)2 following challenge. In contrast, non-allergic individuals displayed distinct innate MPS responses to allergen challenge: predominant infiltration of myeloid-derived suppressor cells (MDSC: HLA-DRlow/CD14+ monocytes) and cDC2 expressing inhibitory/tolerogenic transcripts. These divergent patterns were confirmed in ex vivo stimulated MPS nasal biopsy cells. Thus, we identified not only MPS cell clusters involved in airway allergic inflammation but also highlight novel roles for non-inflammatory innate MPS responses by MDSC to allergens in non-allergic individuals. Future therapies should address MDSC activity as treatment for inflammatory airway diseases., (© 2023 Voskamp et al.)
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- 2023
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27. Type-2 CD8 + T-cell formation relies on interleukin-33 and is linked to asthma exacerbations.
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van der Ploeg EK, Krabbendam L, Vroman H, van Nimwegen M, de Bruijn MJW, de Boer GM, Bergen IM, Kool M, Tramper-Standers GA, Braunstahl GJ, Huylebroeck D, Hendriks RW, and Stadhouders R
- Subjects
- Animals, Humans, Mice, CD8-Positive T-Lymphocytes, Cytokines, Immunity, Innate, Inflammation, T-Lymphocytes, Cytotoxic, Asthma, Interleukin-33
- Abstract
CD4
+ T helper 2 (Th2) cells and group 2 innate lymphoid cells are considered the main producers of type-2 cytokines that fuel chronic airway inflammation in allergic asthma. However, CD8+ cytotoxic T (Tc) cells - critical for anti-viral defense - can also produce type-2 cytokines (referred to as 'Tc2' cells). The role of Tc cells in asthma and virus-induced disease exacerbations remains poorly understood, including which micro-environmental signals and cell types promote Tc2 cell formation. Here we show increased circulating Tc2 cell abundance in severe asthma patients, reaching peak levels during exacerbations and likely emerging from canonical IFNγ+ Tc cells through plasticity. Tc2 cell abundance is associated with increased disease burden, higher exacerbations rates and steroid insensitivity. Mouse models of asthma recapitulate the human disease by showing extensive type-2 skewing of lung Tc cells, which is controlled by conventional type-1 dendritic cells and IFNγ. Importantly, we demonstrate that the alarmin interleukin-33 (IL-33) critically promotes type-2 cytokine production by lung Tc cells in experimental allergic airway inflammation. Our data identify Tc cells as major producers of type-2 cytokines in severe asthma and during exacerbations that are remarkably sensitive to alterations in their inflammatory tissue micro-environment, with IL-33 emerging as an important regulator of Tc2 formation., (© 2023. Springer Nature Limited.)- Published
- 2023
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28. 3D chromatin reprogramming primes human memory T H 2 cells for rapid recall and pathogenic dysfunction.
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Onrust-van Schoonhoven A, de Bruijn MJW, Stikker B, Brouwer RWW, Braunstahl GJ, van IJcken WFJ, Graf T, Huylebroeck D, Hendriks RW, Stik G, and Stadhouders R
- Subjects
- Humans, Transcription Factors genetics, Promoter Regions, Genetic, Chromatin genetics, Gene Expression Regulation
- Abstract
Memory T cells provide long-lasting defense responses through their ability to rapidly reactivate, but how they efficiently "recall" an inflammatory transcriptional program remains unclear. Here, we show that human CD4
+ memory T helper 2 (TH 2) cells carry a chromatin landscape synergistically reprogrammed at both one-dimensional (1D) and 3D levels to accommodate recall responses, which is absent in naive T cells. In memory TH 2 cells, recall genes were epigenetically primed through the maintenance of transcription-permissive chromatin at distal (super)enhancers organized in long-range 3D chromatin hubs. Precise transcriptional control of key recall genes occurred inside dedicated topologically associating domains ("memory TADs"), in which activation-associated promoter-enhancer interactions were preformed and exploited by AP-1 transcription factors to promote rapid transcriptional induction. Resting memory TH 2 cells from patients with asthma showed premature activation of primed recall circuits, linking aberrant transcriptional control of recall responses to chronic inflammation. Together, our results implicate stable multiscale reprogramming of chromatin organization as a key mechanism underlying immunological memory and dysfunction in T cells.- Published
- 2023
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29. Decoding the genetic and epigenetic basis of asthma.
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Stikker BS, Hendriks RW, and Stadhouders R
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- Humans, Epigenesis, Genetic, Epigenomics, Genomics, Genetic Predisposition to Disease, Genome-Wide Association Study, Asthma genetics
- Abstract
Asthma is a complex and heterogeneous chronic inflammatory disease of the airways. Alongside environmental factors, asthma susceptibility is strongly influenced by genetics. Given its high prevalence and our incomplete understanding of the mechanisms underlying disease susceptibility, asthma is frequently studied in genome-wide association studies (GWAS), which have identified thousands of genetic variants associated with asthma development. Virtually all these genetic variants reside in non-coding genomic regions, which has obscured the functional impact of asthma-associated variants and their translation into disease-relevant mechanisms. Recent advances in genomics technology and epigenetics now offer methods to link genetic variants to gene regulatory elements embedded within non-coding regions, which have started to unravel the molecular mechanisms underlying the complex (epi)genetics of asthma. Here, we provide an integrated overview of (epi)genetic variants associated with asthma, focusing on efforts to link these disease associations to biological insight into asthma pathophysiology using state-of-the-art genomics methodology. Finally, we provide a perspective as to how decoding the genetic and epigenetic basis of asthma has the potential to transform clinical management of asthma and to predict the risk of asthma development., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)
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- 2023
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30. Niche-expressed Galectin-1 is involved in pre-B acute lymphoblastic leukemia relapse through pre-B cell receptor activation.
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Pelletier J, Balzano M, Destin J, Montersino C, Delahaye MC, Marchand T, Bailly AL, Bardin F, Coppin E, Goubard A, Castellano R, de Bruijn MJW, Rip J, Collette Y, Dubreuil P, Tarte K, Broccardo C, Hendriks RW, Schiff C, Vey N, Aurrand-Lions M, and Mancini SJC
- Abstract
B-cell acute lymphoblastic leukemia (B-ALL) reflects the malignant counterpart of developing B cells in the bone marrow (BM). Despite tremendous progress in B-ALL treatment, the overall survival of adults at diagnosis and patients at all ages after relapse remains poor. Galectin-1 (GAL1) expressed by BM supportive niches delivers proliferation signals to normal pre-B cells through interaction with the pre-B cell receptor (pre-BCR). Here, we asked whether GAL1 gives non-cell autonomous signals to pre-BCR
+ pre-B ALL, in addition to cell-autonomous signals linked to genetic alterations. In syngeneic and patient-derived xenograft (PDX) murine models, murine and human pre-B ALL development is influenced by GAL1 produced by BM niches through pre-BCR-dependent signals, similarly to normal pre-B cells. Furthermore, targeting pre-BCR signaling together with cell-autonomous oncogenic pathways in pre-B ALL PDX improved treatment response. Our results show that non-cell autonomous signals transmitted by BM niches represent promising targets to improve B-ALL patient survival., Competing Interests: The authors declare no competing financial interests., (© 2023 The Author(s).)- Published
- 2023
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31. B Cell Signaling and Activation in Autoimmunity.
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Hendriks RW and Corneth OBJ
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- Humans, B-Lymphocytes, Signal Transduction, Autoimmunity, Autoimmune Diseases
- Abstract
Autoreactive B cells play a key role in the initiation or aggravation of many systemic and tissue-specific autoimmune disorders [...].
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- 2023
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32. Bruton's Tyrosine Kinase in Neutrophils Is Crucial for Host Defense against Klebsiella pneumoniae.
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Liu Z, De Porto APNA, De Beer R, Roelofs JJTH, De Boer OJ, Florquin S, Van't Veer C, Hendriks RW, Van der Poll T, and De Vos AF
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- Animals, Humans, Mice, Agammaglobulinaemia Tyrosine Kinase metabolism, Klebsiella pneumoniae, Neutrophils metabolism, Bacterial Infections, Sepsis
- Abstract
Humans with dysfunctional Bruton's tyrosine kinase (Btk) are highly susceptible to bacterial infections. Compelling evidence indicates that Btk is essential for B cell-mediated immunity, whereas its role in myeloid cell-mediated immunity against infections is controversial. In this study, we determined the contribution of Btk in B cells and neutrophils to host defense against the extracellular bacterial pathogen Klebsiella pneumoniae, a common cause of pulmonary infections and sepsis. Btk-/- mice were highly susceptible to Klebsiella infection, which was not reversed by Btk re-expression in B cells and restoration of natural antibody levels. Neutrophil-specific Btk deficiency impaired host defense against Klebsiella to a similar extent as complete Btk deficiency. Neutrophil-specific Btk deficiency abolished extracellular reactive oxygen species production in response to Klebsiella. These data indicate that expression of Btk in neutrophils is crucial, while in B cells, it is dispensable for in vivo host defense against K. pneumoniae., (© 2022 The Author(s). Published by S. Karger AG, Basel.)
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- 2023
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33. Stratification of COPD patients towards personalized medicine: reproduction and formation of clusters.
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van Zelst CM, Goossens LMA, Witte JA, Braunstahl GJ, Hendriks RW, Rutten-van Molken MPMH, and Veen JCCMI
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- Humans, Precision Medicine, Activities of Daily Living, Respiratory Function Tests, Quality of Life, Pulmonary Disease, Chronic Obstructive diagnosis, Pulmonary Disease, Chronic Obstructive epidemiology, Pulmonary Disease, Chronic Obstructive therapy
- Abstract
Background: The global initiative for chronic obstructive lung disease (GOLD) 2020 emphasizes that there is only a weak correlation between FEV
1 , symptoms and impairment of the health status of patients with chronic obstructive pulmonary disease (COPD). Various studies aimed to identify COPD phenotypes by cluster analyses, but behavioral aspects besides smoking were rarely included., Methods: The aims of the study were to investigate whether (i) clustering analyses are in line with the classification into GOLD ABCD groups; (ii) clustering according to Burgel et al. (Eur Respir J. 36(3):531-9, 2010) can be reproduced in a real-world COPD cohort; and (iii) addition of new behavioral variables alters the clustering outcome. Principal component and hierarchical cluster analyses were applied to real-world clinical data of COPD patients newly referred to secondary care (n = 155). We investigated if the obtained clusters paralleled GOLD ABCD subgroups and determined the impact of adding several variables, including quality of life (QOL), fatigue, satisfaction relationship, air trapping, steps per day and activities of daily living, on clustering., Results: Using the appropriate corresponding variables, we identified clusters that largely reflected the GOLD ABCD groups, but we could not reproduce Burgel's clinical phenotypes. Adding six new variables resulted in the formation of four new clusters that mainly differed from each other in the following parameters: number of steps per day, activities of daily living and QOL., Conclusions: We could not reproduce previously identified clinical COPD phenotypes in an independent population of COPD patients. Our findings therefore indicate that COPD phenotypes based on cluster analysis may not be a suitable basis for treatment strategies for individual patients., (© 2022. The Author(s).)- Published
- 2022
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34. Aberrant B Cell Signaling in Autoimmune Diseases.
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Corneth OBJ, Neys SFH, and Hendriks RW
- Subjects
- Animals, B-Lymphocytes, Signal Transduction genetics, Toll-Like Receptors metabolism, Receptors, Antigen, B-Cell metabolism, Autoimmune Diseases
- Abstract
Aberrant B cell signaling plays a critical in role in various systemic and organ-specific autoimmune diseases. This is supported by genetic evidence by many functional studies in B cells from patients or specific animal models and by the observed efficacy of small-molecule inhibitors. In this review, we first discuss key signal transduction pathways downstream of the B cell receptor (BCR) that ensure that autoreactive B cells are removed from the repertoire or functionally silenced. We provide an overview of aberrant BCR signaling that is associated with inappropriate B cell repertoire selection and activation or survival of peripheral B cell populations and plasma cells, finally leading to autoantibody formation. Next to BCR signaling, abnormalities in other signal transduction pathways have been implicated in autoimmune disease. These include reduced activity of several phosphates that are downstream of co-inhibitory receptors on B cells and increased levels of BAFF and APRIL, which support survival of B cells and plasma cells. Importantly, pathogenic synergy of the BCR and Toll-like receptors (TLR), which can be activated by endogenous ligands, such as self-nucleic acids, has been shown to enhance autoimmunity. Finally, we will briefly discuss therapeutic strategies for autoimmune disease based on interfering with signal transduction in B cells.
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- 2022
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35. Low-Dose JAK3 Inhibition Improves Antitumor T-Cell Immunity and Immunotherapy Efficacy.
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Dammeijer F, van Gulijk M, Klaase L, van Nimwegen M, Bouzid R, Hoogenboom R, Joosse ME, Hendriks RW, van Hall T, and Aerts JG
- Subjects
- Animals, Mice, Phosphorylation, Receptors, Interleukin-2 metabolism, STAT5 Transcription Factor metabolism, Immunotherapy, Janus Kinase 3 antagonists & inhibitors, Neoplasms therapy, T-Lymphocytes immunology
- Abstract
Terminal T-cell exhaustion poses a significant barrier to effective anticancer immunotherapy efficacy, with current drugs aimed at reversing exhaustion being limited. Recent investigations into the molecular drivers of T-cell exhaustion have led to the identification of chronic IL2 receptor (IL2R)-STAT5 pathway signaling in mediating T-cell exhaustion. We targeted the key downstream IL2R-intermediate JAK 3 using a clinically relevant highly specific JAK3-inhibitor (JAK3i; PF-06651600) that potently inhibited STAT5-phosphorylation in vitro. Whereas pulsed high-dose JAK3i administration inhibited antitumor T-cell effector function, low-dose chronic JAK3i significantly improved T-cell responses and decreased tumor load in mouse models of solid cancer. Low-dose JAK3i combined with cellular and peptide vaccine strategies further decreased tumor load compared with both monotherapies alone. Collectively, these results identify JAK3 as a novel and promising target for combination immunotherapy., (©2022 American Association for Cancer Research.)
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- 2022
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36. Human T-bet+ B cell development is associated with BTK activity and suppressed by evobrutinib.
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Rijvers L, van Langelaar J, Bogers L, Melief MJ, Koetzier SC, Blok KM, Wierenga-Wolf AF, de Vries HE, Rip J, Corneth OB, Hendriks RW, Grenningloh R, Boschert U, Smolders J, and van Luijn MM
- Subjects
- Agammaglobulinaemia Tyrosine Kinase, Humans, Phosphorylation, Piperidines, Pyrimidines pharmacology, Pyrimidines therapeutic use, Multiple Sclerosis drug therapy, T-Box Domain Proteins metabolism
- Abstract
Recent clinical trials have shown promising results for the next-generation Bruton's tyrosine kinase (BTK) inhibitor evobrutinib in the treatment of multiple sclerosis (MS). BTK has a central role in signaling pathways that govern the development of B cells. Whether and how BTK activity shapes B cells as key drivers of MS is currently unclear. Compared with levels of BTK protein, we found higher levels of phospho-BTK in ex vivo blood memory B cells from patients with relapsing-remitting MS and secondary progressive MS compared with controls. In these MS groups, BTK activity was induced to a lesser extent after anti-IgM stimulation. BTK positively correlated with CXCR3 expression, both of which were increased in blood B cells from clinical responders to natalizumab (anti-VLA-4 antibody) treatment. Under in vitro T follicular helper-like conditions, BTK phosphorylation was enhanced by T-bet-inducing stimuli, IFN-γ and CpG-ODN, while the expression of T-bet and T-bet-associated molecules CXCR3, CD21, and CD11c was affected by evobrutinib. Furthermore, evobrutinib interfered with in vitro class switching, as well as memory recall responses, and disturbed CXCL10-mediated migration of CXCR3+ switched B cells through human brain endothelial monolayers. These findings demonstrate a functional link between BTK activity and disease-relevant B cells and offer valuable insights into how next-generation BTK inhibitors could modulate the clinical course of patients with MS.
- Published
- 2022
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37. Bruton's Tyrosine Kinase Deficiency Ameliorates Antimicrobial Host Defense during Peritonitis Induced by Pathogenic Escherichia coli.
- Author
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Liu Z, van 't Veer C, Hendriks RW, Roelofs JJTH, van der Poll T, and de Vos AF
- Subjects
- Agammaglobulinaemia Tyrosine Kinase metabolism, Animals, Anti-Bacterial Agents, Escherichia coli metabolism, Mice, Anti-Infective Agents, Escherichia coli Infections, Peritonitis, Sepsis
- Abstract
Peritonitis and abdominal sepsis remain major health problems and challenge for clinicians. Bruton's tyrosine kinase (Btk) is a versatile signaling protein involved in the regulation of B cell development and function, as well as innate host defense. In the current study, we aimed to explore the role of Btk in the host response during peritonitis and sepsis in mice induced by a gradually growing pathogenic strain of Escherichia coli bacteria. We found that Btk deficiency ameliorated antibacterial host defense during the late stage of E. coli-induced peritonitis. Btk was not required for cytokine and chemokine release in response to either E. coli or lipopolysaccharide and did not impact organ damage evoked by E. coli. Btk deficiency also did not alter neutrophil influx to the primary site of infection. However, the absence of Btk modestly enhanced phagocytosis of E. coli by neutrophils. These results indicate that Btk-mediated signaling is superfluous for inflammatory responses and remarkably detrimental for antibacterial defense during E. coli-induced peritonitis.
- Published
- 2022
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38. Peripheral Blood T Cells of Patients with IPAH Have a Reduced Cytokine-Producing Capacity.
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van Uden D, Koudstaal T, van Hulst JAC, Vink M, van Nimwegen M, van den Toorn LM, Chandoesing PP, van den Bosch AE, Kool M, Hendriks RW, and Boomars KA
- Subjects
- CD8-Positive T-Lymphocytes, CTLA-4 Antigen, Cytokines, Familial Primary Pulmonary Hypertension etiology, Humans, Interleukin-17, Hypertension, Pulmonary
- Abstract
Pulmonary arterial hypertension (PAH) is rare disease that is categorized as idiopathic (IPAH) when no underlying cause can be identified. Lungs of most patients with IPAH contain increased numbers of T cells and dendritic cells (DCs), suggesting involvement of the immune system in its pathophysiology. However, our knowledge on circulating immune cells in IPAH is rather limited. We used flow cytometry to characterize peripheral blood DCs and T cells in treatment-naive IPAH patients, compared with connective-tissue disease-PAH (CTD-PAH) patients and healthy controls (HCs). At diagnosis, T-helper (Th) cells of IPAH patients were less capable of producing TNFα, IFNγ, IL-4 and IL-17 compared to HCs. IPAH patients showed a decreased frequency of Th2 cells and significantly enhanced expression of the CTLA4 checkpoint molecule in naive CD4
+ T cells and both naive and memory CD8+ T cells. Frequencies and surface marker expression of circulating DCs and monocytes were essentially comparable between IPAH patients and HCs. Principal component analysis (PCA) separated IPAH patients-but not CTD-PAH patients-from HCs, based on T-cell cytokine profiles. At 1-year follow-up, the frequencies of IL-17+ production by memory CD4+ T cells were increased in IPAH patients and accompanied by increased proportions of Th17 and Tc17 cells, as well as decreased CTLA4 expression. Treatment-naive IPAH patients displayed a unique T-cell phenotype that was different from CTD-PAH patients and was characterized by reduced cytokine-producing capacity. These findings point to involvement of adaptive immune responses in IPAH, which may have an implication for the development of therapeutic interventions.- Published
- 2022
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39. Decreased BAFF Receptor Expression and Unaltered B Cell Receptor Signaling in Circulating B Cells from Primary Sjögren's Syndrome Patients at Diagnosis.
- Author
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Neys SFH, Verstappen GM, Bootsma H, Kroese FGM, Hendriks RW, and Corneth OBJ
- Subjects
- Agammaglobulinaemia Tyrosine Kinase metabolism, B-Lymphocytes metabolism, Humans, B-Cell Activation Factor Receptor genetics, B-Cell Activation Factor Receptor metabolism, B-Lymphocyte Subsets metabolism, Receptors, Antigen, B-Cell metabolism, Sjogren's Syndrome diagnosis, Sjogren's Syndrome metabolism
- Abstract
Animal models of autoimmunity and human genetic association studies indicate that the dysregulation of B-cell receptor (BCR) signaling is an important driver of autoimmunity. We previously showed that in circulating B cells from primary Sjögren's syndrome (pSS) patients with high systemic disease activity, protein expression of the BCR signaling molecule Bruton's tyrosine kinase (BTK) was increased and correlated with T-cell infiltration in the target organ. We hypothesized that these alterations could be driven by increased B-cell activating factor (BAFF) levels in pSS. Here, we investigated whether altered BCR signaling was already present at diagnosis and distinguished pSS from non-SS sicca patients. Using (phospho-)flow cytometry, we quantified the phosphorylation of BCR signaling molecules, and investigated BTK and BAFF receptor (BAFFR) expression in circulating B cell subsets in an inception cohort of non-SS sicca and pSS patients, as well as healthy controls (HCs). We found that both BTK protein levels and BCR signaling activity were comparable among groups. Interestingly, BAFFR expression was significantly downregulated in pSS, but not in non-SS sicca patients, compared with HCs, and correlated with pSS-associated alterations in B cell subsets. These data indicate reduced BAFFR expression as a possible sign of early B cell involvement and a diagnostic marker for pSS.
- Published
- 2022
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40. Evidence for a Role of CCR6+ T Cells in Chronic Thromboembolic Pulmonary Hypertension.
- Author
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van Uden D, Koudstaal T, van Hulst JAC, van den Bosch TPP, Vink M, Bergen IM, Lila KA, van den Bosch AE, Bresser P, Kool M, von der Thüsen JH, Hendriks RW, and Boomars KA
- Subjects
- CD8-Positive T-Lymphocytes metabolism, CTLA-4 Antigen, Cytokines, Humans, Interleukin-17 metabolism, Tumor Necrosis Factor-alpha, Hypertension, Pulmonary, Receptors, CCR6 metabolism
- Abstract
Introduction: Previous studies have shown an increase of T cells and chemokines in vascular lesions of patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, detailed characterization of these T cells is still lacking, nor have treatment effects been evaluated., Methods: We included 41 treatment-naive CTEPH patients at diagnosis, 22 patients at 1-year follow-up, and 17 healthy controls (HCs). Peripheral blood T cells were characterized by flow cytometry for subset distribution, cytokine expression and activation marker profile. We used multiplex immunofluorescence to identify CCR6
+ T cells in endarterectomy tissue from 25 patients., Results: At diagnosis, proportions of CCR6+ CD4+ T cells were increased in CTEPH patients compared with HCs. Patients displayed a significantly reduced production capacity of several cytokines including TNFα, IFNγ, GM-CSF and IL-4 in CD4+ T cells, and TNFα and IFNγ in CD8+ T cells. CD4+ and CD8+ T cells showed increased expression of the immune checkpoint protein CTLA4. Multivariate analysis separated CTEPH patients from HCs, based on CCR6 and CTLA4 expression. At 1-year follow-up, proportions of CCR6+ CD4+ T cells were further increased, IFNγ and IL-17 production capacity of CD4+ T cells was restored. In nearly all vascular lesions we found substantial numbers of CCR6+ T cells., Conclusion: The observed increase of CCR6+ T cells and modulation of the IFNγ and IL-17 production capacity of circulating CD4+ T cells at diagnosis and 1-year follow-up - together with the presence of CCR6+ T cells in vascular lesions - support the involvement of the Th17-associated CCR6+ T cell subset in CTEPH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 van Uden, Koudstaal, van Hulst, van den Bosch, Vink, Bergen, Lila, van den Bosch, Bresser, Kool, von der Thüsen, Hendriks and Boomars.)- Published
- 2022
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41. Severe COVID-19-associated variants linked to chemokine receptor gene control in monocytes and macrophages.
- Author
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Stikker BS, Stik G, van Ouwerkerk AF, Trap L, Spicuglia S, Hendriks RW, and Stadhouders R
- Subjects
- Genome-Wide Association Study, Humans, Macrophages metabolism, Receptors, CCR5 genetics, Receptors, CCR5 metabolism, Receptors, Chemokine genetics, Receptors, Chemokine metabolism, SARS-CoV-2, COVID-19 genetics, Monocytes metabolism
- Abstract
Genome-wide association studies have identified 3p21.31 as the main risk locus for severe COVID-19, although underlying mechanisms remain elusive. We perform an epigenomic dissection of 3p21.31, identifying a CTCF-dependent tissue-specific 3D regulatory chromatin hub that controls the activity of several chemokine receptor genes. Risk SNPs colocalize with regulatory elements and are linked to increased expression of CCR1, CCR2 and CCR5 in monocytes and macrophages. As excessive organ infiltration of inflammatory monocytes and macrophages is a hallmark of severe COVID-19, our findings provide a rationale for the genetic association of 3p21.31 variants with elevated risk of hospitalization upon SARS-CoV-2 infection., (© 2022. The Author(s).)
- Published
- 2022
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42. Loss of immune homeostasis in patients with idiopathic pulmonary arterial hypertension.
- Author
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Heukels P, Corneth OBJ, van Uden D, van Hulst JAC, van den Toorn LM, van den Bosch AE, Wijsenbeek MS, Boomars KA, Kool M, and Hendriks RW
- Subjects
- Animals, Familial Primary Pulmonary Hypertension, Homeostasis, Humans, Mice, Connective Tissue Diseases, Heart Defects, Congenital, Hypertension, Pulmonary
- Abstract
Introduction: Autoreactivity against pulmonary vascular structures is thought to be involved in idiopathic pulmonary arterial hypertension (IPAH), but the underlying mechanisms remain poorly understood. We hypothesised that aberrant B-cell activation contributes to IPAH aetiology., Methods: Mice with enhanced B-cell activation due to B-cell-specific overexpression of the B-cell receptor (BCR) signalling molecule Bruton's tyrosine kinase (BTK) were subjected to lung injury and examined for several pulmonary hypertension (PH) indices. Peripheral blood lymphocytes from patients with IPAH (n=13), connective tissue disease-associated PAH (CTD-PAH, n=9), congenital heart disease PAH (n=7), interstitial lung disease associated PH (n=17) and healthy controls (n=19) were characterised by 14-colour flow cytometry., Results: Following pulmonary injury, BTK-overexpressing mice showed prolonged activation of B cells and CXCR5
+ follicular T-helper (Tfh) cells, as well as features of PH development. Patients with CTD-PAH and CHD-PAH displayed reduced proportions of circulating non-switched-memory B cells (p=0.03, p=0.02, respectively). Interestingly, we observed increased BTK protein expression in naive (p=0.007) and memory B-cell subsets of patients with IPAH and CTD-PAH. BTK was particularly high in patients with IPAH with circulating autoantibodies (p=0.045). IPAH patients had low frequencies of circulating CXCR5+ Tfh cells (p=0.005). Hereby, the increased BTK protein expression in B cells was associated with high proportions of Tfh17 (p=0.018) and Tfh17.1 (p=0.007) cells within the circulating Tfh population., Conclusions: Our study shows that pulmonary injury in combination with enhanced B-cell activation is sufficient to induce PH symptoms in mice. In parallel, immune homeostasis in patients with IPAH is compromised, as evidenced by increased BCR signalling and cTfh17 polarisation, indicating that adaptive immune activation contributes to IPAH disease induction or progression., Competing Interests: Competing interests: MSW reports research grants from Boehringer Ingelheim, Hoffmann-La Roche, Galapagos, Respivant outside the submitted work (all paid to her institution)., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)- Published
- 2021
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43. Dietary Fibers: Effects, Underlying Mechanisms and Possible Role in Allergic Asthma Management.
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Verstegen REM, Kostadinova AI, Merenciana Z, Garssen J, Folkerts G, Hendriks RW, and Willemsen LEM
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- Animals, Asthma microbiology, Dietary Fiber therapeutic use, Gastrointestinal Tract microbiology, Humans, Hypersensitivity microbiology, Lung microbiology, Mice, Microbiota immunology, Asthma immunology, Dietary Fiber metabolism, Gastrointestinal Tract immunology, Hypersensitivity immunology, Lung immunology
- Abstract
The prevalence of asthma is increasing, but the cause remains under debate. Research currently focuses on environmental and dietary factors that may impact the gut-lung axis. Dietary fibers are considered to play a crucial role in supporting diversity and activity of the microbiome, as well as immune homeostasis in the gut and lung. This review discusses the current state of knowledge on how dietary fibers and their bacterial fermentation products may affect the pathophysiology of allergic asthma. Moreover, the impact of dietary fibers on early type 2 asthma management, as shown in both pre-clinical and clinical studies, is described. Short-chain fatty acids, fiber metabolites, modulate host immunity and might reduce the risk of allergic asthma development. Underlying mechanisms include G protein-coupled receptor activation and histone deacetylase inhibition. These results are supported by studies in mice, children and adults with allergic asthma. Fibers might also exert direct effects on the immune system via yet to be elucidated mechanisms. However, the effects of specific types of fiber, dosages, duration of treatment, and combination with probiotics, need to be explored. There is an urgent need to further valorize the potential of specific dietary fibers in prevention and treatment of allergic asthma by conducting more large-scale dietary intervention trials.
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- 2021
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44. Adult but not childhood onset asthma is associated with the metabolic syndrome, independent from body mass index.
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de Boer GM, Tramper-Stranders GA, Houweling L, van Zelst CM, Pouw N, Verhoeven GT, Boxma-de Klerk BM, In 't Veen JCCM, van Rossum EFC, Hendriks RW, and Braunstahl GJ
- Subjects
- Adiponectin blood, Adolescent, Adult, Age of Onset, Biomarkers blood, Child, Cross-Sectional Studies, Humans, Interleukin-6 blood, Leptin blood, Male, Middle Aged, Respiratory Function Tests, Asthma metabolism, Asthma physiopathology, Body Mass Index, Metabolic Syndrome metabolism
- Abstract
Introduction: Adult-onset asthma (AOA) is usually more severe compared to childhood onset asthma (CoA). Given the increasing evidence that AoA is associated with obesity, we investigated the relationship of other related metabolic comorbid conditions with AoA compared to CoA., Study Design and Methods: This cross-sectional study compared the metabolic syndrome and lipid derived inflammatory markers in patients with AoA, CoA and age- and sex-matched control subjects without asthma. Participants were asthma patients visiting the outpatient clinic of two teaching hospitals in Rotterdam, The Netherlands. All participants underwent lung function tests, blood tests and physical activity tracking. AoA was defined as asthma age of onset after the age of 18 years. Metabolic syndrome was defined according to the international joint interim statement criteria., Results: Eighty-one participants were included (27 AoA, 25 CoA, 29 controls). AoA was associated with the metabolic syndrome (Odds Ratio = 3.64 95% CI (1.16-11.42) p = 0.03, Nagelkerke R
2 = 0.26), adjusted for age, sex, body mass index and smoking habits. AoA patients had higher median serum IL-6 and leptin-adiponectin (LA) ratio compared to controls (IL-6 (pg/mL): 3.10 [1.11-4.30] vs. 1.13 [0.72-1.58], p = 0.002 and LA ratio (pg/mL): 6.21 [2.45-14.11] vs. 2.24 [0.67-4.71], p = 0.0390). This was not observed in CoA and controls., Conclusion: AoA was associated with the metabolic syndrome and its related pro-inflammatory endocrine and cytokine status. This may suggest adipose tissue derived inflammatory markers play a role in the pathophysiology of AoA., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)- Published
- 2021
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45. Overexpression of Transmembrane TNF Drives Development of Ectopic Lymphoid Structures in the Bone Marrow and B Cell Lineage Alterations in Experimental Spondyloarthritis.
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Kaaij MH, Rip J, Jeucken KCM, Kan YY, van Rooijen CCN, Saris J, Pots D, Frey S, Grootjans J, Schett G, van Duivenvoorde LM, Nolte MA, Hendriks RW, Corneth OBJ, van Hamburg JP, Baeten DLP, and Tas SW
- Subjects
- Animals, Bone Marrow pathology, Cell Differentiation, Cell Lineage, Cells, Cultured, Disease Models, Animal, Humans, Immunoglobulin A metabolism, Membrane Proteins genetics, Mice, Signal Transduction, Tumor Necrosis Factor-alpha genetics, B-Lymphocytes immunology, Bone Marrow metabolism, Germinal Center immunology, Membrane Proteins metabolism, Osteitis immunology, Spondylitis, Ankylosing immunology, T-Lymphocytes immunology, Tertiary Lymphoid Structures immunology, Tumor Necrosis Factor-alpha metabolism
- Abstract
TNF is important in immune-mediated inflammatory diseases, including spondyloarthritis (SpA). Transgenic (tg) mice overexpressing transmembrane TNF (tmTNF) develop features resembling human SpA. Furthermore, both tmTNF tg mice and SpA patients develop ectopic lymphoid aggregates, but it is unclear whether these contribute to pathology. Therefore, we characterized the lymphoid aggregates in detail and studied potential alterations in the B and T cell lineage in tmTNF tg mice. Lymphoid aggregates developed in bone marrow (BM) of vertebrae and near the ankle joints prior to the first SpA features and displayed characteristics of ectopic lymphoid structures (ELS) including presence of B cells, T cells, germinal centers, and high endothelial venules. Detailed flow cytometric analyses demonstrated more germinal center B cells with increased CD80 and CD86 expression, along with significantly more T follicular helper, T follicular regulatory, and T regulatory cells in tmTNF tg BM compared with non-tg controls. Furthermore, tmTNF tg mice exhibited increased IgA serum levels and significantly more IgA
+ plasma cells in the BM, whereas IgA+ plasma cells in the gut were not significantly increased. In tmTNF tg × TNF-RI-/- mice, ELS were absent, consistent with reduced disease symptoms, whereas in tmTNF tg × TNF-RII-/- mice, ELS and clinical symptoms were still present. Collectively, these data show that tmTNF overexpression in mice results in osteitis and ELS formation in BM, which may account for the increased serum IgA levels that are also observed in human SpA. These effects are mainly dependent on TNF-RI signaling and may underlie important aspects of SpA pathology., (Copyright © 2021 by The American Association of Immunologists, Inc.)- Published
- 2021
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46. Bruton's Tyrosine Kinase-Mediated Signaling in Myeloid Cells Is Required for Protective Innate Immunity During Pneumococcal Pneumonia.
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de Porto AP, Liu Z, de Beer R, Florquin S, Roelofs JJTH, de Boer OJ, den Haan JMM, Hendriks RW, van 't Veer C, van der Poll T, and de Vos AF
- Subjects
- Agammaglobulinaemia Tyrosine Kinase genetics, Animals, B-Lymphocytes metabolism, Disease Models, Animal, Female, Humans, Lipopolysaccharides, Lung pathology, Macrophages, Alveolar metabolism, Male, Mice, Mice, Inbred C57BL, Phagocytosis, Pneumonia, Pneumococcal genetics, Signal Transduction, Streptococcus pneumoniae physiology, Teichoic Acids, Agammaglobulinaemia Tyrosine Kinase metabolism, Immunity, Innate, Myeloid Cells immunology, Pneumonia, Pneumococcal immunology, Pneumonia, Pneumococcal metabolism, Sepsis metabolism
- Abstract
Bruton's tyrosine kinase (Btk) is a cytoplasmic kinase expressed in B cells and myeloid cells. It is essential for B cell development and natural antibody-mediated host defense against bacteria in humans and mice, but little is known about the role of Btk in innate host defense in vivo . Previous studies have indicated that lack of (natural) antibodies is paramount for impaired host defense against Streptococcus (S.) pneumoniae in patients and mice with a deficiency in functional Btk. In the present study, we re-examined the role of Btk in B cells and myeloid cells during pneumococcal pneumonia and sepsis in mice. The antibacterial defense of Btk
-/- mice was severely impaired during pneumococcal pneumosepsis and restoration of natural antibody production in Btk-/- mice by transgenic expression of Btk specifically in B cells did not suffice to protect against infection. Btk-/- mice with reinforced Btk expression in MhcII+ cells, including B cells, dendritic cells and macrophages, showed improved antibacterial defense as compared to Btk-/- mice. Bacterial outgrowth in Lysmcre-Btkfl /Y mice was unaltered despite a reduced capacity of Btk-deficient alveolar macrophages to respond to pneumococci. Mrp8cre-Btkfl /Y mice with a neutrophil specific paucity in Btk expression, however, demonstrated impaired antibacterial defense. Neutrophils of Mrp8cre-Btkfl /Y mice displayed reduced release of granule content after pulmonary installation of lipoteichoic acid, a gram-positive bacterial cell wall component relevant for pneumococci. Moreover, Btk deficient neutrophils showed impaired degranulation and phagocytosis upon incubation with pneumococci ex vivo . Taken together, the results of our study indicate that besides regulating B cell-mediated immunity, Btk is critical for regulation of myeloid cell-mediated, and particularly neutrophil-mediated, innate host defense against S. pneumoniae in vivo ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 de Porto, Liu, de Beer, Florquin, Roelofs, de Boer, den Haan, Hendriks, van ‘t Veer, van der Poll and de Vos.)- Published
- 2021
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47. Bruton's tyrosine kinase inhibition induces rewiring of proximal and distal B-cell receptor signaling in mice.
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Rip J, de Bruijn MJW, Neys SFH, Singh SP, Willar J, van Hulst JAC, Hendriks RW, and Corneth OBJ
- Subjects
- Agammaglobulinaemia Tyrosine Kinase genetics, Animals, Antineoplastic Agents pharmacology, B-Lymphocytes cytology, Benzamides pharmacology, Extracellular Signal-Regulated MAP Kinases metabolism, Immunoglobulin M immunology, Lymphoma, B-Cell pathology, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B metabolism, Phosphatidylinositol 3-Kinases metabolism, Phosphorylation genetics, Proto-Oncogene Proteins c-akt metabolism, Pyrazines pharmacology, Signal Transduction immunology, Syk Kinase metabolism, Agammaglobulinaemia Tyrosine Kinase antagonists & inhibitors, B-Lymphocytes immunology, CD79 Antigens metabolism, Phospholipase C gamma metabolism, Receptors, Antigen, B-Cell metabolism
- Abstract
Bruton's tyrosine kinase (Btk) is a crucial signaling molecule in BCR signaling and a key regulator of B- cell differentiation and function. Btk inhibition has shown impressive clinical efficacy in various B-cell malignancies. However, it remains unknown whether inhibition additionally induces changes in BCR signaling due to feedback mechanisms, a phenomenon referred to as BCR rewiring. In this report, we studied the impact of Btk activity on major components of the BCR signaling pathway in mice. As expected, NF-κB and Akt/S6 signaling was decreased in Btk-deficient B cells. Unexpectedly, phosphorylation of several proximal signaling molecules, including CD79a, Syk, and PI3K, as well as the key Btk-effector PLCγ2 and the more downstream kinase Erk, were significantly increased. This pattern of BCR rewiring was essentially opposite in B cells from transgenic mice overexpressing Btk. Importantly, prolonged Btk inhibitor treatment of WT mice or mice engrafted with leukemic B cells also resulted in increased phosho-CD79a and phospho-PLCγ2 in B cells. Our findings show that Btk enzymatic function determines phosphorylation of proximal and distal BCR signaling molecules in B cells. We conclude that Btk inhibitor treatment results in rewiring of BCR signaling, which may affect both malignant and healthy B cells., (© 2021 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)
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- 2021
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48. Bruton's Tyrosine Kinase Inhibition as an Emerging Therapy in Systemic Autoimmune Disease.
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Neys SFH, Rip J, Hendriks RW, and Corneth OBJ
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- Autoimmunity drug effects, B-Lymphocytes drug effects, Clinical Trials as Topic, Humans, Lymphocyte Activation drug effects, Receptors, Antigen, B-Cell metabolism, Signal Transduction drug effects, Agammaglobulinaemia Tyrosine Kinase antagonists & inhibitors, Autoimmune Diseases drug therapy
- Abstract
Systemic autoimmune disorders are complex heterogeneous chronic diseases involving many different immune cells. A significant proportion of patients respond poorly to therapy. In addition, the high burden of adverse effects caused by "classical" anti-rheumatic or immune modulatory drugs provides a need to develop more specific therapies that are better tolerated. Bruton's tyrosine kinase (BTK) is a crucial signaling protein that directly links B-cell receptor (BCR) signals to B-cell activation, proliferation, and survival. BTK is not only expressed in B cells but also in myeloid cells, and is involved in many different signaling pathways that drive autoimmunity. This makes BTK an interesting therapeutic target in the treatment of autoimmune diseases. The past decade has seen the emergence of first-line BTK small-molecule inhibitors with great efficacy in the treatment of B-cell malignancies, but with unfavorable safety profiles for use in autoimmunity due to off-target effects. The development of second-generation BTK inhibitors with superior BTK specificity has facilitated the investigation of their efficacy in clinical trials with autoimmune patients. In this review, we discuss the role of BTK in key signaling pathways involved in autoimmunity and provide an overview of the different inhibitors that are currently being investigated in clinical trials of systemic autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, as well as available results from completed trials., (© 2021. The Author(s).)
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- 2021
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49. Bacterial lysate add-on therapy to reduce exacerbations in severe asthma: A double-blind placebo-controlled trial.
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de Boer GM, Braunstahl GJ, van der Ploeg EK, van Zelst CM, van Bruggen A, Epping G, van Nimwegen M, Verhoeven G, Birnie E, Boxma-de Klerk BM, de Bruijn MJW, Stadhouders R, Hendriks RW, and Tramper-Stranders GA
- Subjects
- Adolescent, Adult, Double-Blind Method, Female, Humans, Male, Middle Aged, Young Adult, Adjuvants, Immunologic therapeutic use, Asthma drug therapy, Asthma immunology, Cell Extracts therapeutic use
- Abstract
Background: Asthma exacerbations are frequently induced by respiratory tract infections (RTIs). Bacterial lysates have been described to possess immune-modulatory effects and reduce RTIs as well as asthma symptoms in children. However, whether bacterial lysates have similar effects in adult asthma patients is unknown., Aims: To reduce asthma exacerbations by add-on bacterial lysate therapy in adults with severe asthma and to characterize the clinical and immune-modulatory effects of this treatment., Methods: Asthma patients (GINA 4) with ≥2 annual exacerbations in the previous year were included. The intervention regimen consisted of OM-85/placebo for 10 consecutive days per month for 6 months during two winter seasons. Primary end-point was the number of severe asthma exacerbations within 18 months. The study was approved by the national and local ethical review board and registered in the Dutch Trial Registry (NL5752). All participants provided written informed consent., Results: Seventy-five participants were included (38 OM-85; 37 placebo). Exacerbation frequencies were not different between the groups after 18 months (incidence rate ratio 1.07, 95%CI [0.68-1.69], p = 0.77). With the use of OM-85, FEV1% increased by 3.81% (p = 0.04) compared with placebo. Nasopharyngeal swabs taken during RTIs detected a virus less frequently in patients using OM-85 compared to placebo (30.5% vs. 48.0%, p = 0.02). In subjects with type 2 inflammation adherent to the protocol (22 OM-85; 20 placebo), a non-statistically significant decrease in exacerbations in the OM-85 group was observed (IRR = 0.71, 95%CI [0.39-1.26], p = 0.25). Immune-modulatory effects included an increase in several plasma cytokines in the OM-85 group, especially IL-10 and interferons. Peripheral blood T- and B cell subtyping, including regulatory T cells, did not show differences between the groups., Conclusion: Although OM-85 may have immune-modulatory effects, it did not reduce asthma exacerbations in this heterogeneous severe adult asthma group. Post hoc analysis showed a potential clinical benefit in patients with type 2 inflammation., (© 2021 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)
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- 2021
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50. Consistent B Cell Receptor Immunoglobulin Features Between Siblings in Familial Chronic Lymphocytic Leukemia.
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Kolijn PM, Muggen AF, Ljungström V, Agathangelidis A, Wolvers-Tettero ILM, Beverloo HB, Pál K, Hengeveld PJ, Darzentas N, Hendriks RW, van Dongen JJM, Rosenquist R, and Langerak AW
- Abstract
Key processes in the onset and evolution of chronic lymphocytic leukemia (CLL) are thought to include chronic (antigenic) activation of mature B cells through the B cell receptor (BcR), signals from the microenvironment, and acquisition of genetic alterations. Here we describe three families in which two or more siblings were affected by CLL. We investigated whether there are immunogenetic similarities in the leukemia-specific immunoglobulin heavy (IGH) and light (IGL/IGK) chain gene rearrangements of the siblings in each family. Furthermore, we performed array analysis to study if similarities in CLL-associated chromosomal aberrations are present within each family and screened for somatic mutations using paired tumor/normal whole-genome sequencing (WGS). In two families a consistent IGHV gene mutational status (one IGHV-unmutated, one IGHV-mutated) was observed. Intriguingly, the third family with four affected siblings was characterized by usage of the lambda IGLV3-21 gene, with the hallmark R110 mutation of the recently described clinically aggressive IGLV3-21
R110 subset. In this family, the CLL-specific rearrangements in two siblings could be assigned to either stereotyped subset #2 or the immunogenetically related subset #169, both of which belong to the broader IGLV3-21R110 subgroup. Consistent patterns of cytogenetic aberrations were encountered in all three families. Furthermore, the CLL clones carried somatic mutations previously associated with IGHV mutational status, cytogenetic aberrations and stereotyped subsets, respectively. From these findings, we conclude that similarities in immunogenetic characteristics in familial CLL, in combination with genetic aberrations acquired, point towards shared underlying mechanisms behind CLL development within each family., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kolijn, Muggen, Ljungström, Agathangelidis, Wolvers-Tettero, Beverloo, Pál, Hengeveld, Darzentas, Hendriks, Dongen, Rosenquist and Langerak.)- Published
- 2021
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