Laura van Dam

All Publications

• Cytotoxic T cell recognition of α-synuclein drives pathogenic immune responses in multiple system atrophy. Proceedings of the National Academy of Sciences of the United States of America Moon, J. S., Moutusy, S. I., Zhang, M., Ndayisaba, A., Rodriguez, D., El Kodsi, D. N., Kuzkina, A., Younis, S., Jahanbani, S., Dam, L. S., Courtney, Y., Netanel, A., Sharpe, O., Miglis, M. G., Steinman, L., Khurana, V., Jahanbani, F., Robinson, W. H. 2026; 123 (14): e2537271123

  Abstract

  Multiple system atrophy (MSA) is a progressive neurologic disease, known as an α-synucleinopathy. There are currently no effective disease-modifying therapies for MSA. While neuroinflammation is a hallmark of MSA, the contribution of adaptive immune mechanisms remains poorly understood. Here, we profiled peripheral and central T cell responses in patients with MSA, in comparison with Parkinson's disease (PD) and healthy control cohorts, using single-cell transcriptomics, flow cytometry, and antigen-specific functional assays. We demonstrated that peripheral T cells from MSA patients are activated and skewed toward cytotoxic and inflammatory phenotypes. Single-cell transcriptomics further revealed clonal expansion of cytotoxic CD8+ T cells expressing GZMB, GNLY, and chemokine and integrin programs associated with brain homing. We also demonstrated that both CD4+ and CD8+ T cells from MSA patients recognize α-synuclein monomers and preformed fibrils in an HLA class I/II-dependent manner, driving proliferation, clonal expansion, and acquisition of cytotoxic features. Consistent with these peripheral responses, CD8+ T cell density was increased in the parietal cortex of postmortem MSA brain tissues, along with cytotoxic (GZMB+, GZMK+) and proinflammatory (IFNγ+) CD8+ T cells. Together, these findings demonstrate that cytotoxic T cells targeting α-synuclein are engaged in MSA, suggesting that their activity may contribute to neuroinflammation and disease progression, and highlighting this immune axis as a candidate therapeutic target for further investigation.

  View details for DOI 10.1073/pnas.2537271123

  View details for PubMedID 41911451

• Antigen-specific B cells cross-present citrullinated proteins to activate CD8 T cells in rheumatoid arthritis Moon, J., Van Dam, L., Smith, M., Donlin, L. T., Sharpe, O., Robinson, W. H. OXFORD UNIV PRESS. 2025

  View details for DOI 10.1093/jimmun/vkaf283.2076

  View details for Web of Science ID 001627485800001

• Characterizing ANCA-specific B Cells in ANCA-associated Vasculitis van Dam, L., Zhang, M., Parsafar, S., Horomanski, A., Rasouli, S., Sharpe, O., van Leeuwen, J., Lanz, T., van Kooten, C., Teng, O., Robinson, W. H. WILEY. 2025: 3288-3292

  View details for Web of Science ID 001671398104004

• Identification of Autoreactive Cytotoxic T Cells in ANCA-Associated Vasculitis van Dam, L., Younis, S., Moon, J., Zhang, M., Parfasar, S., Horomanski, A., Sharpe, O., van Leeuwen, J., Lanz, T., van Kooten, C., Teng, O., Robinson, W. WILEY. 2024: 3781-3785

  View details for Web of Science ID 001331419105286

• ExploriNg DUrable Remission with Rituximab in ANCA-associatEd vasculitis (ENDURRANCE trial): protocol for a randomised controlled trial. BMJ open Dirikgil, E., van Leeuwen, J. R., Bredewold, O. W., Ray, A., Jonker, J. T., Soonawala, D., Remmelts, H. H., van Dam, B., Bos, W. J., van Kooten, C., Rotmans, J., Rabelink, T., Teng, Y. K. 2022; 12 (9): e061339

  Abstract

  Both rituximab (RTX) and cyclophosphamide (CYC) are effectively used in combination with steroids as remission induction therapy for patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Several studies have shown that the effect on achieving (clinical) remission, frequency and severity of relapses is equivalent for both therapies, but there is accumulating data that the long-term safety profile of RTX might outperform CYC. Combination of RTX with low-dose CYC (LD-CYC) has been investigated in only a few uncontrolled cohort studies, in which clinical remission and a favourable immunological state with low relapse rates was quickly achieved. In this randomised controlled trial, we aim to investigate whether the combination treatment (RTX+LD CYC) is superior in comparison to standard care with RTX only.This study is an open-label, multicentre, 1:1 randomised, prospective study for patients with AAV with generalised disease, defined as involvement of major organs, that is, kidneys, lungs, heart and nervous system. In total, 100 patients will be randomised 1:1 to receive either remission induction therapy with standard of care (RTX) or combination treatment (RTX+LD CYC) in addition to steroids and both arms are followed by maintenance with RTX retreatments (tailored to B-cell and ANCA status). Our primary outcome is the number of retreatments needed to maintain clinical remission over 2 years. Secondary outcomes are relevant clinical endpoints, safety, quality of life and immunological responses.This study has received approval of the Medical Ethics Committee of the Leiden University Medical Center (P18.216, NL67515.058.18, date: 7 March 2019). The results of this trial (positive and negative) will be submitted for publication in relevant peer-reviewed publications and the key findings presented at national and international conferences.NCT03942887.

  View details for DOI 10.1136/bmjopen-2022-061339

  View details for PubMedID 36130755

  View details for PubMedCentralID PMC9494556

• Compassionate Use of Avacopan in Difficult-to-Treat Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Kidney international reports van Leeuwen, J. R., Bredewold, O. W., van Dam, L. S., Werkman, S. L., Jonker, J. T., Geelhoed, M., Langeveld, A. P., Remmelts, H. H., van den Broecke, M. M., Ray, A., Rabelink, T. J., Teng, Y. K. 2022; 7 (3): 624-628

  View details for DOI 10.1016/j.ekir.2021.11.036

  View details for PubMedID 35257076

  View details for PubMedCentralID PMC8897689

• PR3-ANCAs predict relapses in ANCA-associated vasculitis patients after rituximab. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association van Dam, L. S., Dirikgil, E., Bredewold, E. W., Ray, A., Bakker, J. A., van Kooten, C., Rabelink, T. J., Teng, Y. K. 2021; 36 (8): 1408-1417

  Abstract

  The primary challenge of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patient care is the early detection of relapses to prevent organ damage and increase survival. Potential biomarkers for relapses are ANCA and B cells, but their predictive value is a matter of debate. Therefore this study investigated how ANCA and B-cell status related to relapses in AAV patients treated with rituximab (RTX) as remission induction (RI).This single-centre cohort study identified 110 ANCA-positive AAV patients treated with RTX between 2006 and 2018. Serial ANCA, CD19+ B-cell status and relapses were assessed >2 years.Patients (31/110) relapsed within 2 years after RTX RI treatment. Patients who achieved and maintained PR3-ANCA negativity (n = 29) had few relapses (3%), while persistent proteinase 3 (PR3)-ANCA positivity (n = 49) and reappearance of PR3-ANCAs (n = 10) associated significantly with more relapses (37%, P = 0.002 and 50%, P = 0.002). Patients with incomplete B-cell depletion (n = 11) had significantly more relapses (54%) as compared with patients with B-cell depletion [n = 76 (26%), P = 0.02]. Also, patients with repopulation of B cells (n = 58) had significantly more relapses (41%) as compared with patients without B-cell repopulation [n = 27 (15%), P = 0.03]. Overall, the absence of PR3- or myeloperoxidase (MPO)-ANCA positivity was highly predictive for remaining relapse-free. In PR3-ANCA-positive patients, 96% of the relapses occurred with persistent or reappearance of PR3-ANCAs and 81% with B-cell repopulation. In MPO-ANCA-positive patients, all relapses were restricted to patients with persistent MPO-ANCAs and B-cell repopulation.Upon RI treatment with RTX in AAV patients, ANCA and B-cell status were predictive of the majority of relapses and specifically their absence strongly predicted a relapse-free status. Therefore the implementation of ANCA and B-cell monitoring could guide therapeutic decision-making to prevent relapses in AAV patients treated with RTX.

  View details for DOI 10.1093/ndt/gfaa066

  View details for PubMedID 32601673

  View details for PubMedCentralID PMC8311572

• Long-term effects of combined B-cell immunomodulation with rituximab and belimumab in severe, refractory systemic lupus erythematosus: 2-year results. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association Kraaij, T., Arends, E. J., van Dam, L. S., Kamerling, S. W., van Daele, P. L., Bredewold, O. W., Ray, A., Bakker, J. A., Scherer, H. U., Huizinga, T. J., Rabelink, T. J., van Kooten, C., Teng, Y. K. 2021; 36 (8): 1474-1483

  Abstract

  Anti-CD20 B-cell depletion has not shown superior efficacy to standard immunosuppression in patients with systemic lupus erythematosus (SLE). Besides trial design, potential explanations are incomplete B-cell depletion in relation to substantial surges in B-cell-activating factor (BAFF). To improve B-cell targeting strategies, we conducted the first study in SLE patients aimed at investigating immunological effects and feasibility of combining rituximab (RTX; anti-CD20) and belimumab (BLM; anti-BAFF).Reported is the long-term follow-up of a Phase 2 proof-of-concept study in 15 patients with SLE including 12 (80%) with lupus nephritis (LN).In 10/15 (67%) patients, a clinical response was observed by achievement of lupus low disease activity state, of which 8 (53%) continued treatment (BLM + ≤7.5 mg prednisolone) for the complete 2 years of follow-up. Five patients (33%) were referred to as 'non-responders' due to persistent LN, major flare or repetitive minor flares. Out of 12 LN patients, 9 (75%) showed a renal response including 8 (67%) complete renal responders. All anti-dsDNA+ patients converted to negative, and both anti-C1q and extractable nuclear antigen autoantibodies showed significant reductions. CD19+ B cells showed a median decrease from baseline of 97% at 24 weeks, with a persistent reduction of 84% up to 104 weeks. When comparing responders with non-responders, CD20+ B cells were depleted significantly less in non-responders and double-negative (DN) B cells repopulated significantly earlier.Combined B-cell targeted therapy with RTX and BLM prevented full B-cell repopulation including DN B cells, with concomitant specific reduction of SLE-relevant autoantibodies. The observed immunological and clinical benefits in a therapy-refractory SLE population prompt further studies on RTX + BLM.

  View details for DOI 10.1093/ndt/gfaa117

  View details for PubMedID 32591783

  View details for PubMedCentralID PMC8311580

• Highly Sensitive Flow Cytometric Detection of Residual B-Cells After Rituximab in Anti-Neutrophil Cytoplasmic Antibodies-Associated Vasculitis Patients. Frontiers in immunology van Dam, L. S., Oskam, J. M., Kamerling, S. W., Arends, E. J., Bredewold, O. W., Berkowska, M. A., van Dongen, J. J., Rabelink, T. J., van Kooten, C., Teng, Y. K. 2020; 11: 566732

  Abstract

  B-cell depletion with rituximab (RTX) is an effective treatment for anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) patients. Nevertheless, relapses are frequent after RTX, often preceded by B-cell repopulation suggesting that residual autoreactive B-cells persist despite therapy. Therefore, this study aimed to identify minimal residual autoimmunity (MRA) in the B-cell compartment of AAV patients treated with RTX.EuroFlow-based highly-sensitive flow cytometry (HSFC) was employed to study B-cell and plasma cell (PC) subsets in-depth in AAV patients before and after RTX treatment. Additionally, peripheral blood mononuclear cells (PBMCs) of these RTX-treated AAV patients were cultured and in vitro stimulated with CpG, IL-2, and IL-21 to induce antibody-secreting cells (ASC). (ANCA)-IgG was measured in these supernatants by ELISA.By employing EuroFlow-based HSFC, we detected circulating CD19+ B-cells at all timepoints after RTX treatment, in contrast to conventional low-sensitive flow cytometry. Pre-germinal center (Pre-GC) B-cells, memory B-cells and CD20+CD138- plasmablasts (PBs) were rapidly and strongly reduced, while CD20-CD138- PrePC and CD20-CD138+ mature (m)PCs were reduced slower and remained detectable. Both memory B-cells and CD20- PCs remained detectable after RTX. Serum ANCA-IgG decreased significantly upon RTX. Changes in ANCA levels strongly correlated with changes in naive, switched CD27+ and CD27- (double-negative) memory B-cells, but not with plasma cells. Lastly, we demonstrated in vitro ANCA production by AAV PBMCs, 24 and 48 weeks after RTX treatment reflecting MRA in the memory compartment of AAV patients.We demonstrated that RTX induced strong reductions in circulating B-cells, but never resulted in complete B-cell depletion. Despite strongly reduced B-cell numbers after RTX, ANCA-specific memory B-cells were still detectable in AAV patients. Thus, MRA is identifiable in AAV and can provide a potential novel approach in personalizing RTX treatment in AAV patients.

  View details for DOI 10.3389/fimmu.2020.566732

  View details for PubMedID 33384685

  View details for PubMedCentralID PMC7770159

• A reverse translational study on the effect of rituximab, rituximab plus belimumab, or bortezomib on the humoral autoimmune response in SLE. Rheumatology (Oxford, England) van Dam, L. S., Osmani, Z., Kamerling, S. W., Kraaij, T., Bakker, J. A., Scherer, H. U., Rabelink, T. J., Voll, R. E., Alexander, T., Isenberg, D. A., van Kooten, C., Teng, Y. K. 2020; 59 (10): 2734-2745

  Abstract

  SLE is a severe autoimmune disease characterized by autoreactive B cells and IC formation, which causes systemic inflammation. B cell-targeted therapy could be a promising treatment strategy in SLE patients; nevertheless, randomized clinical trials have not always been successful. However, some groups have demonstrated beneficial effects in severe SLE patients with off-label rituximab (RTX) with belimumab (BLM), or bortezomib (BTZ), which targeted different B cells subsets. This study assembled sera from SLE cohorts treated with RTX+BLM (n = 15), BTZ (n = 11) and RTX (n = 16) to get an in-depth insight into the immunological effects of these therapies on autoantibodies and IC formation.Autoantibodies relevant for IC formation and the avidity of anti-dsDNA were determined by ELISA. IC-mediated inflammation was studied by complement levels and ex vivo serum-induced neutrophil extracellular trap formation.Reductions in autoantibodies were observed after all approaches, but the spectrum differed depending upon the treatment. Specifically, only RTX+BLM significantly decreased anti-C1q. Achieving seronegativity of ≥1 autoantibody, specifically anti-C1q, was associated with lower disease activity. In all SLE patients, the majority of anti-dsDNA autoantibodies had low avidity. RTX+BLM significantly reduced low-, medium- and high-avidity anti-dsDNA, while RTX and BTZ only significantly reduced medium avidity. IC-mediated inflammation, measured by C3 levels and neutrophil extracellular trap formation, improved after RTX+BLM and RTX but less after BTZ.This study demonstrated the impact of different B cell-targeted strategies on autoantibodies and IC formation and their potential clinical relevance in SLE.

  View details for DOI 10.1093/rheumatology/kez623

  View details for PubMedID 31951278

  View details for PubMedCentralID PMC7516125

• Intrinsically Distinct Role of Neutrophil Extracellular Trap Formation in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Compared to Systemic Lupus Erythematosus. Arthritis & rheumatology (Hoboken, N.J.) van Dam, L. S., Kraaij, T., Kamerling, S. W., Bakker, J. A., Scherer, U. H., Rabelink, T. J., van Kooten, C., Teng, Y. K. 2019; 71 (12): 2047-2058

  Abstract

  Different studies have demonstrated that neutrophil extracellular traps (NETs) may be involved in the pathophysiology of both antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and systemic lupus erythematosus (SLE). AAV and SLE are clinically and pathologically divergent autoimmune diseases with different autoantibodies. However, the respective autoantigens recognized in AAV and SLE have been shown to be an intricate part of NETs. This study aimed to examine whether the mechanisms of NET formation and the composition of NETs are distinct between AAV and SLE.To investigate this hypothesis, healthy neutrophils were stimulated with serum from patients with AAV (n = 80) and patients with SLE (n = 59), and the mechanisms of NET formation and NET composition were compared.Both patients with AAV and patients with SLE had excessive NET formation, which correlated with the extent of disease activity (in AAV r = 0.5, P < 0.0001; in SLE r = 0.35, P < 0.01). Lytic NET formation over several hours was observed in patients with AAV, as compared to rapid (within minutes), non-lytic NET formation coinciding with clustering of neutrophils in patients with SLE. AAV-induced NET formation was triggered independent of IgG ANCAs, whereas SLE immune complexes (ICx) induced NET formation through Fcγ receptor signaling. AAV-induced NET formation was dependent on reactive oxygen species and peptidyl arginine deaminases, and AAV-induced NETs were enriched for citrullinated histones (mean ± SEM 23 ± 2%). In contrast, SLE-induced NETs had immunogenic properties, including binding with high mobility group box chromosomal protein 1 (mean ± SEM 30 ± 3%) and enrichment for oxidized mitochondrial DNA, and were involved in ICx formation.The morphologic features, kinetics, induction pathways, and composition of excessive NET formation are all intrinsically distinct in AAV compared to SLE. Recognizing the diversity of NET formation between AAV and SLE provides a better understanding of the pathophysiologic role of NETs in these different autoimmune diseases.

  View details for DOI 10.1002/art.41047

  View details for PubMedID 31313503

  View details for PubMedCentralID PMC7384043

• Clinical Implications of Excessive Neutrophil Extracellular Trap Formation in Renal Autoimmune Diseases. Kidney international reports van Dam, L. S., Rabelink, T. J., van Kooten, C., Teng, Y. K. 2019; 4 (2): 196-211

  Abstract

  Neutrophil extracellular traps (NETs) are extracellular DNA structures covered with antimicrobial peptides, danger molecules, and autoantigens that can be released by neutrophils. NETs are an important first-line defense mechanism against bacterial, viral, fungal, and parasitic infections, but they can also play a role in autoimmune diseases. NETs are immunogenic and toxic structures that are recognized by the autoantibodies of patients with antineutrophil cytoplasmic antibodies-associated vasculitis (AAV) (i.e., against myeloperoxidase or proteinase-3) and systemic lupus erythematosus (SLE) (i.e., against double-stranded DNA, histones, or nucleosomes). There is cumulating preclinical and clinical evidence that both excessive formation and impaired degradation of NETs are involved in the pathophysiology of AAV and SLE. These autoimmune diseases give rise to 2 clinically and pathologically distinct forms of glomerulonephritis (GN), respectively, crescentic pauci-immune GN and immune complex-mediated GN. Therefore, it is relevant to understand the different roles NET formation can play in the pathophysiology of these most prevalent renal autoimmune diseases. This review summarizes the current concepts on the role of NET formation in the pathophysiology of AAV and SLE, and provides a translational perspective on the clinical implications of NETs, such as potential therapeutic approaches that target NET formation in these renal autoimmune diseases.

  View details for DOI 10.1016/j.ekir.2018.11.005

  View details for PubMedID 30775617

  View details for PubMedCentralID PMC6365354

• A High-throughput Assay to Assess and Quantify Neutrophil Extracellular Trap Formation. Journal of visualized experiments : JoVE Arends, E. J., van Dam, L. S., Kraaij, T., Kamerling, S. W., Rabelink, T. J., van Kooten, C., Teng, Y. K. 2019

  Abstract

  Neutrophil extracellular traps (NETs) are immunogenic extracellular DNA structures that can be released by neutrophils upon a wide variety of triggers. NETs have been demonstrated to serve as an important host defense mechanism that traps and kills microorganisms. On the other hand, they have been implicated in diverse systemic autoimmune diseases. NETs are immunogenic and toxic structures that contain a pool of relevant autoantigens including anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) and systemic lupus erythematosus (SLE). Different forms of NETs can be induced depending on the stimulus. The amount of NETs can be quantified using different techniques including measuring DNA release in supernatants, measuring DNA-complexed with NET-molecules like myeloperoxidase (MPO) or neutrophil elastase (NE), measuring the presence of citrullinated histones by fluorescence microscopy, or flow cytometric detection of NET-components which all have different features regarding their specificity, sensitivity, objectivity, and quantity. Here is a protocol to quantify ex vivo NET formation in a highly-sensitive, high-throughput manner by using three-dimensional immunofluorescence confocal microscopy. This protocol can be applied to address various research questions about NET formation and degradation in health and disease.

  View details for DOI 10.3791/59150

  View details for PubMedID 30774133

• Excessive neutrophil extracellular trap formation in ANCA-associated vasculitis is independent of ANCA. Kidney international Kraaij, T., Kamerling, S. W., van Dam, L. S., Bakker, J. A., Bajema, I. M., Page, T., Brunini, F., Pusey, C. D., Toes, R. E., Scherer, H. U., Rabelink, T. J., van Kooten, C., Teng, Y. K. 2018; 94 (1): 139-149

  Abstract

  Neutrophil extracellular traps (NETs) are auto-antigenic strands of extracellular DNA covered with myeloperoxidase (MPO) and proteinase3 (PR3) that can be a source for the formation of anti-neutrophil cytoplasmic autoantibodies (ANCAs). The presence of NETs was recently demonstrated in renal tissue of patients with ANCA-associated vasculitis (AAV). NET formation was enhanced in AAV, suggesting that MPO-ANCA could trigger NET formation, supporting a vicious circle placing NETs in the center of AAV pathogenesis. Here we investigated NET formation in 99 patients with AAV by a novel highly sensitive and automated assay. There was a significant excess of ex vivo NET formation in both MPO-ANCA- and PR3-ANCA-positive patients with AAV compared to healthy individuals. Excessive NET formation did not correlate with serum ANCA levels. Likewise, immunoglobulin G depletion had no effect on excessive NET formation in patients with AAV, indicating an ANCA-independent process. Next, we explored the relation of excessive NET formation to clinical disease in ten patients with AAV and showed that excessive NET formation was predominantly found during active disease, more so than during remission. Excessive NET formation was found in patients with AAV hospitalized for disease relapse but not during severe infection. Thus, excessive NET formation in AAV is independent of ANCA, and an excess of ex vivo NET formation was related to active clinical disease in patients with AAV and a marker of autoimmunity rather than infection.

  View details for DOI 10.1016/j.kint.2018.01.013

  View details for PubMedID 29606398

• Expression and clinical association of programmed cell death-1, programmed death-ligand-1 and CD8+ lymphocytes in primary sarcomas is subtype dependent. Oncotarget van Erp, A. E., Versleijen-Jonkers, Y. M., Hillebrandt-Roeffen, M. H., van Houdt, L., Gorris, M. A., van Dam, L. S., Mentzel, T., Weidema, M. E., Savci-Heijink, C. D., Desar, I. M., Merks, H. H., van Noesel, M. M., Shipley, J., van der Graaf, W. T., Flucke, U. E., Meyer-Wentrup, F. A. 2017; 8 (41): 71371-71384

  Abstract

  In order to explore the potential of immune checkpoint blockade in sarcoma, we investigated expression and clinical relevance of programmed cell death-1 (PD-1), programmed death ligand-1 (PD-L1) and CD8 in tumors of 208 sarcoma patients. Primary untreated osteosarcoma (n = 46), Ewing sarcoma (n = 32), alveolar rhabdomyosarcoma (n = 20), embryonal rhabdomyosarcoma (n = 77), synovial sarcoma (n = 22) and desmoplastic small round cell tumors (DSRCT) (n = 11) were examined immunohistochemically. PD-L1 expression was predominantly detected in alveolar and embryonal rhabdomyosarcomas (15% and 16%, respectively). In the alveolar subtype PD-L1 expression was associated with better overall, event-free and metastases-free survival. PD-1 expression on lymphocytes was predominantly seen in synovial sarcomas (18%). High levels of CD8+ lymphocytes were predominantly detected in osteosarcomas (35%) and associated with worse event-free survival in synovial sarcomas. Ewing sarcoma and DSRCTs showed PD-1 on tumor cells instead of on tumor infiltrating lymphocytes. Overall, expression and clinical associations were found to be subtype dependent. For the first time PD-1 expression on Ewing sarcoma (19%) and DSRCT (82%) tumor cells was described.

  View details for DOI 10.18632/oncotarget.19071

  View details for PubMedID 29050367

  View details for PubMedCentralID PMC5642642

• Deficiency of Nuclear Receptor Nur77 Aggravates Mouse Experimental Colitis by Increased NFkB Activity in Macrophages PLOS ONE Hamers, A. A. J., van Dam, L., Duarte, J., Vos, M., Marinkovic, G., van Tiel, C. M., Meijer, S. L., van Stalborch, A., Huveneers, S., Velde, A., de Jonge, W. J., de Vries, C. J. M. 2015; 10 (8): e0133598

  Abstract

  Nuclear receptor Nur77, also referred to as NR4A1 or TR3, plays an important role in innate and adaptive immunity. Nur77 is crucial in regulating the T helper 1/regulatory T-cell balance, is expressed in macrophages and drives M2 macrophage polarization. In this study we aimed to define the function of Nur77 in inflammatory bowel disease. In wild-type and Nur77-/- mice, colitis development was studied in dextran sodium sulphate (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced models. To understand the underlying mechanism, Nur77 was overexpressed in macrophages and gut epithelial cells. Nur77 protein is expressed in colon tissues from Crohn's disease and Ulcerative colitis patients and colons from colitic mice in inflammatory cells and epithelium. In both mouse colitis models inflammation was increased in Nur77-/- mice. A higher neutrophil influx and enhanced IL-6, MCP-1 and KC production was observed in Nur77-deficient colons after DSS-treatment. TNBS-induced influx of T-cells and inflammatory monocytes into the colon was higher in Nur77-/- mice, along with increased expression of MCP-1, TNFα and IL-6, and decreased Foxp3 RNA expression, compared to wild-type mice. Overexpression of Nur77 in lipopolysaccharide activated RAW macrophages resulted in up-regulated IL-10 and downregulated TNFα, MIF-1 and MCP-1 mRNA expression through NFκB repression. Nur77 also strongly decreased expression of MCP-1, CXCL1, IL-8, MIP-1α and TNFα in gut epithelial Caco-2 cells. Nur77 overexpression suppresses the inflammatory status of both macrophages and gut epithelial cells and together with the in vivo mouse data this supports that Nur77 has a protective function in experimental colitis. These findings may have implications for development of novel targeted treatment strategies regarding inflammatory bowel disease and other inflammatory diseases.

  View details for DOI 10.1371/journal.pone.0133598

  View details for Web of Science ID 000358942700017

  View details for PubMedID 26241646

  View details for PubMedCentralID PMC4524678

• The role of programmed cell death-1 (PD-1) and its ligands in pediatric cancer. Pediatric blood & cancer van Dam, L. S., de Zwart, V. M., Meyer-Wentrup, F. A. 2015; 62 (2): 190-197

  Abstract

  Programmed cell death-1 (PD-1) and its ligands, PD-L1 and PD-L2 maintain self-tolerance and modulate physiological immune responses. Recently, targeting the PD-1/PD-L1 pathway with blocking antibodies has emerged as a potentially promising approach to treat advanced cancers in adult patients. Since tumor PD-L1 expression is currently considered the most important predictive biomarker for successful checkpoint blockade, we summarize expression data for the most common tumors of childhood. Additionally, we give an introduction into PD-1 function in the immune system to then focus on PD-1 mediated tumor immune escape. Pediatr Blood Cancer 2015;62:190-197. © 2014 Wiley Periodicals, Inc.

  View details for DOI 10.1002/pbc.25284

  View details for PubMedID 25327979