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Introduction
Publications
Publications (183)
Objective:
This study was undertaken to identify key disease pathways driving conventional dendritic cell (cDC) alterations in systemic sclerosis (SSc).
Methods:
Transcriptomic profiling was performed on peripheral blood CD1c+ cDCs (cDC2s) isolated from 12 healthy donors and 48 patients with SSc, including all major disease subtypes. We performe...
Background
Adolescents with chronic disease are often exposed to inflammatory, metabolic, and hemodynamic risk factors for early atherosclerosis. Since postmortem studies have shown that atherogenesis starts in the aorta, the CDACD (Cardiovascular Disease in Adolescents with Chronic Disease) study investigated preclinical aortic atherosclerosis in...
Introduction
Plasmacytoid dendritic cells (pDCs) are the main producers of type I interferon (IFN) in SLE. pDCs express high secretory carrier membrane protein 5 (SCAMP5). Recent work in transfected HEK cells connects SCAMP5 to the type I IFN secretory pathway. To further study the role of SCAMP5 in IFNα secretion by pDCs, we focused on the subcell...
Objectives
To identify key disease pathways driving conventional dendritic cell (cDC) alterations in Systemic Sclerosis (SSc).
Methods
Transcriptomic profiling was performed on peripheral blood CD1c+ cDCs (cDC2s) isolated from 12 healthy donors and 48 SSc patients with all major disease subtypes. Differential expression analysis comparing the diff...
Background
Neuroblastoma (NBL) is an embryonic tumor originating from neural crest precursor cells. It is one of the most prevalent pediatric solid tumors, with an estimated five-year progression free survival of less than 50% in stage-4 patients. While T-cell mediated therapies, including immune checkpoint inhibition, have marked activity against...
Objectives
While physicians are often confronted with immunoglobulin A (IgA) deficiency in children with recurrent infections, the clinical relevance of this finding is unclear. Large-scale studies examining the significance of IgA deficiency in children are hampered by differences in techniques for measuring IgA and the physiological increase of I...
Invariant Natural Killer T (iNKT) cells respond to the ligation of lipid antigen-CD1d complexes via their T-cell receptor and are implicated in various immunometabolic diseases. We considered that immunometabolic factors might affect iNKT cell function. To this end, we investigated iNKT cell phenotype and function in a cohort of adolescents with ch...
The main complication of hemophilia A treatment is the development of neutralizing antibodies (inhibitors) against factor VIII (FVIII). Immune tolerance induction (ITI) is the prescribed treatment for inhibitor eradication, although its working mechanism remains unresolved. To clarify this mechanism, we compared blood samples of hemophilia A patien...
Background: Coronavirus disease of 2019 (COVID-19) is associated with a prothrombotic state and a high incidence of thrombotic event(s) (TE). Objectives: To study platelet reactivity in hospitalized COVID-19 patients and determine a possible association with the clinical outcomes thrombosis and all-cause mortality. Methods: Seventy nine hospitalize...
After initial introduction for B-cell lymphomas as adjuvant therapies to established cancer treatments, immune checkpoint inhibitors and other immunotherapies are now integrated in mainstream regimens, both in adult and pediatric patients. We here provide an overview of the current status of combination therapies for B-cell lymphoma, by in-depth an...
Objectives
Studies that compare immune cell phenotype and function in psoriatic arthritis (PsA) versus psoriasis limited to cutaneous involvement (Pso) are scarce, yet critical to understand the pathogenesis of PsA.
Methods
First, in‐depth immunophenotyping of different T cell and Dendritic cell subsets was performed in PsA, Pso, axial spondyloart...
Background
Signals at the contact site of antigen-presenting cells (APCs) and T cells help orchestrate the adaptive immune response. CD155 on APCs can interact with the stimulatory receptor DNAM1 or inhibitory receptor TIGIT on T cells. The CD155/DNAM1/TIGIT axis is under extensive investigation as immunotherapy target in inflammatory diseases incl...
RNA sequencing and DNA methylomic profiling were performed after differentiating monocytes for 6 days into moDCs with/without CXCL4 presence. We show that CXCL4 downregulates genes associated with tolerogenicity in DCs including C1Q. Expression profiles of C1Q genes were negatively correlated with their DNA methylation profiles and with immunogenic...
Autoimmune rheumatic diseases (AIRD) are categorized seropositive or seronegative, dependent on the presence or absence of specific autoreactive antibodies, including rheumatoid factor and anti‐citrullinated protein antibodies. Autoantibody‐based diagnostics have proven helpful in patient care, not only for diagnosis, but also for monitoring of dis...
Fibrosis is a condition shared by numerous inflammatory diseases. Our incomplete understanding of the molecular mechanisms underlying fibrosis has severely hampered effective drug development. CXCL4 is associated with the onset and extent of fibrosis development in multiple inflammatory and fibrotic diseases. Here, we used monocyte-derived cells as...
Objective:
To identify novel serum proteins involved in the pathogenesis of PsA as compared with healthy controls, psoriasis (Pso) and AS, and to explore which proteins best correlated to major clinical features of the disease.
Methods:
A high-throughput serum biomarker platform (Olink) was used to assess the level of 951 unique proteins in seru...
Ankylosing spondylitis (AS) is associated with autoantibody production to Class II MHC‐associated invariant chain peptide, CD74/CLIP. In this study, we considered that anti‐CD74/CLIP autoantibodies present in sera from AS might recognize CD74 degradation products that accumulate upon deficiency of the enzyme signal peptide peptidase‐like 2A (SPPL2a...
Dendritic cells (DC) have the unique capacity to activate naïve T cells by presenting T cell receptor specific peptides from exogenously acquired antigens bound to Major Histocompatibility Complex (MHC) molecules. MHC molecules are displayed on the DC plasma membrane as well as on extracellular vesicles (EV) that are released by DC, and both have a...
Thrombocytopenia is a common complication of influenza virus infection, and its severity predicts the clinical outcome of critically ill patients. The underlying cause(s) remain incompletely understood. In this study, in patients with an influenza A/H1N1 virus infection, viral load and platelet count correlated inversely during the acute infection...
Objectives:
Granzymes are serine proteases involved in eliminating tumour cells and virally infected cells. In addition, extracellular granzyme levels are elevated in inflammatory conditions, including several types of infection and autoimmune diseases, such as rheumatoid arthritis (RA). While GrA and GrB have been associated with RA, a role for t...
Psoriatic arthritis (PsA) is a heterogeneous, chronic inflammatory musculoskeletal disorder that affects ~0.1% of the population. PsA may severely impact quality-of-life and constitutes a significant economic burden on our health care system. While early effective treatment is deemed essential to prevent irreversible joint damage and functional imp...
Fibrosis is a condition shared by numerous inflammatory diseases. Our incomplete understanding of the molecular mechanisms underlying fibrosis has severely hampered effective drug development. CXCL4 is associated with the onset and extent of fibrosis development in systemic sclerosis, a prototypic inflammatory and fibrotic disease. Here, we integra...
The chemokine CXCL4 has been implicated in several immune diseases. Exposure of monocyte-derived dendritic cells (moDCs) to CXCL4 potentiates the production of inflammatory cytokines in the presence of TLR3 or TLR7/8 agonists. Here we investigated the transcriptional and post-transcriptional events underlying the augmented inflammatory responses in...
Introduction: Nowadays, one of the most serious treatment complications in haemophilia A is the formation of neutralizing antibodies against coagulation factor VIII (FVIII). These so-called inhibitors develop in about 30% of all patients with severe haemophilia A. Once formed, inhibitors reduce FVIII efficacy in blood coagulation, which has a negat...
Background:
Natural killer T (NKT) cells in adipose tissue (AT) contribute to whole body energy homeostasis.
Results:
Inhibition of the glucosylceramide synthesis in adipocytes impairs iNKT cell activity.
Conclusion:
Glucosylceramide biosynthesis pathway is important for endogenous lipid antigen activation of iNKT cells in adipocytes.
Signifi...
Extracellular vesicles (EV) that are released by immune cells are studied intensively for their functions in immune regulation and are scrutinized for their potential in human immunotherapy, for example against cancer. In our search for signals that stimulate the release of functional EV by dendritic cells we observed that LPS-activated human monoc...
Pediatric neuroblastoma tumors are notorious nonimmunogenic cancers. In contrast to adult tumor types, neuroblastoma cells express low MHC-1, a derivative of its embryonic cell origin expressing little MHC-1. We here address the role of the nuclear factor kappa B (NFκB) pathway in controlling MHC-1 expression in embryonic neural crest cells, during...
Neuroblastoma is the second most common tumor in children. The cause of neuroblastoma is thought to lie in aberrant development of embryonic neural crest cells and is accompanied by low MHC-1 expression and suppression of the NF-κB transcription factor, thereby gearing cells toward escape from immunosurveillance. Here, we assess regulation of the M...
Background
Aberrant accumulation of extracellular matrix (ECM) in multiple organs or fibrosis is one of the three hallmarks that characterises the pathogenesis of systemic sclerosis (SSc), together with immune dysregulation and small vessel vasculopathy. Recent studies have shown that CXCL4 (Chemokine CXC motif ligand 4) levels are increased in pat...
Background
Few studies have compared the immune cell phenotype or function from patients with psoriatic arthritis (PsA) to patients with psoriasis limited to cutaneous involvement (Pso). Head-to-head comparisons of the immune cells in PsA and Pso can provide essential insights into the link between epithelial/cutaneous disease and rheumatic disease...
Invariant natural killer T (iNKT) cells are lipid-reactive T cells with profound immunomodulatory potential. They are unique in their restriction to lipid antigens presented in CD1d molecules, which underlies their role in lipid-driven disorders such as obesity and atherosclerosis. In this review, we discuss the contribution of iNKT cell activation...
Background:
PSTPIP1 is a cytosolic adaptor protein involved with T-cell activation, differentiation, and migration. Upon cognate T-cell contact, PSTPIP1 is recruited to surface-expressed CD2, where it regulates f-actin remodeling. An immune synapse (IS) is thereby rapidly formed, consisting of TCR clusters surrounded by a ring of adhesion molecule...
At first sight the bleeding disorder hemophilia A seems to have little in common with immune disorders, but immunology research intersects with other disciplines including hematology.
Nowadays, the most important complication in the treatment of hemophilia A is the development of neutralizing antibodies (inhibitors) against exogenous administered f...
Primary immunodeficiency disorders (PIDs) convey increased susceptibility to infections and sometimes to malignancies, particularly lymphomas. Such cancer development can be contributed by immune impairments resulting in weakened immunological surveillance against (pre)malignant cells and oncogenic viruses. Molecular defects in PID-patients are the...
Viruses may interfere with the MHC class I antigen presentation pathway in order to avoid CD8+ T cell-mediated immunity. A key target within this pathway is the peptide transporter TAP. This transporter plays a central role in MHC class I-mediated peptide presentation of endogenous antigens. In addition, TAP plays a role in antigen cross-presentati...
The global obesity epidemic and its associated co-morbidities, including type 2 diabetes, cardiovascular disease and certain types of cancers, have drawn attention to the pivotal role of adipocytes in health and disease. Besides their ‘classical’ function in energy storage and release, adipocytes interact with adipose-tissue resident immune cells,...
Background
CXCL4 is a chemokine produced by activated platelets and immune cells. Several studies have reported that CXCL4 plays a critical role on physiological processes since it affects the proliferation and maturation of megakaryocytic and hematopoietic progenitor cells, regulates coagulation and wound healing, displays anti-tumoral and angiost...
Chemokines have been shown to play immune-modulatory functions unrelated to steering cell migration. CXCL4 is a chemokine abundantly produced by activated platelets and immune cells. Increased levels of circulating CXCL4 are associated with immune-mediated conditions, including systemic sclerosis. Considering the central role of dendritic cells (DC...
Autoinflammatory disorders (AID) are a heterogeneous group of diseases, characterized by an unprovoked innate immune response, resulting in recurrent or ongoing systemic inflammation and fever(1-3) . Inflammasomes are protein complexes with an essential role in pyroptosis and the caspase-1-mediated activation of the proinflammatory cytokines IL-1β,...
Patients who suffer from autoinflammatory disease (AID) exhibit seemingly uncontrolled release of interleukin (IL)-1β. The presence of this inflammatory cytokine triggers immune activation in absence of pathogens and foreign material. The mechanisms that contribute to 'sterile inflammation' episodes in AID patients are not fully understood, althoug...
Granzymes are serine proteases involved in killing of tumor cells and virally infected cells. However, granzymes are also upregulated in blood under inflammatory conditions and contribute to cytokine release and processing. Here, we show that granzyme M (GrM) and to a lesser extent GrK are transiently elevated in the circulation following LPS admin...
Primary immunodeficiencies (PIDs) are a heterogeneous group of immune-related diseases. PIDs develop due to defects in gene-products that have consequences to immune cell function. A number of PID-proteins is involved in the remodeling of filamentous actin (f-actin) to support the generation of a contact zone between the antigen-specific T cell and...
In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring au...
Neuroblastoma is the most common solid tumor in children, with mortality rates after conventional treatments still being 80% for high-risk (stage 4) disease. There is a clear medical need for development of new treatment strategies. Recently, immunotherapy has gained traction. However, restrained MHC I expression evades recognition of neuroblastoma...
Vaccines based on nonspreading Rift Valley fever virus (NSR) induce strong humoral and robust cellular immune responses with pronounced Th1 polarisation. The present work was aimed to gain insight into the molecular basis of NSR-mediated immunity. Recent studies have demonstrated that wild-type Rift Valley fever virus efficiently targets and replic...
Inflammatory Bowel Disease (IBD) is a multifactorial disorder involving dysregulation of the immune response and bacterial translocation through the intestinal mucosal barrier. Previously, we have shown that activation of the bile acid sensor Farnesoid X Receptor (FXR), which belongs to the family of nuclear receptors, improves experimental intesti...
Lipid overload and adipocyte dysfunction are key to the development of insulin resistance and can be induced by a high fat diet (HFD). CD1d-restricted iNKT cells have been proposed as mediators between lipid overload and insulin resistance, but recent studies found decreased iNKT cell numbers and marginal effects of iNKT cell depletion on insulin r...
Autologous hematopoietic stem cell transplantation (HSCT) is increasingly considered for patients with severe autoimmune diseases whose prognosis is poor with standard treatments. Regulatory T cells (Tregs) are thought to be important for disease remission after HSCT. However, eliciting the role of donor and host Tregs in autologous HSCT is not pos...
Neuroblastoma is the most common solid tumor in children with an estimated 5-year progression free survival of 20-40% in stage 4 disease. Neuroblastoma actively avoids recognition by natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Although immunotherapy has gained traction for neuroblastoma treatment, these immune escape mechanisms re...
Mutations in STAT3 have recently been shown to cause autoimmune diseases through increased lymphoproliferation. We describe a novel Pro471Arg STAT3 mutation in a patient with multiple autoimmune diseases, causing hyperactivation of the Th17 pathway. We show that IL-17 production by primary T cells was enhanced and could not be further increased by...
Autoinflammatory disorders (AID) are characterized by chronic or recurrent systemic inflammation associated with various clinical presentations. It is a genetically heterogeneous group of diseases. Recently, gain of function mutations in NLRC4 have been described to be associated with autoinflammatory disease. Here, we report a novel NLRC4 mutation...
Innate lymphoid cells (ILCs) are a recently discovered group of cells essential to epithelial homeostasis and implicated in psoriasis (Pso) pathogenesis, yet have never been reported in psoriatic arthritis (PsA).
ILC classes and subsets were characterized in the peripheral blood (PB) of healthy controls (HC), Pso, PsA and in synovial fluid (SF) of...
Replicon particles of Rift Valley fever virus, referred to as nonspreading RVFV (NSR), are intrinsically safe and highly immunogenic. Here, we demonstrate that NSR-infected human dendritic cells can activate CD8+ T-cells in vitro, and that prophylactic and therapeutic vaccination of mice with NSR encoding a tumor associated CD8 peptide can control...
Neuroblastoma is the most common solid tumor in pediatric patients, with a clear unmet need as survival rates are <20% for stage IV disease. As adjuvant immunotherapy is considered to have additional anti-tumor activity we aim to increase cytotoxic T lymphocyte (CTL)-mediated immune surveillance in neuroblastoma patients by administration of a dend...
The poor survival rates of refractory/relapsed acute myeloid leukemia (AML) patients after hematopoietic cell transplantation (HCT) requires the development of additional immune therapeutic strategies. As the elicitation of tumor-antigen specific cytotoxic T lymphocytes (CTLs) is associated with reduced relapses and enhanced survival, enhanced prim...
Rheumatic diseases can be divided in two groups, autoinflammatory and autoimmune disorders. The clinical presentation of both types of diseases overlap, but the pathological pathways underlying rheumatic autoinflammation and autoimmunity are distinct and are the subject of ongoing research. There are a number of ways in which these groups of diseas...
People suffering from autoinflammatory disease (AID) have recurring sterile inflammation due to dysregulated inflammasome activation. Although certain genes have been associated with several AIDs, the molecular underpinnings of seemingly spontaneous inflammation are not well understood. Emerging data now suggest that mitochondrial reactive oxygen s...
Common Variable Immunodeficiency (CVID) is the most prevalent primary antibody deficiency, and characterized by defective generation of high-affinity antibodies. Patients have therefore increased risk to recurrent infections of the respiratory and intestinal tract. Development of high-affinity antigen-specific antibodies involves two key actions of...
Neuroblastoma is the most common extracranial solid tumor in children, causing 12% of all pediatric cancer mortality. Neuroblastoma specific T-cells have been detected in patients, but usually fail to attack and eradicate the tumors. Tumor immune evasion may thus play an important role in neuroblastoma pathogenicity. Recent research in adult cancer...
