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De Bruin A.M.,Academical Medical Center | Libregts S.F.,Academical Medical Center | Libregts S.F.,Sanquin Research and Landsteiner Laboratory | Valkhof M.,Erasmus Medical Center | And 4 more authors.
Blood | Year: 2012

Steady-state hematopoiesis is altered on infection, but the cellular and molecular mechanisms driving these changes are largely unknown. Modulation of hematopoiesis is essential to increase the output of the appropriate type of effector cell required to combat the invading pathogen. In the present study, we demonstrate that the pro-inflammatory cytokine IFNγ is involved in orchestrating inflammation-induced myelopoiesis. Using both mouse models and in vitro assays, we show that IFNγ induces the differentiation of monocytes over neutrophils at the level of myeloid progenitors. Infection with lymphocytic choriomeningitis virus induces monopoiesis in wild-type mice, but causes increased neutrophil production in IFNγ -/- mice. We demonstrate that IFNγ enhances the expression of the monopoiesis-inducing transcription factors IRF8 and PU.1 in myeloid progenitor cells, whereas it reduces G-CSF-driven neutrophil differentiation via a SOCS3- dependent inhibition of STAT3 phosphorylation. These results establish a critical role for IFNγ in directing monocyte versus neutrophil development during immune activation. © 2012 by The American Society of Hematology.


Pouw M.F.,Jan van Breemen Research Institute Reade | Pouw M.F.,Sanquin Research and Landsteiner Laboratory | Krieckaert C.L.,Jan van Breemen Research Institute Reade | Nurmohamed M.T.,Jan van Breemen Research Institute Reade | And 5 more authors.
Annals of the Rheumatic Diseases | Year: 2015

Objective: To determine a concentration-effect curve of adalimumab in rheumatoid arthritis (RA) patients taking into account the effect of methotrexate (MTX) on concentration and effect and to identify a therapeutic range for adalimumab concentrations. Methods: In a prospective observational cohort study, 221 consecutive patients with RA were treated with 40 mg adalimumab subcutaneously every other week. The relationship between adalimumab trough level and clinical efficacy after 28 weeks of follow-up was determined in a concentration-effect curve. A receiver-operator characteristics (ROC) curve established a therapeutic cut-off concentration. The effect of MTX on adalimumab trough levels was shown by dividing patients that are and are not concomitantly using MTX in the concentration-effect curve and a concentration table. Results: Clinical efficacy improved with increasing adalimumab concentration and reached a maximum (mean disease activity score in 28 joints improvement of 2) with levels between 5-8 μg/mL. Levels exceeding 8 μg/mL were illustrated to have no additional beneficial effect on disease activity. The ROC curve showed an area under the curve of 0.695 (95% CI 0.626 to 0.764) for European League Against Rheumatism response and adalimumab levels: good responders versus non-responders and moderate responders. A cut-off of 5 μg/mL had a sensitivity of 91% and a specificity of 43%. Adalimumab levels are influenced by concomitant MTX use: patients on adalimumab monotherapy had a median adalimumab level of 4.1 μg/mL (IQR 1.3-7.7), whereas patients concomitantly taking MTX had a median level of 7.4 μg/mL (IQR 5.3-10.6, p<0.001). Conclusions: Adalimumab trough levels in a range of 5-8 μg/mL are sufficient to reach adequate clinical response. These levels are influenced substantially by concomitant MTX use.


Nair-Gupta P.,Mount Sinai School of Medicine | Baccarini A.,Mount Sinai School of Medicine | Tung N.,Mount Sinai School of Medicine | Seyffer F.,Goethe University Frankfurt | And 10 more authors.
Cell | Year: 2014

Adaptation of the endoplasmic reticulum (ER) pathway for MHC class I (MHC-I) presentation in dendritic cells enables cross-presentation of peptides derived from phagocytosed microbes, infected cells, or tumor cells to CD8 T cells. How these peptides intersect with MHC-I molecules remains poorly understood. Here, we show that MHC-I selectively accumulate within phagosomes carrying microbial components, which engage Toll-like receptor (TLR) signaling. Although cross-presentation requires Sec22b-mediated phagosomal recruitment of the peptide loading complex from the ER-Golgi intermediate compartment (ERGIC), this step is independent of TLR signaling and does not deliver MHC-I. Instead, MHC-I are recruited from an endosomal recycling compartment (ERC), which is marked by Rab11a, VAMP3/cellubrevin, and VAMP8/endobrevin and holds large reserves of MHC-I. While Rab11a activity stocks ERC stores with MHC-I, MyD88-dependent TLR signals drive IκB-kinase (IKK)2-mediated phosphorylation of phagosome-associated SNAP23. Phospho-SNAP23 stabilizes SNARE complexes orchestrating ERC-phagosome fusion, enrichment of phagosomes with ERC-derived MHC-I, and subsequent cross-presentation during infection. PaperFlick © 2014 Elsevier Inc.


Stapleton N.M.,Sanquin Research and Landsteiner Laboratory | Einarsdottir H.K.,Sanquin Research and Landsteiner Laboratory | Stemerding A.M.,Gelre Ziekenhuizen | Vidarsson G.,Sanquin Research and Landsteiner Laboratory
Immunological Reviews | Year: 2015

The neonatal Fc receptor, FcRn, is best known for its role in transporting IgG in various tissues, providing newborns with humoral immunity, and for prolonging the half-life of IgG. Recent findings implicate the involvement of FcRn in a far wider range of biological and immunological processes, as FcRn has been found to bind and extend the half-life of albumin; to be involved in IgG transport and antigen sampling at mucosal surfaces; and to be crucial for efficient IgG-mediated phagocytosis. Herein, the function of FcRn will be reviewed, with emphasis on its recently documented significance for IgG polymorphisms affecting the half-life and biodistribution of IgG3, on its role in phagocyte biology, and the subsequent role for the presentation of antigens to lymphocytes. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


O'Neill A.S.G.,King's College London | Van Den Berg T.K.,Sanquin Research and Landsteiner Laboratory | Mullen G.E.D.,King's College London
Immunology | Year: 2013

Sialoadhesin (Sn, also known as Siglec-1 and CD169) is a macrophage-restricted cell surface receptor that is conserved across mammals. Sn is a member of the sialic acid-binding IgG-like lectin (Siglec) family of proteins characterized by affinity to specifically sialylated ligands, and under normal conditions is expressed on subsets of macrophages in secondary lymphoid tissues, such as lymph node and spleen. However, Sn-positive macrophages can also be found in a variety of pathological conditions, including (autoimmune) inflammatory infiltrates and tumours. Sn has been shown to contribute to sialylated pathogen uptake, antigen presentation and lymphocyte proliferation, and to influence both immunity and tolerance. This review presents Sn as a macrophage-specific marker of inflammation and immunoregulation with the potential to becoming an important biomarker for immunologically active macrophages and a target for therapy. © 2012 Blackwell Publishing Ltd.


Sesarman A.,Albert Ludwigs University of Freiburg | Vidarsson G.,Sanquin Research and Landsteiner Laboratory | Sitaru C.,Albert Ludwigs University of Freiburg
Cellular and Molecular Life Sciences | Year: 2010

Therapy approaches based on lowering levels of pathogenic autoantibodies represent rational, effective, and safe treatment modalities of autoimmune diseases. The neonatal Fc receptor (FcRn) is a major factor regulating the serum levels of IgG antibodies. While FcRn-mediated halflife extension is beneficial for IgG antibody responses against pathogens, it also prolongs the serum half-life of IgG autoantibodies and thus promotes tissue damage in autoimmune diseases. In the present review article, we examine current evidence on the relevance of FcRn in maintaining high autoantibody levels and discuss FcRntargeted therapeutic approaches. Further investigation of the FcRn-IgG interaction will not only provide mechanistic insights into the receptor function, but should also greatly facilitate the design of therapeutics combining optimal pharmacokinetic properties with the appropriate antibody effector functions in autoimmune diseases. © Springer Basel AG 2010.


van de Vijver E.,University of Amsterdam | van de Vijver E.,Sanquin Research and Landsteiner Laboratory | van den Berg T.K.,Sanquin Research and Landsteiner Laboratory | Kuijpers T.W.,University of Amsterdam
Hematology/Oncology Clinics of North America | Year: 2013

During inflammation, leukocytes play a key role in maintaining tissue homeostasis through elimination of pathogens and removal of damaged tissue. Leukocytes migrate to the site of inflammation by crawling over and through the blood vessel wall, into the tissue. Leukocyte adhesion deficiencies (ie, LAD-I, -II, and LAD-I/variant, the latter also known as LAD-III) are caused by defects in the adhesion of leukocytes to the vessel wall, resulting in severe recurrent nonpussing infections and neutrophilia, often preceded by delayed separation of the umbilical cord. Although dependent on the genetic defect, hematopoietic stem cell transplantation is often the only curative treatment. © 2013 Elsevier Inc.


Grech G.,University of Malta | Von Lindern M.,Sanquin Research and Landsteiner Laboratory
Comparative and Functional Genomics | Year: 2012

Organisation of RNAs into functional subgroups that are translated in response to extrinsic and intrinsic factors underlines a relatively unexplored gene expression modulation that drives cell fate in the same manner as regulation of the transcriptome by transcription factors. Recent studies on the molecular mechanisms of inflammatory responses and haematological disorders indicate clearly that the regulation of mRNA translation at the level of translation initiation, mRNA stability, and protein isoform synthesis is implicated in the tight regulation of gene expression. This paper outlines how these posttranscriptional control mechanisms, including control at the level of translation initiation factors and the role of RNA binding proteins, affect hematopoiesis. The clinical relevance of these mechanisms in haematological disorders indicates clearly the potential therapeutic implications and the need of molecular tools that allow measurement at the level of translational control. Although the importance of miRNAs in translation control is well recognised and studied extensively, this paper will exclude detailed account of this level of control. Copyright © 2012 Godfrey Grech and Marieke von Lindern.


Van Schouwenburg P.A.,Sanquin Research and Landsteiner Laboratory | Krieckaert C.L.,Jan Van Breemen Research Institute Reade | Rispens T.,Sanquin Research and Landsteiner Laboratory | Aarden L.,Sanquin Research and Landsteiner Laboratory | And 3 more authors.
Annals of the Rheumatic Diseases | Year: 2013

Background and objectives Therapeutic monoclonal antibodies are effective drugs for many different diseases. However, the formation of anti-drug antibodies (ADA) against a biological can result in reduced clinical response in some patients. Measurement of ADA in the presence of (high) drug levels is difficult due to drug interference in most assays, including the commonly used antigen binding test (ABT). Methods We recently published a novel method which enables the measurement of complexed antibodies against adalimumab (an anti-TNF antibody) in the presence of drug. Here we use this pH-shift-anti-idiotype ABT (PIA) to measure anti-adalimumab antibodies (AAA) in 99 rheumatoid arthritis (RA) patients treated for up to 3 years with adalimumab. Results 53 out of 99 RA patients produced AAA. In 50 of these PIA positive patients, AAA could be detected within the first 28 weeks of treatment. Patients in which AAA could be detected in the PIA after 28 weeks of treatment were more prone to declining adalimumab levels (≤5 mg/ml) ( p≤0.01) and high AAA levels which could be detected in the ABT ( p≤0.05) at later time points. We observed transient AAA formation in 17/53 patients. Conclusions Results show that AAA develop early in treatment. However, levels that completely neutralise the drug may be reached much later in treatment. Furthermore, the patients positive for PIA at 28 weeks have an increased chance to develop clinical nonresponse due to immunogenicity. In some of the patients, AAA formation is transient.


Van Lier R.A.W.,Sanquin Research and Landsteiner Laboratory
Immunology Letters | Year: 2014

Studies on antiviral immunity in man are hampered by the impossibility to standardize the infection as is done in experimental animal studies. An exception is the occurrence of cytomegalovirus infection transmitted by a donor organ into a transplant-recipient, where the time-point of infection is exactly known. Moreover, its strong interaction with the human immune system during evolution and the strong immunogenic properties of this persistent virus, as well as the need for intervention e.g. by vaccine development, all make studies towards the immune response against just this virus very attractive and relevant. In this work, we will present an overview of the studies on this topic that were performed in the departments of Experimental and Clinical Immunology in the AMC and Sanquin in Amsterdam. © 2014 Elsevier B.V.

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