Publications by authors named "Esther van de Vosse"

74 Publications

Human IFN-γ immunity to mycobacteria is governed by both IL-12 and IL-23.

Sci Immunol 2018 12;3(30)

Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, Turkey.

Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12Rβ1 deficiency have been diagnosed over the last 20 years. They typically suffer from invasive mycobacteriosis and, occasionally, from mucocutaneous candidiasis. Susceptibility to these infections is thought to be due to impairments of IL-12-dependent IFN-γ immunity and IL-23-dependent IL-17A/IL-17F immunity, respectively. We report here patients with autosomal recessive, complete IL-12Rβ2 or IL-23R deficiency, lacking responses to IL-12 or IL-23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. We show that αβ T, γδ T, B, NK, ILC1, and ILC2 cells from healthy donors preferentially produce IFN-γ in response to IL-12, whereas NKT cells and MAIT cells preferentially produce IFN-γ in response to IL-23. We also show that the development of IFN-γ-producing CD4 T cells, including, in particular, mycobacterium-specific T1* cells (CD45RACCR6), is dependent on both IL-12 and IL-23. Last, we show that , , and have similar frequencies of deleterious variants in the general population. The comparative rarity of symptomatic patients with IL-12Rβ2 or IL-23R deficiency, relative to IL-12Rβ1 deficiency, is, therefore, due to lower clinical penetrance. There are fewer symptomatic IL-23R- and IL-12Rβ2-deficient than IL-12Rβ1-deficient patients, not because these genetic disorders are rarer, but because the isolated absence of IL-12 or IL-23 is, in part, compensated by the other cytokine for the production of IFN-γ, thereby providing some protection against mycobacteria. These experiments of nature show that human IL-12 and IL-23 are both required for optimal IFN-γ-dependent immunity to mycobacteria, both individually and much more so cooperatively.
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http://dx.doi.org/10.1126/sciimmunol.aau6759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380365PMC
December 2018

Susceptibility to mycobacterial disease due to mutations in IL-12Rβ1 in three Iranian patients.

Immunogenetics 2018 06 18;70(6):373-379. Epub 2017 Dec 18.

Mycobacteriology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

In the last decade, autosomal recessive interleukin-12 receptor β1 (IL-12Rβ1) deficiency, the most common cause of Mendelian susceptibility to mycobacterial disease (MSMD), has been diagnosed in a few children and adults with severe tuberculosis in Iran. Here, we report three cases referred to the Immunology, Asthma and Allergy ward at the National Research Institute of Tuberculosis and Lung Diseases (NRITLD) at Masih Daneshvari Hospital from 2012 to 2017 with Mycobacterium tuberculosis and non-tuberculous mycobacteria infections due to defects in IL-12Rβ1 but with different clinical manifestations. All three were homozygous for either an IL-12Rβ1 missense or nonsense mutation that caused the IL-12Rβ1 protein not to be expressed on the cell membrane and completely abolished the cellular response to recombinant IL-12. Our findings suggest that the presence of IL-12Rβ1 deficiency should be determined in children with mycobacterial infections at least in countries with a high prevalence of parental consanguinity and in areas endemic for TB like Iran.
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http://dx.doi.org/10.1007/s00251-017-1041-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943370PMC
June 2018

A 38-year-old woman with necrotising cervical lymphadenitis due to Histoplasma capsulatum.

Infection 2017 Dec 18;45(6):917-920. Epub 2017 Aug 18.

Department of Infectious Diseases, Leiden University Medical Center, Room C5-42, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.

Case Presentation: We analysed a 38-year-old woman with disseminated histoplasmosis for primary immunodeficiency. Her blood showed no IFN-γ response while her peripheral blood mononuclear cells (PBMCs) did. We identified IFN-γ autoantibodies of the IgG class in her serum.

Conclusion: IFN-γ autoantibodies leading to infections were so far mainly detected in people from Asian descent, where it was found to be associated with certain HLA types. This may be the first patient of African descent, and without the typical HLA types that predispose to this problem, that produces IFN-γ autoantibodies.
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http://dx.doi.org/10.1007/s15010-017-1060-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696445PMC
December 2017

IFN-γR1 defects: Mutation update and description of the IFNGR1 variation database.

Hum Mutat 2017 10 3;38(10):1286-1296. Epub 2017 Aug 3.

Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.

IFN-γ signaling is essential for the innate immune defense against mycobacterial infections. IFN-γ signals through the IFN-γ receptor, which consists of a tetramer of two IFN-γR1 chains in complex with two IFN-γR2 chains, where IFN-γR1 is the ligand-binding chain of the interferon-γ receptor and IFN-γR2 is the signal-transducing chain of the IFN-γ receptor. Germline mutations in the gene IFNGR1 encoding the IFN-γR1 cause a primary immunodeficiency that mainly leads to mycobacterial infections. Here, we review the molecular basis of this immunodeficiency in the 130 individuals described to date, and report mutations in five new individuals, bringing the total number to 135 individuals from 98 kindreds. Forty unique IFNGR1 mutations have been reported and they exert either an autosomal dominant or an autosomal recessive effect. Mutations resulting in premature stopcodons represent the majority of IFNGR1 mutations (60%; 24 out of 40), followed by amino acid substitutions (28%, 11 out of 40). All known mutations, as well as 287 other variations, have been deposited in the online IFNGR1 variation database (www.LOVD.nl/IFNGR1). In this article, we review the function of IFN-γR1 and molecular genetics of human IFNGR1.
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http://dx.doi.org/10.1002/humu.23302DOI Listing
October 2017

Recurrent respiratory tract infections (RRTI) in the elderly: A late onset mild immunodeficiency?

Clin Immunol 2017 07 6;180:111-119. Epub 2017 May 6.

Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.

Elderly with late-onset recurrent respiratory tract infections (RRTI) often have specific anti-polysaccharide antibody deficiency (SPAD). We hypothesized that late-onset RRTI is caused by mild immunodeficiencies, such as SPAD, that remain hidden through adult life. We analyzed seventeen elderly RRTI patients and matched controls. We determined lymphocyte subsets, expression of BAFF receptors, serum immunoglobulins, complement pathways, Pneumovax-23 vaccination response and genetic variations in BAFFR and MBL2. Twelve patients (71%) and ten controls (59%) had SPAD. IgA was lower in patients than in controls, but other parameters did not differ. However, a high percentage of both patients (53%) and controls (65%) were MBL deficient, much more than in the general population. Often, MBL2 secretor genotypes did not match functional deficiency, suggesting that functional MBL deficiency can be an acquired condition. In conclusion, we found SPAD and MBL deficiency in many elderly, and conjecture that at least the latter arises with age.
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http://dx.doi.org/10.1016/j.clim.2017.05.008DOI Listing
July 2017

Repurposing QuantiFERON for Detection of Neutralizing Interferon-γ Autoantibodies in Patients With Nontuberculous Mycobacterial Infections.

Clin Infect Dis 2017 Aug;65(3):518-521

Department I of Internal Medicine, University Hospital of Cologne.

Nontuberculous mycobacterial infections due to autoantibodies targeting interferon-γ are an emerging medical problem. However, case finding is hampered due to highly complex diagnostic procedures not available in routine laboratories. We show that QuantiFERON assays can be exploited as a simple screening tool that may facilitate adequate and timely treatment.
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http://dx.doi.org/10.1093/cid/cix372DOI Listing
August 2017

A Functional Genomics Approach to Understand Variation in Cytokine Production in Humans.

Cell 2016 11;167(4):1099-1110.e14

Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 HP Nijmegen, the Netherlands. Electronic address:

As part of the Human Functional Genomics Project, which aims to understand the factors that determine the variability of immune responses, we investigated genetic variants affecting cytokine production in response to ex vivo stimulation in two independent cohorts of 500 and 200 healthy individuals. We demonstrate a strong impact of genetic heritability on cytokine production capacity after challenge with bacterial, fungal, viral, and non-microbial stimuli. In addition to 17 novel genome-wide significant cytokine QTLs (cQTLs), our study provides a comprehensive picture of the genetic variants that influence six different cytokines in whole blood, blood mononuclear cells, and macrophages. Important biological pathways that contain cytokine QTLs map to pattern recognition receptors (TLR1-6-10 cluster), cytokine and complement inhibitors, and the kallikrein system. The cytokine QTLs show enrichment for monocyte-specific enhancers, are more often located in regions under positive selection, and are significantly enriched among SNPs associated with infections and immune-mediated diseases. PAPERCLIP.
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http://dx.doi.org/10.1016/j.cell.2016.10.017DOI Listing
November 2016

Transduction of Herpesvirus saimiri-Transformed T Cells with Exogenous Genes of Interest.

Curr Protoc Immunol 2016 11 1;115:7.21C.1-7.21C.12. Epub 2016 Nov 1.

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York.

Human T cells can be transformed and expanded with herpesvirus saimiri (HVS). HVS-transformed T cells from patients have facilitated the study of a broad range of primary immunodeficiencies (PID) in which T-cell development or function is altered. However, the utility of HVS-transformed T cells for genetic studies has been limited by technical challenges in the expression of exogenous genes, including wild-type or mutant alleles. A novel, gamma retrovirus-based method for the simple and reliable transduction, purification, and study of HVS-transformed T cells is described. © 2016 by John Wiley & Sons, Inc.
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http://dx.doi.org/10.1002/cpim.15DOI Listing
November 2016

Deletion of the entire interferon-γ receptor 1 gene causing complete deficiency in three related patients.

J Clin Immunol 2016 Apr 1;36(3):195-203. Epub 2016 Mar 1.

Department of Pediatrics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.

Purpose: Complete interferon-γ receptor 1 (IFN-γR1) deficiency is a primary immunodeficiency causing predisposition to severe infection due to intracellular pathogens. Only 36 cases have been reported worldwide. The purpose of this article is to describe a large novel deletion found in 3 related cases, which resulted in the complete removal of the IFNGR1 gene.

Methods: Whole blood from three patients was stimulated with lipopolysaccharide (LPS) and IFN-γ to determine production of tumor necrosis factor (TNF), interleukin-12 p40 (IL-12p40) and IL-10. Expression of IFN-γR1 on the cell membrane of patients' monocytes was assessed using flow cytometry. IFNGR1 transcript was analyzed in RNA and the gene and adjacent regions were analyzed in DNA. Finally, IL22RA2 transcript levels were analyzed in whole blood cells and dendritic cells.

Results: There was no expression of the IFN-γR1 on the monocytes. Consistent with this finding, there was no IFN-γ response in the whole blood assay as measured by effect on LPS-induced IL-12p40, TNF and IL-10 production. A 119.227 nt homozygous deletion on chromosome 6q23.3 was identified, removing the IFNGR1 gene completely and ending 117 nt upstream of the transcription start of the IL22RA2 gene. Transcript levels of IL22RA2 were similar in patient and control.

Conclusions: We identified the first large genomic deletion of IFNGR1 causing complete IFN-γR1 deficiency. Despite the deletion ending very close to the IL22RA2 gene, it does not appear to affect IL22RA2 transcription and, therefore, may not have any additional clinical consequence.
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http://dx.doi.org/10.1007/s10875-016-0244-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4792359PMC
April 2016

Genetic variation in TLR10 is not associated with chronic Q fever, despite the inhibitory effect of TLR10 on Coxiella burnetii-induced cytokines in vitro.

Cytokine 2016 Jan 11;77:196-202. Epub 2015 Sep 11.

Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands. Electronic address:

Coxiella burnetii, the causative agent of Q fever, is recognized by TLR2. TLR10 can act as an inhibitory receptor on TLR2-derived immune responses. Therefore, we investigated the role of TLR10 on C. burnetii-induced cytokine production and assessed whether genetic polymorphisms in TLR10 influences the development of chronic Q fever. HEK293 cells, transfected with TLR2, TLR10 or TLR2/TLR10, and human peripheral blood mononuclear cells (PBMCs) in the presence of anti-TLR10, were stimulated with C. burnetii. In both assays, the absence of TLR10 resulted in increased cytokine responses after C. burnetii stimulation. In addition, the effect of single nucleotide polymorphisms (SNPs) in TLR10 was examined in healthy volunteers whose PBMCs were stimulated with C. burnetii Nine Mile or the Dutch outbreak isolate C. burnetii 3262. Individuals bearing SNPs in TLR10 displayed increased cytokine production upon C. burnetii 3262 stimulation. Furthermore, 139 chronic Q fever patients and 220 controls were genotyped for TLR10 N241H, I775V and I369L. None of these polymorphisms were associated with increased susceptibility to chronic Q fever. In conclusion, TLR10 has an inhibitory effect on in vitro cytokine production by C. burnetii, but the presence of TLR10 polymorphisms does not lead to an increased risk of developing chronic Q fever.
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http://dx.doi.org/10.1016/j.cyto.2015.09.005DOI Listing
January 2016

Urinary proteins, vitamin D and genetic polymorphisms as risk factors for febrile urinary tract infection and relation with bacteremia: a case control study.

PLoS One 2015 25;10(3):e0121302. Epub 2015 Mar 25.

Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.

Objective/purpose: Febrile urinary tract infection (UTI) is a common bacterial disease that may lead to substantial morbidity and mortality especially among the elderly. Little is known about biomarkers that predict a complicated course. Our aim was to determine the role of certain urinary cytokines or antimicrobial proteins, plasma vitamin D level, and genetic variation in host defense of febrile UTI and its relation with bacteremia.

Methods: A case-control study. Out of a cohort of consecutive adults with febrile UTI (n = 787) included in a multi-center observational cohort study, 46 cases with bacteremic E.coli UTI and 45 cases with non-bacteremic E.coli UTI were randomly selected and compared to 46 controls. Urinary IL-6, IL-8, LL37, β-defensin 2 and uromodulin as well as plasma 25-hydroxyvitamin D were measured. In 440 controls and 707 UTI patients polymorphisms were genotyped in the genes CXCR1, DEFA4, DEFB1, IL6, IL8, MYD88, UMOD, TIRAP, TLR1, TLR2, TLR5 and TNF.

Results: IL-6, IL-8, and LL37 are different between controls and UTI patients, although these proteins do not distinguish between patients with and without bacteremia. While uromodulin did not differ between groups, inability to produce uromodulin is more common in patients with bacteremia. Most participants in the study, including the controls, had insufficient vitamin D and, at least in winter, UTI patients have lower vitamin D than controls. Associations were found between the CC genotype of IL6 SNP rs1800795 and occurrence of bacteremia and between TLR5 SNP rs5744168 and protection from UTI. The rare GG genotype of IL6 SNP rs1800795 was associated with higher β-defensin 2 production.

Conclusion: Although no biomarker was able to distinguish between UTI with or without bacteremia, two risk factors for bacteremia were identified. These were inability to produce uromodulin and an IL6 rs1800795 genotype.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121302PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373833PMC
February 2016

Genetic Variation in Pattern Recognition Receptors and Adaptor Proteins Associated With Development of Chronic Q Fever.

J Infect Dis 2015 Sep 26;212(5):818-29. Epub 2015 Feb 26.

Department of Infectious Diseases, Leiden University Medical Center, The Netherlands.

Background: Q fever is an infection caused by Coxiella burnetii. Persistent infection (chronic Q fever) develops in 1%-5% of patients. We hypothesize that inefficient recognition of C. burnetii and/or activation of host-defense in individuals carrying genetic variants in pattern recognition receptors or adaptors would result in an increased likelihood to develop chronic Q fever.

Methods: Twenty-four single-nucleotide polymorphisms in genes encoding Toll-like receptors, nucleotide-binding oligomerization domain-like receptor-2, αvβ3 integrin, CR3, and adaptors myeloid differentiation primary response protein 88 (MyD88), and Toll interleukin 1 receptor domain-containing adaptor protein (TIRAP) were genotyped in 139 patients with chronic Q fever and in 220 controls with cardiovascular risk-factors and previous exposure to C. burnetii. Associations between these single-nucleotide polymorphisms and chronic Q fever were assessed by means of univariate logistic regression models. Cytokine production in whole-blood stimulation assays was correlated with relevant genotypes.

Results: Polymorphisms in TLR1 (R80T), NOD2 (1007fsX1), and MYD88 (-938C>A) were associated with chronic Q fever. No association was observed for polymorphisms in TLR2, TLR4, TLR6, TLR8, ITGAV, ITGB3, ITGAM, and TIRAP. No correction for multiple testing was performed because only genes with a known role in initial recognition of C. burnetii were included. In the whole-blood assays, individuals carrying the TLR1 80R-allele showed increased interleukin 10 production with C. burnetii exposure.

Conclusions: Polymorphisms in TLR1 (R80T), NOD2 (L1007fsX1), and MYD88 (-938C>A) are associated with predisposition to development of chronic Q fever. For TLR1, increased interleukin 10 responses to C. burnetii in individuals carrying the risk allele may contribute to the increased risk of chronic Q fever.
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http://dx.doi.org/10.1093/infdis/jiv113DOI Listing
September 2015

The C-type lectin receptor CLECSF8/CLEC4D is a key component of anti-mycobacterial immunity.

Cell Host Microbe 2015 Feb;17(2):252-9

Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK; Division of Immunology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, 792 Cape Town, South Africa. Electronic address:

The interaction of microbes with pattern recognition receptors (PRRs) is essential for protective immunity. While many PRRs that recognize mycobacteria have been identified, none is essentially required for host defense in vivo. Here, we have identified the C-type lectin receptor CLECSF8 (CLEC4D, MCL) as a key molecule in anti-mycobacterial host defense. Clecsf8-/- mice exhibit higher bacterial burdens and increased mortality upon M. tuberculosis infection. Additionally, Clecsf8 deficiency is associated with exacerbated pulmonary inflammation, characterized by enhanced neutrophil recruitment. Clecsf8-/- mice show reduced mycobacterial uptake by pulmonary leukocytes, but infection with opsonized bacteria can restore this phagocytic defect as well as decrease bacterial burdens. Notably, a CLECSF8 polymorphism identified in humans is associated with an increased susceptibility to pulmonary tuberculosis. We conclude that CLECSF8 plays a non-redundant role in anti-mycobacterial immunity in mouse and in man.
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http://dx.doi.org/10.1016/j.chom.2015.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334100PMC
February 2015

The Hd, Hj, and Hz66 flagella variants of Salmonella enterica serovar Typhi modify host responses and cellular interactions.

Sci Rep 2015 Jan 22;5:7947. Epub 2015 Jan 22.

1] The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam [2] Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, United Kingdom [3] The London School of Hygiene and Tropical Medicine, London, United Kingdom.

Salmonella Typhi, the causative agent of typhoid fever, is a monophyletic, human-restricted bacterium that exhibits limited phenotypic variation. S. Typhi from Indonesia are a notable exception, with circulating strains expressing diverse flagella antigens including Hj, Hd and Hz66. Hypothesizing that S. Typhi flagella plays a key role during infection, we constructed an S. Typhi fliC mutant and otherwise isogenic S. Typhi strains expressing the Hj, Hd, Hz66 flagella antigens. Phenotyping revealed differences in flagellum structure, strain motility and immunogenicity, but not in the ability of flagellated isolates to induce TLR5 activity. Invasion assays using epithelial and macrophage cell lines revealed differences in the ability of these S. Typhi derivatives to invade cells or induce cellular restructuring in the form of ruffles. Notably, the Hj variant induced substantial ruffles that were not fully dependent on the GTPases that contribute to this process. These data highlight important differences in the phenotypic properties of S. Typhi flagella variation and how they impact on the pathogenesis of S. Typhi.
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http://dx.doi.org/10.1038/srep07947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302301PMC
January 2015

Gastric cancer in three relatives of a patient with a biallelic IL12RB1 mutation.

Fam Cancer 2015 Mar;14(1):89-94

Department of Human Genetics, Radboud university medical center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands,

IL-12Rβ1 deficiency, also known as immunodeficiency 30 (IMD30, OMIM 614891), is a rare immunodeficiency syndrome caused by biallelic mutations in IL12RB1. Three second-degree relatives of a patient with this syndrome, all women, developed intestinal-type gastric cancer (GC). In the Netherlands the incidence of non-cardia GC in women is only 7 per 100,000 person years. Both relatives that were available for testing proved to be heterozygous for the familial IL12RB1 mutation, suggesting there might be a causal relation. Testing 29 index patients from families with early onset and/or a familial history of GC for germline mutations in both IL12RB1 and IL12RB2, that encodes the binding partner of IL-12Rβ1, did not reveal other germline mutations in these genes. Therefore heterozygous inactivating mutations in IL12RB1 and IL12RB2 are unlikely to be frequently involved in GC predisposition. Additional research in families with IL12RB1 mutations is required to determine whether carriers of IL12RB1 mutations have an increased (gastric) cancer risk.
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http://dx.doi.org/10.1007/s10689-014-9764-xDOI Listing
March 2015

Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer.

PLoS Pathog 2014 Oct 30;10(10):e1004485. Epub 2014 Oct 30.

Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.

The anti-tuberculosis-vaccine Bacillus Calmette-Guérin (BCG) is the most widely used vaccine in the world. In addition to its effects against tuberculosis, BCG vaccination also induces non-specific beneficial effects against certain forms of malignancy and against infections with unrelated pathogens. It has been recently proposed that the non-specific effects of BCG are mediated through epigenetic reprogramming of monocytes, a process called trained immunity. In the present study we demonstrate that autophagy contributes to trained immunity induced by BCG. Pharmacologic inhibition of autophagy blocked trained immunity induced in vitro by stimuli such as β-glucans or BCG. Single nucleotide polymorphisms (SNPs) in the autophagy genes ATG2B (rs3759601) and ATG5 (rs2245214) influenced both the in vitro and in vivo training effect of BCG upon restimulation with unrelated bacterial or fungal stimuli. Furthermore, pharmacologic or genetic inhibition of autophagy blocked epigenetic reprogramming of monocytes at the level of H3K4 trimethylation. Finally, we demonstrate that rs3759601 in ATG2B correlates with progression and recurrence of bladder cancer after BCG intravesical instillation therapy. These findings identify a key role of autophagy for the nonspecific protective effects of BCG.
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http://dx.doi.org/10.1371/journal.ppat.1004485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214925PMC
October 2014

Role of genetic variants of autophagy genes in susceptibility for non-medullary thyroid cancer and patients outcome.

PLoS One 2014 16;9(4):e94086. Epub 2014 Apr 16.

Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands; Division of Endocrinology, Radboud University Medical Centre, Nijmegen, The Netherlands.

Autophagy is a central process in regulation of cell survival, cell death and proliferation and plays an important role in carcinogenesis, including thyroid carcinoma. Genetic variation in autophagy components has been demonstrated to influence the capacity to execute autophagy and is associated with disease susceptibility, progression and outcome. In the present study, we assessed whether genetic variation in autophagy genes contributes to susceptibility to develop thyroid carcinoma, disease progression and/or patient outcome. The results indicate that patients carrying the ATG5 single nucleotide polymorphisms rs2245214 have a higher probability to develop thyroid carcinoma (OR 1.85 (95% CI 1.04-3.23), P = 0.042). In contrast, no significant differences could be observed for the other genetic variants studied in terms of thyroid carcinoma susceptibility. Furthermore, none of the selected genetic variants were associated with clinical parameters of disease progression and outcome. In conclusion, genetic variation in ATG5, a central player in the autophagy process, is found to be associated with increased susceptibility for thyroid carcinoma, indicating a role for autophagy in thyroid carcinogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0094086PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3989221PMC
January 2015

Correlating interleukin-12 stimulated interferon-γ production and the absence of ectodermal dysplasia and anhidrosis (EDA) in patients with mutations in NF-κB essential modulator (NEMO).

J Clin Immunol 2014 May 28;34(4):436-43. Epub 2014 Feb 28.

Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands,

Objective: Patients with hypomorphic mutations in Nuclear Factor-κB Essential Modulator (NEMO) are immunodeficient (ID) and most display ectodermal dysplasia and anhidrosis (EDA). We compared cytokine production by NEMO-ID patients with and without EDA.

Methods: PBMCs of NEMO-ID patients, four with EDA carrying E315A, C417R, D311N and Q403X, and three without EDA carrying E315A, E311_L333del and R254G, were cultured with PHA, PHA plus IL-12p70, LPS, LPS plus IFN-γ, TNF and IL-1β. The production of various cytokines was measured in the supernatants. Fifty-nine healthy individuals served as controls.

Results: PBMCs of NEMO-ID patients without EDA produce subnormal amounts of IFN-γ after stimulation with PHA, but normal amounts of IFN-γ after PHA plus IL-12p70. In contrast, IFN-γ production by patients with EDA was low in both cases. Patients with EDA also generate lower PHA-stimulated IL-10 and IL-1β than controls, whereas the production of these cytokines by patients without EDA was normal.

Conclusion: Responses of PBMCs in NEMO-ID patients with EDA to PHA with and without IL-12p70 appear less robust than in NEMO-ID patients without EDA. This possibly indicates a better preserved NEMO function in our patients without EDA.
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http://dx.doi.org/10.1007/s10875-014-9998-2DOI Listing
May 2014

Intact IFN-γR1 expression and function distinguishes Langerhans cell histiocytosis from mendelian susceptibility to mycobacterial disease.

J Clin Immunol 2014 Jan 20;34(1):84-93. Epub 2013 Nov 20.

Immunology Laboratory, Willem Alexander Children's Hospital, Leiden University Medical Center, Leiden, The Netherlands.

Purpose: Poly-ostotic Langerhans Cell Histiocytosis (LCH) can be difficult to distinguish clinically and histologically from disseminated infection in manifesting specific subtypes of Mendelian Susceptibility to Mycobacterial Disease (MSMD). In MSMD-patients, dominant negative germline mutations in the IFN-γR1 gene, in particular in exon 6, lead to autosomal dominant IFN-γ receptor 1 deficiency (ADIFNGR1) and can mimic LCH. We hypothesized that similar defects might underlie the pathogenesis of LCH.

Methods: IFN-γR1 expression was immunohistochemically determined at disease onset in biopsies from 11 LCH-patients and four ADIFNGR1-patients. IFN-γR1 function was analyzed in 18 LCH-patients and 13 healthy controls by assessing the IFN-γ-induced upregulation of Fc-gamma-receptor I (FcγRI) expression on monocytes. Pro-inflammatory cytokine production was measured after stimulation of whole blood with LPS and IFN-γ. Exon 6 of the IFN-γR1 gene was sequenced in 67 LCH-patients to determine whether mutations were present.

Results: IFN-γR1 expression was high in three LCH-affected biopsies, similar to ADIFNGR1-affected biopsies, but varied from negative to moderate in eight other LCH-affected biopsies. No functional differences in IFN-γ signaling were detected between LCH-patients with active or non-active disease and healthy controls. No germline mutations in exon 6 of the IFN-γR1 gene were detected in any of the 67 LCH-patients.

Conclusions: In contrast to ADIFNGR1-patients, IFN-γ signaling is fully functional in LCH-patients. Either performed before, during or after treatment, these non-invasive functional assays can distinguish LCH-patients from ADIFNGR1-patients and thereby facilitate correct therapy regimens for patients with recurrent osteolytic lesions.
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http://dx.doi.org/10.1007/s10875-013-9959-1DOI Listing
January 2014

Nontuberculous mycobacterial infections in children with inborn errors of the immune system.

J Infect 2014 Jan 8;68 Suppl 1:S134-50. Epub 2013 Oct 8.

Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Electronic address:

Severe mycobacterial disease is mostly confined to patients who are immunocompromized either by acquired or inherited causes. One such genetic disorder is Mendelian Susceptibility to Mycobacterial Disease (MSMD), a hot topic within the field of primary immunodeficiency. This single gene disorder is characterized by isolated infection with mycobacteria or Salmonella due to a defect in the type-1 cytokine response. In the last two decades, ten genes have been labeled as causing MSMD when they harbor germline mutations, namely IL12B, IL12RB1, IFNGR1, IFNGR2, STAT1, IKBKG, CYBB, TYK2, IRF8 and ISG15. The mutations lead to either insufficient production of IFN-γ, or to an insufficient response to the cytokine. Current treatment options include recombinant IFN-γ and hematologic stem cell transplantation (HSCT). In the future, gene therapy, antisense-mediated exon skipping and chemical intervention in glycosylation problems may become successful alternatives. Furthermore, it is likely that many new candidate genes and pathways crucial for mycobacterial immunity will be identified.
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http://dx.doi.org/10.1016/j.jinf.2013.09.024DOI Listing
January 2014

Differential expression and function of human IL-12Rβ2 polymorphic variants.

Mol Immunol 2013 Dec 1;56(4):380-9. Epub 2013 Aug 1.

Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.

The receptor for interleukin-12, formed by IL-12Rβ1 and IL-12Rβ2, mediates the type I immune responses of various types of lymphocytes. Polymorphisms in IL12RB2, the gene encoding IL-12Rβ2, were reported to be associated with several immune related diseases, such as Crohn's disease. Because the IL23R and IL12RB2 genes are located in close proximity on the genome, the reported associations might also be attributable to linked polymorphisms in IL23R, which were found to be associated with immune related diseases as well. To clarify the role of IL-12Rβ2 in immune diseases, we investigated the functional consequences of thirteen amino acid substitutions in IL-12Rβ2. We developed a model with retroviral expression of IL-12Rβ2 in B cell lines. With the use of this model the expression and function of the variants was compared within the same genetic background. Four of the IL-12Rβ2 variants, N271Y, R313G, A604V and L808R showed reduced IL-12 responses compared to the wild type variant. Two of these are relatively common in some populations and may be used in future association studies to reveal a role for IL-12 in infectious and/or immune related diseases.
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http://dx.doi.org/10.1016/j.molimm.2013.07.002DOI Listing
December 2013

IL-12Rβ1 deficiency: mutation update and description of the IL12RB1 variation database.

Hum Mutat 2013 Oct 8;34(10):1329-39. Epub 2013 Aug 8.

Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.

IL-12Rβ1 deficiency is an autosomal recessive disorder characterized by predisposition to recurrent and/or severe infections caused by otherwise poorly pathogenic mycobacteria and salmonella. IL-12Rβ1 is a receptor chain of both the IL-12 and the IL-23 receptor and deficiency of IL-12Rβ1 thus abolishes both IL-12 and IL-23 signaling. IL-12Rβ1 deficiency is caused by bi-allelic mutations in the IL12RB1 gene. Mutations resulting in premature stop codons, such as nonsense, frame shift, and splice site mutations, represent the majority of IL-12Rβ1 deficiency causing mutations (66%; 46/70). Also every other morbid mutation completely inactivates the IL-12Rβ1 protein. In addition to disease-causing mutations, rare and common variations with unknown functional effect have been reported in IL12RB1. All these variants have been deposited in the online IL12RB1 variation database (www.LOVD.nl/IL12RB1). In this article, we review the function of IL-12Rβ1 and molecular genetics of human IL12RB1.
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http://dx.doi.org/10.1002/humu.22380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104692PMC
October 2013

The influence of influenza virus infections on the development of tuberculosis.

Tuberculosis (Edinb) 2013 May 7;93(3):338-42. Epub 2013 Mar 7.

Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.

Recently, it was shown that interferon-γ mediated immune responses, which play a major role in the control of infection with Mycobacterium tuberculosis (Mtb), can be inhibited by type I interferons. Since type I interferons are abundantly induced during viral infections, we hypothesized that infections with influenza viruses might play a role in the development of active TB disease either directly after exposure to Mtb or through reactivation of latent Mtb infection. To explore this hypothesis we investigated in a retrospective study whether newly diagnosed adult tuberculosis patients from Indonesia had had recent influenza infection. Plasma samples from TB patients and controls were assayed for antibodies against two subtypes of at that time relevant, seasonal influenza A viruses. Overall, no correlation was observed with the presence of antibodies and manifest tuberculosis. Still, antibody titers against circulating A/H3N2 influenza virus were slightly enhanced in tuberculosis patients as compared to controls, and highest in cases of advanced tuberculosis. This suggests that tuberculosis patients were recently infected with influenza, before clinical manifestation of the disease. Alternatively, the production of antibodies and susceptibility to tuberculosis may be influenced by a common confounding factor, for example the ability of patients to induce interferon-α. We conclude that in an endemic country like Indonesia, an influenza virus infection is not a major determinant for developing clinically manifest tuberculosis.
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http://dx.doi.org/10.1016/j.tube.2013.02.006DOI Listing
May 2013

The R156H variation in IL-12Rβ1 is not a mutation.

Ital J Pediatr 2013 Feb 14;39:12. Epub 2013 Feb 14.

Palamaro et al. describe a child with recurrent bronchopneumonia and very high IgE levels in which a variation, R156H, was found in the IL12RB1 gene that encodes the IL-12Rβ1 chain. Based on the absence of this variation in 50 unrelated individuals they conclude it is a mutation. We (van de Vosse and van Dissel) feel there is no reason to suspect a defect in IL-12 signaling based on the clinical data, nor evidence for a functional defect in IL-12 signaling in this patient. In addition, the variation is not novel and known as a polymorphism. Without any functional evidence that R156H is a mutation, the current claim is not substantiated. Palamaro et al. respond to argue that the amino acid substitution, R156H described in the described case exerts a summatory effect, as a genetic cofactor, along with an additional and still unidentified molecular alteration of the same pathway.
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http://dx.doi.org/10.1186/1824-7288-39-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3584738PMC
February 2013

Inhibition of the type I immune responses of human monocytes by IFN-α and IFN-β.

Cytokine 2013 Feb 5;61(2):645-55. Epub 2013 Jan 5.

Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.

Interleukin-12 (IL-12), IL-23 and interferon-γ (IFN-γ) are pivotal cytokines acting in concert with tumor necrosis factor (TNF) and IL-1β to shape type I immune responses against bacterial pathogens. Recently, several groups reported that type I immunity can be inhibited by IFN-α/β. Here we show the extent of the inhibitory effects of IFN-α and IFN-β on the responsiveness of human monocytes to Toll like receptor-ligands and IFN-γ. Both IFN-α and IFN-β strongly reduced the production of IL-12p40, IL-1β and TNF and the IFN-γ induced CD54 and CD64 expression. High IFN-γ concentrations could not counterbalance the inhibitions and IFN-α still inhibited monocytes 24h after stimulation in vitro as well as in vivo in patients undergoing IFN-α treatment. Next, we explored the mechanism of inhibition. We confirm that IFN-α/β interferes with the IFN-γR1 expression, by studying the kinetics of IFN-γR1 downregulation. However, IFN-γR1 downregulation occurred only after two hours of IFN-α/β stimulation and was transient, which cannot explain the IFN-γ unresponsiveness observed directly and late after IFN-α/β stimulation. Additional experiments indeed indicate that other mechanisms are involved. IFN-α may interfere with IFN-γ-elicited phosphorylation of signal transducer and activator of transcription 1 (STAT1). IFN-α may also activate methyltransferases which in turn reduce, at least partly, the TNF and IL-1β production and CD54 expression. IFN-α also induces the protein inhibitor of activated STAT1 (PIAS1). In conclusion, IFN-α and IFN-β strongly inhibit the IFN-γ responsiveness and the production of type I cytokines of monocytes, probably via various mechanisms. Our findings indicate that IFN-α/β play a significant role in the immunopathogenesis of bacterial infections, for example Mycobacterium tuberculosis infection.
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http://dx.doi.org/10.1016/j.cyto.2012.12.005DOI Listing
February 2013

Genome-wide expression profiling identifies type 1 interferon response pathways in active tuberculosis.

PLoS One 2012 21;7(9):e45839. Epub 2012 Sep 21.

Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), remains the leading cause of mortality from a single infectious agent. Each year around 9 million individuals newly develop active TB disease, and over 2 billion individuals are latently infected with M.tb worldwide, thus being at risk of developing TB reactivation disease later in life. The underlying mechanisms and pathways of protection against TB in humans, as well as the dynamics of the host response to M.tb infection, are incompletely understood. We carried out whole-genome expression profiling on a cohort of TB patients longitudinally sampled along 3 time-points: during active infection, during treatment, and after completion of curative treatment. We identified molecular signatures involving the upregulation of type-1 interferon (α/β) mediated signaling and chronic inflammation during active TB disease in an Indonesian population, in line with results from two recent studies in ethnically and epidemiologically different populations in Europe and South Africa. Expression profiles were captured in neutrophil-depleted blood samples, indicating a major contribution of lymphocytes and myeloid cells. Expression of type-1 interferon (α/β) genes mediated was also upregulated in the lungs of M.tb infected mice and in infected human macrophages. In patients, the regulated gene expression-signature normalized during treatment, including the type-1 interferon mediated signaling and a concurrent opposite regulation of interferon-gamma. Further analysis revealed IL15RA, UBE2L6 and GBP4 as molecules involved in the type-I interferon response in all three experimental models. Our data is highly suggestive that the innate immune type-I interferon signaling cascade could be used as a quantitative tool for monitoring active TB disease, and provide evidence that components of the patient's blood gene expression signature bear similarities to the pulmonary and macrophage response to mycobacterial infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045839PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448682PMC
February 2013

Cutaneous leukocytoclastic vasculitis due to Salmonella enteritidis in a child with interleukin-12 receptor beta-1 deficiency.

Pediatr Dermatol 2014 Mar-Apr;31(2):236-40. Epub 2012 Sep 25.

Department of Pediatric Allergy and Immunology, Akdeniz University School of Medicine, Antalya, TurkeyDepartment of Pediatric Hematology, Akdeniz University School of Medicine, Antalya, TurkeyDepartment of Pathology, Akdeniz University School of Medicine, Antalya, TurkeyDepartment of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.

Defects in the interleukin 12 (IL-12)/interferon gamma (IFN-γ) pathway result in Mendelian susceptibility to mycobacterial disease (MSMD). IL-12 receptor beta 1 (IL-12Rβ1) deficiency, the most common form of MSMD, is associated with weakly virulent mycobacteria and salmonella. Infections in patients with this deficiency are extraintestinal, or septicemic, recurrent infections with nontyphoid salmonellae. Here we report a case of an IL-12Rβ1 deficiency with cutaneous leukocytoclastic vasculitis due to Salmonella enteritidis.
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http://dx.doi.org/10.1111/j.1525-1470.2012.01856.xDOI Listing
January 2015
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