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Article: Whole Blood Profiling of Bacillus Calmette-Guérin-Induced Trained Innate Immunity in Infants Identifies Epidermal Growth Factor, IL-6, Platelet-Derived Growth Factor-AB/BB, and Natural Killer Cell Activation.

Smith, Steven G / Kleinnijenhuis, Johanneke / Netea, Mihai G / Dockrell, Hazel M

2017 Volume 8, Page(s) 644

Abstract: Vaccination of infants with bacillus Calmette-Guérin (BCG) activates both the innate and adaptive arms of the immune response. The antimycobacterial effects of these responses most likely account for the ability of BCG to protect against childhood forms ... ...

Abstract	Vaccination of infants with bacillus Calmette-Guérin (BCG) activates both the innate and adaptive arms of the immune response. The antimycobacterial effects of these responses most likely account for the ability of BCG to protect against childhood forms of tuberculosis (TB). There is also evidence for a heterologous protective effect of BCG vaccination against TB-unrelated mortality in low birth weight infants. A possible mechanism of action of this effect, the induction of trained innate immunity, has been demonstrated when cells from BCG-vaccinated adults are restimulated
Language	English
Publishing date	2017-06-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2017.00644
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Article ; Online: Trained immunity: consequences for the heterologous effects of BCG vaccination.

Kleinnijenhuis, Johanneke / van Crevel, Reinout / Netea, Mihai G

Transactions of the Royal Society of Tropical Medicine and Hygiene

2015 Volume 109, Issue 1, Page(s) 29–35

Abstract: A growing body of evidence from epidemiologic and immunologic studies have shown that in addition to target disease-specific effects, vaccines have heterologous effects towards unrelated pathogens. Like some other vaccines, bacille Calmette-Guerin (BCG) ... ...

Abstract	A growing body of evidence from epidemiologic and immunologic studies have shown that in addition to target disease-specific effects, vaccines have heterologous effects towards unrelated pathogens. Like some other vaccines, bacille Calmette-Guerin (BCG) has shown in observational studies and randomized clinical trials to increase survival beyond the disease burden of the target disease. The immunologic substrate for these non-specific protective effects have been ascertained to heterologous T cell effects on the one hand, and to priming of innate immunity on the other hand. The term 'trained immunity' has been proposed to describe these potentiating effects of vaccines on innate immune responses. This process can explain the rapid effects of BCG vaccination and has been suggested to be mediated by epigenetic programming of monocytes or macrophages. This novel concept has important implications for the possible use of vaccines, for vaccination policy and even for the design of novel immunotherapeutic approaches.
MeSH term(s)	Adaptive Immunity/drug effects ; Adaptive Immunity/immunology ; BCG Vaccine/administration & dosage ; Epigenesis, Genetic ; Evidence-Based Medicine ; Humans ; Immunity, Heterologous/drug effects ; Immunity, Heterologous/immunology ; Immunity, Innate/drug effects ; Immunity, Innate/immunology ; Immunologic Memory/drug effects ; Inflammation Mediators/immunology ; Observational Studies as Topic ; Policy Making ; Randomized Controlled Trials as Topic ; T-Lymphocytes/immunology ; Tuberculosis/mortality ; Tuberculosis/prevention & control
Chemical Substances	BCG Vaccine ; Inflammation Mediators
Language	English
Publishing date	2015-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	441375-1
ISSN	1878-3503 ; 0035-9203
ISSN (online)	1878-3503
ISSN	0035-9203
DOI	10.1093/trstmh/tru168
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Article ; Online: Corticosteroid therapy for the management of paradoxical inflammatory reaction in patients with pulmonary tuberculosis.

Done, Macky M / Akkerman, Onno W / Al-Kailany, Wud / de Lange, Wiel C M / de Jonge, Gonda / Kleinnijenhuis, Johanneke / Stienstra, Riejanne / van der Werf, Tjip S

Infection

2020 Volume 48, Issue 4, Page(s) 641–645

Abstract: Background: Paradoxical reaction after the initiation of tuberculosis treatment is defined as increased inflammation following effective antimycobacterial treatment. This is a phenomenon that can severely complicate a patient's recovery, potentially ... ...

Abstract	Background: Paradoxical reaction after the initiation of tuberculosis treatment is defined as increased inflammation following effective antimycobacterial treatment. This is a phenomenon that can severely complicate a patient's recovery, potentially leading to further morbidity and residual deficits. Paradoxical reaction remains poorly understood regarding its pathophysiology and management. Only a limited number of reports look critically at the available therapeutic options, with evidence of the efficacy of prednisolone therapy being primarily limited to extrapulmonary PR only. Case: We describe two HIV negative patients who were admitted to our department with pulmonary tuberculosis, presenting with inflammatory patterns attributable to PR and their response to adjunctive steroid therapy. Discussion and conclusions: The presented cases further highlight the need for immunological studies and randomized trials for corticosteroid therapy are needed to better understand this phenomenon as well as provide an evidence-base for anti-inflammatory treatment. Furthermore, by means of this case series, we are also able to highlight the potential variability in the symptomatology of the lesser known PR phenomenon, in which we observed a hypotensive shock-like syndrome not previously described in literature.
MeSH term(s)	Adrenal Cortex Hormones/administration & dosage ; Adult ; Anti-Inflammatory Agents/administration & dosage ; France ; Humans ; Inflammation/drug therapy ; Inflammation/microbiology ; Male ; Middle Aged ; Morocco/ethnology ; Poland/ethnology ; Tuberculosis, Pulmonary/complications ; Tuberculosis, Pulmonary/immunology ; Tuberculosis, Pulmonary/microbiology
Chemical Substances	Adrenal Cortex Hormones ; Anti-Inflammatory Agents
Language	English
Publishing date	2020-04-24
Publishing country	Germany
Document type	Case Reports ; Journal Article
ZDB-ID	185104-4
ISSN	1439-0973 ; 0300-8126 ; 0173-2129
ISSN (online)	1439-0973
ISSN	0300-8126 ; 0173-2129
DOI	10.1007/s15010-020-01430-7
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Article ; Online: The role of autophagy in host defence against Mycobacterium tuberculosis infection.

Songane, Mário / Kleinnijenhuis, Johanneke / Netea, Mihai G / van Crevel, Reinout

Tuberculosis (Edinburgh, Scotland)

2012 Volume 92, Issue 5, Page(s) 388–396

Abstract: Autophagy is a vital homeostatic process triggered by starvation and other cellular stresses, in which cytoplasmatic cargo is targeted for degradation in specialized structures termed autophagosomes. Autophagy is involved in nutrient regeneration, ... ...

Abstract	Autophagy is a vital homeostatic process triggered by starvation and other cellular stresses, in which cytoplasmatic cargo is targeted for degradation in specialized structures termed autophagosomes. Autophagy is involved in nutrient regeneration, protein and organelle degradation, but also in clearance of intracellular pathogens such as Mycobacterium tuberculosis, the causative agent of tuberculosis. Recent studies suggest that induction of autophagy in macrophages is an effective mechanism to enhance intracellular killing of M. tuberculosis, and that the ability of the pathogen to inhibit this process is of paramount importance for its survival. Patient studies have shown genetic associations between tuberculosis and the autophagy gene IRGM, as well as with several genes indirectly involved in autophagy. In this review we will discuss the complex interplay between M. tuberculosis and autophagy, as well as the effect of polymorphisms in autophagy-related genes on susceptibility to tuberculosis.
MeSH term(s)	Autophagy/genetics ; Case-Control Studies ; Cholecalciferol/genetics ; Cytokines/genetics ; GTP-Binding Proteins/genetics ; Gene Frequency ; Genetic Predisposition to Disease ; Host-Pathogen Interactions ; Humans ; Mycobacterium tuberculosis/genetics ; Mycobacterium tuberculosis/pathogenicity ; Tuberculosis/genetics ; Tuberculosis/pathology ; Tuberculosis/physiopathology ; Tumor Necrosis Factor-alpha/genetics
Chemical Substances	Cytokines ; Tumor Necrosis Factor-alpha ; Cholecalciferol (1C6V77QF41) ; GTP-Binding Proteins (EC 3.6.1.-) ; IRGM protein, human (EC 3.6.1.-)
Language	English
Publishing date	2012-09
Publishing country	Scotland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2046804-0
ISSN	1873-281X ; 1472-9792
ISSN (online)	1873-281X
ISSN	1472-9792
DOI	10.1016/j.tube.2012.05.004
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Article ; Online: Efficacy of ivermectin mass-drug administration to control scabies in asylum seekers in the Netherlands: A retrospective cohort study between January 2014 - March 2016.

Beeres, Dorien T / Ravensbergen, Sofanne J / Heidema, Annelies / Cornish, Darren / Vonk, Machiel / Wijnholds, Leonie D / Hendriks, Jessica J H / Kleinnijenhuis, Johanneke / Omansen, Till F / Stienstra, Ymkje

PLoS neglected tropical diseases

2018 Volume 12, Issue 5, Page(s) e0006401

Abstract: Scabies is a skin infestation with the mite Sarcoptes scabiei causing itch and rash and is a major risk factor for bacterial skin infections and severe complications. Here, we evaluated the treatment outcome of 2866 asylum seekers who received ( ... ...

Abstract	Scabies is a skin infestation with the mite Sarcoptes scabiei causing itch and rash and is a major risk factor for bacterial skin infections and severe complications. Here, we evaluated the treatment outcome of 2866 asylum seekers who received (preventive) scabies treatment before and during a scabies intervention programme (SIP) in the main reception centre in the Netherlands between January 2014 and March 2016. A SIP was introduced in the main national reception centre based on frequent observations of scabies and its complications amongst Eritrean and Ethiopian asylum seekers in the Netherlands. On arrival, all asylum seekers from Eritrea or Ethiopia were checked for clinical scabies signs and received ivermectin/permethrin either as prevention or treatment. A retrospective cohort study was conducted to compare the reinfestations and complications of scabies in asylum seekers who entered the Netherlands before and during the intervention and who received ivermectin/permethrin. In total, 2866 asylum seekers received treatment during the study period (January 2014 -March 2016) of which 1359 (47.4%) had clinical signs of scabies. During the programme, most of the asylum seekers with scabies were already diagnosed on arrival as part of the SIP screening (580 (64.7%) of the 897). Asylum seekers with more than one scabies episode reduced from 42.0% (194/462) before the programme to 27.2% (243/897) during the programme (RR = 0.64, 95% CI = 0.55-0.75). Development of scabies complications later in the asylum procedure reduced from 12.3% (57/462) to 4.6% (41/897). A scabies prevention and treatment programme at start of the asylum procedure was feasible and effective in the Netherlands; patients were diagnosed early and risk of reinfestations and complications reduced. To achieve a further decrease of scabies, implementation of the programme in multiple asylum centres may be needed.
MeSH term(s)	Acaricides/administration & dosage ; Adolescent ; Adult ; Animals ; Female ; Humans ; Ivermectin/administration & dosage ; Male ; Middle Aged ; Netherlands ; Refugees/statistics & numerical data ; Retrospective Studies ; Sarcoptes scabiei/drug effects ; Scabies/drug therapy ; Scabies/parasitology ; Young Adult
Chemical Substances	Acaricides ; Ivermectin (70288-86-7)
Language	English
Publishing date	2018
Publishing country	United States
Document type	Journal Article
ZDB-ID	2429704-5
ISSN	1935-2735 ; 1935-2727
ISSN (online)	1935-2735
ISSN	1935-2727
DOI	10.1371/journal.pntd.0006401
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Article ; Online: Delayed versus standard assessment for excision surgery in patients with Buruli ulcer in Benin: a randomised controlled trial.

Wadagni, Akpeedje C / Barogui, Yves T / Johnson, Roch C / Sopoh, Ghislain E / Affolabi, Dissou / van der Werf, Tjip S / de Zeeuw, Janine / Kleinnijenhuis, Johanneke / Stienstra, Ymkje

The Lancet. Infectious diseases

2018 Volume 18, Issue 6, Page(s) 650–656

Abstract: Background: Surgical intervention was once the mainstay of treatment for Buruli ulcer disease, a neglected tropical disease caused by Mycobacterium ulcerans. Since the introduction of streptomycin and rifampicin for 8 weeks as standard care, surgery has ...

Abstract	Background: Surgical intervention was once the mainstay of treatment for Buruli ulcer disease, a neglected tropical disease caused by Mycobacterium ulcerans. Since the introduction of streptomycin and rifampicin for 8 weeks as standard care, surgery has persisted as an adjunct therapy, but its role is uncertain. We investigated the effect of delaying the decision to operate to 14 weeks on rates of healing without surgery. Methods: In this randomised controlled trial, we enrolled patients aged 3 years or older with confirmed disease at one hospital in Lalo, Benin. Patients were randomly assigned (1:1) to groups assessing the need for excision surgery 8 weeks (standard care) or 14 weeks after initiation of antimicrobial treatment. The primary endpoint was the number of patients healed without the need for surgery (not including skin grafting), assessed in all patients in follow-up at 50 weeks (or last observation for those healed for >10 weeks). A doctor masked to treatment assignment checked the indications for surgery according to predefined criteria. This study is registered with ClinicalTrials.gov, number NCT01432925. Findings: Between July 1, 2011, and Jan 15, 2015, 119 patients were enrolled, with two patients per group lost to follow-up. 55 (96%) of 57 participants in the delayed-decision group and 52 (90%) of 58 participants in the standard-care group had healed lesions 1 year after start of antimicrobial treatment (relative risk [RR] 1·08, 95% CI 0·97-1·19). 37 (67%) of 55 patients in the delayed-decision group had their lesions healed without surgical intervention, as did 25 (48%) of 52 in the standard-care group (RR 1·40, 95% CI 1·00-1·96). The time to heal and residual functional limitations did not differ between the two groups (median time to heal 21 weeks [IQR 10-27] in the delayed-decision group and 21 weeks [10-39] in the standard-care group; functional limitations in six [11%] of 57 and three [5%] of 58 patients; p=0·32). Postponing the decision to operate resulted in reduced median duration of hospitalisation (5 days [IQR 0-187] vs 131 days [0-224]; p=0·024) and wound care (153 days [IQR 56-224] vs 182 days [94-307]; p=0·036). Interpretation: In our study, patients treated for Buruli ulcer benefited from delaying the decision to operate. Even large ulcers can heal with antibiotics alone, without delaying healing rate and without an increase in residual functional limitations. Funding: NWO-VENI grant 241500, BUG Foundation, and UBS OPTIMUS.
MeSH term(s)	Adolescent ; Anti-Bacterial Agents/therapeutic use ; Benin/epidemiology ; Buruli Ulcer/drug therapy ; Buruli Ulcer/epidemiology ; Buruli Ulcer/surgery ; Child ; Child, Preschool ; Female ; Humans ; Male ; Time Factors ; Wound Healing
Chemical Substances	Anti-Bacterial Agents
Language	English
Publishing date	2018-04-05
Publishing country	United States
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	2061641-7
ISSN	1474-4457 ; 1473-3099
ISSN (online)	1474-4457
ISSN	1473-3099
DOI	10.1016/S1473-3099(18)30160-9
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Article ; Online: Innate immune recognition of Mycobacterium tuberculosis.

Kleinnijenhuis, Johanneke / Oosting, Marije / Joosten, Leo A B / Netea, Mihai G / Van Crevel, Reinout

Clinical & developmental immunology

2011 Volume 2011, Page(s) 405310

Abstract: Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is a major health problem, with 10 million new cases diagnosed each year. Innate immunity plays an important role in the host defense against M. tuberculosis, and the first step in this ... ...

Abstract	Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is a major health problem, with 10 million new cases diagnosed each year. Innate immunity plays an important role in the host defense against M. tuberculosis, and the first step in this process is recognition of MTB by cells of the innate immune system. Several classes of pattern recognition receptors (PPRs) are involved in the recognition of M. tuberculosis, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), and Nod-like receptors (NLRs). Among the TLR family, TLR2, TLR4, and TLR9 and their adaptor molecule MyD88 play the most prominent roles in the initiation of the immune response against tuberculosis. In addition to TLRs, other PRRs such as NOD2, Dectin-1, Mannose receptor, and DC-SIGN are also involved in the recognition of M. tuberculosis. Human epidemiological studies revealed that genetic variation in genes encoding for PRRs and downstream signaling products influence disease susceptibility, severity, and outcome. More insight into PRRs and the recognition of mycobacteria, combined with immunogenetic studies in TB patients, does not only lead to a better understanding of the pathogenesis of tuberculosis but also may contribute to the design of novel immunotherapeutic strategies.
MeSH term(s)	Animals ; Genetic Predisposition to Disease ; Humans ; Immunity, Innate/immunology ; Mycobacterium tuberculosis/immunology ; Polymorphism, Genetic ; Signal Transduction/immunology ; Tuberculosis/genetics ; Tuberculosis/immunology
Language	English
Publishing date	2011-04-07
Publishing country	Egypt
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2119646-1
ISSN	1740-2530 ; 1740-2522
ISSN (online)	1740-2530
ISSN	1740-2522
DOI	10.1155/2011/405310
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Article ; Online: Innate Immune Recognition of Mycobacterium tuberculosis

Johanneke Kleinnijenhuis / Marije Oosting / Leo A. B. Joosten / Mihai G. Netea / Reinout Van Crevel

Clinical and Developmental Immunology, Vol

2011 Volume 2011

Abstract	Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is a major health problem, with 10 million new cases diagnosed each year. Innate immunity plays an important role in the host defense against M. tuberculosis, and the first step in this process is recognition of MTB by cells of the innate immune system. Several classes of pattern recognition receptors (PPRs) are involved in the recognition of M. tuberculosis, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), and Nod-like receptors (NLRs). Among the TLR family, TLR2, TLR4, and TLR9 and their adaptor molecule MyD88 play the most prominent roles in the initiation of the immune response against tuberculosis. In addition to TLRs, other PRRs such as NOD2, Dectin-1, Mannose receptor, and DC-SIGN are also involved in the recognition of M. tuberculosis. Human epidemiological studies revealed that genetic variation in genes encoding for PRRs and downstream signaling products influence disease susceptibility, severity, and outcome. More insight into PRRs and the recognition of mycobacteria, combined with immunogenetic studies in TB patients, does not only lead to a better understanding of the pathogenesis of tuberculosis but also may contribute to the design of novel immunotherapeutic strategies.
Keywords	Medicine ; R ; Internal medicine ; RC31-1245 ; Specialties of internal medicine ; RC581-951 ; Immunologic diseases. Allergy ; RC581-607
Subject code	572
Language	English
Publishing date	2011-01-01T00:00:00Z
Publisher	Hindawi Publishing Corporation
Document type	Article ; Online
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Article ; Online: Immunometabolic Pathways in BCG-Induced Trained Immunity.

Arts, Rob J W / Carvalho, Agostinho / La Rocca, Claudia / Palma, Carla / Rodrigues, Fernando / Silvestre, Ricardo / Kleinnijenhuis, Johanneke / Lachmandas, Ekta / Gonçalves, Luís G / Belinha, Ana / Cunha, Cristina / Oosting, Marije / Joosten, Leo A B / Matarese, Giuseppe / van Crevel, Reinout / Netea, Mihai G

Cell reports

2016 Volume 17, Issue 10, Page(s) 2562–2571

Abstract: The protective effects of the tuberculosis vaccine Bacillus Calmette-Guerin (BCG) on unrelated infections are thought to be mediated by long-term metabolic changes and chromatin remodeling through histone modifications in innate immune cells such as ... ...

Abstract	The protective effects of the tuberculosis vaccine Bacillus Calmette-Guerin (BCG) on unrelated infections are thought to be mediated by long-term metabolic changes and chromatin remodeling through histone modifications in innate immune cells such as monocytes, a process termed trained immunity. Here, we show that BCG induction of trained immunity in monocytes is accompanied by a strong increase in glycolysis and, to a lesser extent, glutamine metabolism, both in an in-vitro model and after vaccination of mice and humans. Pharmacological and genetic modulation of rate-limiting glycolysis enzymes inhibits trained immunity, changes that are reflected by the effects on the histone marks (H3K4me3 and H3K9me3) underlying BCG-induced trained immunity. These data demonstrate that a shift of the glucose metabolism toward glycolysis is crucial for the induction of the histone modifications and functional changes underlying BCG-induced trained immunity. The identification of these pathways may be a first step toward vaccines that combine immunological and metabolic stimulation.
MeSH term(s)	Animals ; BCG Vaccine/immunology ; Chromatin Assembly and Disassembly/genetics ; Chromatin Assembly and Disassembly/immunology ; Epigenesis, Genetic/immunology ; Glycolysis/immunology ; Histone Code/genetics ; Humans ; Immunity, Innate ; Immunologic Memory/genetics ; Mice ; Monocytes/immunology ; Tuberculosis/immunology ; Tuberculosis/microbiology ; Tuberculosis/prevention & control
Chemical Substances	BCG Vaccine
Language	English
Publishing date	2016-12-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2016.11.011
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Article ; Online: BCG-induced trained immunity in NK cells: Role for non-specific protection to infection.

Kleinnijenhuis, Johanneke / Quintin, Jessica / Preijers, Frank / Joosten, Leo A B / Jacobs, Cor / Xavier, Ramnik J / van der Meer, Jos W M / van Crevel, Reinout / Netea, Mihai G

Clinical immunology (Orlando, Fla.)

2014 Volume 155, Issue 2, Page(s) 213–219

Abstract: Adaptive features of innate immunity, also termed 'trained immunity', have recently been shown to characterize monocytes of BCG vaccinated healthy volunteers. Trained immunity leads to increased cytokine production in response to non-related pathogens ... ...

Abstract	Adaptive features of innate immunity, also termed 'trained immunity', have recently been shown to characterize monocytes of BCG vaccinated healthy volunteers. Trained immunity leads to increased cytokine production in response to non-related pathogens via epigenetic reprogramming of monocytes. Recently, memory-like properties were also observed in NK cells during viral infections, but it is unknown if memory properties of NK cells contribute to trained immunity due to BCG vaccination. BCG vaccination of healthy volunteers increased proinflammatory cytokine production following ex vivo stimulation of NK cells with mycobacteria and other unrelated pathogens up until at least three months after vaccination. In addition, in a murine model of disseminated candidiasis, BCG vaccination led to an increased survival in SCID mice, which was partially dependent on NK cells. These findings suggest that NK cells may contribute to the non-specific (heterologous) beneficial effects of BCG vaccination.
MeSH term(s)	Adaptive Immunity ; Adult ; Animals ; Antigens, CD/metabolism ; BCG Vaccine/administration & dosage ; BCG Vaccine/immunology ; Candida albicans/immunology ; Candidiasis/immunology ; Candidiasis/prevention & control ; Cross Reactions/immunology ; Cytokines/biosynthesis ; Disease Models, Animal ; Humans ; Immunophenotyping ; Inflammation Mediators/metabolism ; Interferon-gamma/biosynthesis ; Killer Cells, Natural/immunology ; Killer Cells, Natural/metabolism ; Mice ; Phenotype ; Tuberculosis/immunology ; Tuberculosis/prevention & control ; Vaccination ; Young Adult
Chemical Substances	Antigens, CD ; BCG Vaccine ; Cytokines ; Inflammation Mediators ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2014-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1459903-x
ISSN	1521-7035 ; 1521-6616
ISSN (online)	1521-7035
ISSN	1521-6616
DOI	10.1016/j.clim.2014.10.005
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