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2. BCG-induced non-specific effects on heterologous infectious disease in Ugandan neonates: an investigator-blind randomised controlled trial

Author

Prentice, Sarah, Nassanga, Beatrice, Akurut, Hellen, Akello, Florence, Kiwudhu, Fred, Cose, Stephen, Dockrell, Hazel, Webb, Emily, Elliott, Alison, Nabaweesi, Irene, Zziwa, Christopher, Namutebi, Milly, Namarra, Benigna, Nakazibwe, Esther, Amongi, Susan, Kamukama, Grace, Iwala, Susan, Ninsiima, Caroline, Tumusiime, Josephine, Kiwanuka, Fred, Nsubuga, Saadn, Akello, Justin, Owilla, Sebastian, Levin, Jonathan, Nash, Stephen, Kabuubi Nakawungu, Prossy, Abayo, Elson, Nabakooza, Grace, Kaushaaga, Zephyrian, Akello, Miriam, Webb, Emily L, Elliott, Alison M, Arts, Rob J W, Netea, Mihai G, and Dockrell, Hazel M

Published
2021
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3. OTULIN Haploinsufficiency-Related Fasciitis and Skin Necrosis Treated by TNF Inhibition

Author

MMB Onderzoek en Onderwijs, Infection & Immunity, MMB Medische Staf, Arts, Rob J W, van der Linden, Tristan J, van der Made, Caspar I, Hendriks, Marianne M C, van der Heijden, Wouter A, de Mast, Quirijn, Schuurs-Hoeijmakers, Janneke H M, Simons, Annet, Spaan, András N, Mulders-Manders, Catharina M, van de Veerdonk, Frank L, MMB Onderzoek en Onderwijs, Infection & Immunity, MMB Medische Staf, Arts, Rob J W, van der Linden, Tristan J, van der Made, Caspar I, Hendriks, Marianne M C, van der Heijden, Wouter A, de Mast, Quirijn, Schuurs-Hoeijmakers, Janneke H M, Simons, Annet, Spaan, András N, Mulders-Manders, Catharina M, and van de Veerdonk, Frank L

Published
2024

4. OTULIN Haploinsufficiency-Related Fasciitis and Skin Necrosis Treated by TNF Inhibition

Author

Arts, Rob J. W., primary, van der Linden, Tristan J., additional, van der Made, Caspar I., additional, Hendriks, Marianne M. C., additional, van der Heijden, Wouter A., additional, de Mast, Quirijn, additional, Schuurs-Hoeijmakers, Janneke H. M., additional, Simons, Annet, additional, Spaan, András N., additional, Mulders-Manders, Catharina M., additional, and van de Veerdonk, Frank L., additional

Published
2023
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6. Anticytokine Autoantibodies in Infectious Diseases: A Practical Overview.

Author

Arts, Rob J. W., Janssen, Nico A. F., and van de Veerdonk, Frank L.

Subjects
*AUTOANTIBODIES, *COMMUNICABLE diseases, *IMMUNOSPECIFICITY, *AUTOIMMUNITY, *IMMUNOGLOBULINS, *FC receptors
Abstract

Anticytokine autoantibodies (ACAAs) are a fascinating group of antibodies that have gained more and more attention in the field of autoimmunity and secondary immunodeficiencies over the years. Some of these antibodies are characterized by their ability to target and neutralize specific cytokines. ACAAs can play a role in the susceptibility to several infectious diseases, and their infectious manifestations depending on which specific immunological pathway is affected. In this review, we will give an outline per infection in which ACAAs might play a role and whether additional immunomodulatory treatment next to antimicrobial treatment can be considered. Finally, we describe the areas for future research on ACAAs. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Outcomes of controlled human malaria infection after BCG vaccination

Author

Walk, Jona, de Bree, L. Charlotte J., Graumans, Wouter, Stoter, Rianne, van Gemert, Geert-Jan, van de Vegte-Bolmer, Marga, Teelen, Karina, Hermsen, Cornelus C., Arts, Rob J. W., Behet, Marije C., Keramati, Farid, Moorlag, Simone J. C. F. M., Yang, Annie S. P., van Crevel, Reinout, Aaby, Peter, de Mast, Quirijn, van der Ven, André J. A. M., Stabell Benn, Christine, Netea, Mihai G., and Sauerwein, Robert W.

Published
2019
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11. Exploratory analysis of interleukin‐38 in hospitalized COVID‐19 patients.

Author

de Graaf, Dennis M., Teufel, Lisa U., de Nooijer, Aline H., van Gammeren, Adriaan J., Ermens, Antonius A. M., Gaál, Ildikó O., Crișan, Tania O., van de Veerdonk, Frank L., Netea, Mihai G., Dinarello, Charles A., Joosten, Leo A. B., and Arts, Rob J. W.

Subjects
COVID-19, HOSPITAL patients, VIRUS diseases, EXTRACELLULAR matrix proteins, IMMUNOGLOBULIN receptors
Abstract

Introduction: A major contributor to coronavirus disease 2019 (COVID‐19) progression and severity is a dysregulated innate and adaptive immune response. Interleukin‐38 (IL−38) is an IL‐1 family member with broad anti‐inflammatory properties, but thus far little is known about its role in viral infections. Recent studies have shown inconsistent results, as one study finding an increase in circulating IL‐38 in COVID‐19 patients in comparison to healthy controls, whereas two other studies report no differences in IL‐38 concentrations. Methods: Here, we present an exploratory, retrospective cohort study of circulating IL‐38 concentrations in hospitalized COVID‐19 patients admitted to two Dutch hospitals (discovery n = 148 and validation n = 184) and age‐ and sex‐matched healthy subjects. Plasma IL‐38 concentrations were measured by enzyme‐linked immunosorbent assay, disease‐related proteins by proximity extension assay, and clinical data were retrieved from hospital records. Results: IL‐38 concentrations were stable during hospitalization and similar to those of healthy control subjects. IL‐38 was not associated with rates of intensive care unit admission or mortality. Only in men in the discovery cohort, IL‐38 concentrations were positively correlated with hospitalization duration. A positive correlation between IL‐38 and the inflammatory biomarker d‐dimer was observed in men of the validation cohort. In women of the validation cohort, IL‐38 concentrations correlated negatively with thrombocyte numbers. Furthermore, plasma IL‐38 concentrations in the validation cohort correlated positively with TNF, TNFRSF9, IL‐10Ra, neurotrophil 3, polymeric immunoglobulin receptor, CHL1, CD244, superoxide dismutase 2, and fatty acid binding protein 2, and negatively with SERPINA12 and cartilage oligomeric matrix protein. Conclusions: These data indicate that IL‐38 is not associated with disease outcomes in hospitalized COVID‐19 patients. However, moderate correlations between IL‐38 concentrations and biomarkers of disease were identified in one of two cohorts. While we demonstrate that IL‐38 concentrations are not indicative of COVID‐19 severity, its anti‐inflammatory effects may reduce COVID‐19 severity and should be experimentally investigated. [ABSTRACT FROM AUTHOR]

Published
2022
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12. induction of trained immunity in adherent human monocytes

Author

Domínguez-Andrés, Jorge, Arts, Rob J W, Bekkering, Siroon, Bahrar, Harsh, Blok, Bastiaan A, de Bree, L Charlotte J, Bruno, Mariolina, Bulut, Özlem, Debisarun, Priya A, Dijkstra, Helga, Cristina Dos Santos, Jéssica, Ferreira, Anaísa V, Flores-Gomez, Daniela, Groh, Laszlo A, Grondman, Inge, Helder, Leonie, Jacobs, Cor, Jacobs, Liesbeth, Jansen, Trees, Kilic, Gizem, Klück, Viola, Koeken, Valerie A C M, Lemmers, Heidi, Moorlag, Simone J C F M, Mourits, Vera P, van Puffelen, Jelmer H, Rabold, Katrin, Röring, Rutger J, Rosati, Diletta, Tercan, Helin, van Tuijl, Julia, Quintin, Jessica, van Crevel, Reinout, Riksen, Niels P, Joosten, Leo A B, Netea, Mihai G, and CiiM, Zentrum für individualisierte Infektionsmedizin, Feodor-Lynen-Str.7, 30625 Hannover.

Subjects
Cell biology, Cell isolation, Immunology, Cell-based assays
Abstract

A growing number of studies show that innate immune cells can undergo functional reprogramming, facilitating a faster and enhanced response to heterologous secondary stimuli. This concept has been termed "trained immunity." We outline here a protocol to recapitulate this in vitro using adherent monocytes from consecutive isolation of peripheral blood mononuclear cells. The induction of trained immunity and the associated functional reprogramming of monocytes is described in detail using β-glucan (from Candida albicans) and Bacillus Calmette-Guérin as examples. For complete details on the use and execution of this protocol, please refer to Repnik et al. (2003) and Bekkering et al. (2016).

Published
2021

13. Altered Ex-Vivo Cytokine Responses in Children With Asymptomatic Plasmodium falciparum Infection in Burkina Faso: An Additional Argument to Treat Asymptomatic Malaria?

Author

Post, Annelies, primary, Kaboré, Berenger, additional, Berendsen, Mike, additional, Diallo, Salou, additional, Traore, Ousmane, additional, Arts, Rob J. W., additional, Netea, Mihai G., additional, Joosten, Leo A. B., additional, Tinto, Halidou, additional, Jacobs, Jan, additional, de Mast, Quirijn, additional, and van der Ven, André, additional

Published
2021
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14. IMMUNOGENETICS: mTOR- and HIF-lα-mediated aerobic glycolysis as metabolic basis for trained immunity

Author

Cheng, Shih-Chin, Quintin, Jessica, Cramer, Robert A., Shepardson, Kelly M., Saeed, Sadia, Kumar, Vinod, Giamarellos-Bourboulis, Evangelos J., Martens, Joost H. A., Rao, Nagesha Appukudige, Aghajanirefah, Ali, Manjeri, Ganesh R., Li, Yang, Ifrim, Daniela C., Arts, Rob J. W., van der Meer, Brian M. J. W., Deen, Peter M. T., Logie, Colin, OʼNeill, Luke A., Willems, Peter, van de Veerdonk, Frank L., van der Meer, Jos W. M., Ng, Aylwin, Joosten, Leo A. B., Wijmenga, Cisca, Stunnenberg, Hendrik G., Xavier, Ramnik J., and Netea, Mihai G.

Published
2014
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19. Frontline Science: Endotoxin-induced immunotolerance is associated with loss of monocyte metabolic plasticity and reduction of oxidative burst

Author

Grondman, Inge, primary, Arts, Rob J W, additional, Koch, Rebecca M, additional, Leijte, Guus P, additional, Gerretsen, Jelle, additional, Bruse, Niklas, additional, Kempkes, Rosalie W M, additional, ter Horst, Rob, additional, Kox, Matthijs, additional, Pickkers, Peter, additional, Netea, Mihai G, additional, and Gresnigt, Mark S, additional

Published
2019
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20. Metformin Alters Human Host Responses to Mycobacterium tuberculosis in Healthy Subjects

Author

Lachmandas, Ekta, primary, Eckold, Clare, additional, Böhme, Julia, additional, Koeken, Valerie A C M, additional, Marzuki, Mardiana Binte, additional, Blok, Bastiaan, additional, Arts, Rob J W, additional, Chen, Jinmiao, additional, Teng, Karen W W, additional, Ratter, Jacqueline, additional, Smolders, Elise J, additional, Van den Heuvel, Corina, additional, Stienstra, Rinke, additional, Dockrell, Hazel M, additional, Newell, Evan, additional, Netea, Mihai G, additional, Singhal, Amit, additional, Cliff, Jacqueline M, additional, and Van Crevel, Reinout, additional

Published
2019
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22. IL‐38 prevents induction of trained immunity by inhibition of mTOR signaling

Author

Graaf, Dennis M., Teufel, Lisa U., Veerdonk, Frank L., Joosten, Leo A. B., Netea, Mihai G., Dinarello, Charles A., and Arts, Rob J. W.

Abstract

Trained immunity is the acquisition of a hyperresponsive phenotype by innate immune cells (such as monocytes and macrophages) after an infection or vaccination, a de factononspecific memory dependent on epigenetic and metabolic reprogramming of these cells. We have recently shown that induction of trained immunity is dependent on IL‐1β. Here, we show that recombinant IL‐38, an anti‐inflammatory cytokine of the IL‐1‐family, was able to induce long‐term inhibitory changes and reduce the induction of trained immunity by β‐glucan in vivo in C57BL/6 mice and ex vivoin their bone marrow cells. IL‐38 blocked mTOR signaling and prevented the epigenetic and metabolic changes induced by β‐glucan. In healthy subjects, the IL1F10associated single nucleotide polymorphism rs58965312 correlated with higher plasma IL‐38 concentrations and reduced induction of trained immunity by β‐glucan ex vivo. These results indicate that IL‐38 induces long‐term anti‐inflammatory changes and also inhibits the induction of trained immunity. Recombinant IL‐38 could therefore potentially be used as a therapeutic intervention for diseases characterized by exacerbated trained immunity. IL‐38 inhibits the induction of innate immune memory

Published
2021
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23. Inhibiting Inflammation with Myeloid Cell-Specific Nanobiologics Promotes Organ Transplant Acceptance

Author

Braza, Mounia S., Braza, Mounia S., van Leent, Mandy M. T., Lameijer, Marnix, Sanchez-Gaytan, Brenda L., Arts, Rob J. W., Perez-Medina, Carlos, Conde, Patricia, Garcia, Mercedes R., Gonzalez-Perez, Maria, Brahmachary, Manisha, Fay, Francois, Kluza, Ewelina, Kossatz, Susanne, Dress, Regine J., Salem, Fadi, Rialdi, Alexander, Reiner, Thomas, Boros, Peter, Strijkers, Gustav J., Calcagno, Claudia C., Ginhoux, Florent, Marazzi, Ivan, Lutgens, Esther, Nicolaes, Gerry A. F., Weber, Christian, Swirski, Filip K., Nahrendorf, Matthias, Fisher, Edward A., Duivenvoorden, Raphael, Fayad, Zahi A., Netea, Mihai G., Mulder, Willem J. M., Ochando, Jordi, Braza, Mounia S., Braza, Mounia S., van Leent, Mandy M. T., Lameijer, Marnix, Sanchez-Gaytan, Brenda L., Arts, Rob J. W., Perez-Medina, Carlos, Conde, Patricia, Garcia, Mercedes R., Gonzalez-Perez, Maria, Brahmachary, Manisha, Fay, Francois, Kluza, Ewelina, Kossatz, Susanne, Dress, Regine J., Salem, Fadi, Rialdi, Alexander, Reiner, Thomas, Boros, Peter, Strijkers, Gustav J., Calcagno, Claudia C., Ginhoux, Florent, Marazzi, Ivan, Lutgens, Esther, Nicolaes, Gerry A. F., Weber, Christian, Swirski, Filip K., Nahrendorf, Matthias, Fisher, Edward A., Duivenvoorden, Raphael, Fayad, Zahi A., Netea, Mihai G., Mulder, Willem J. M., and Ochando, Jordi

Abstract

Inducing graft acceptance without chronic immunosuppression remains an elusive goal in organ transplantation. Using an experimental transplantation mouse model, we demonstrate that local macrophage activation through dectin-1 and toll-like receptor 4 (TLR4) drives trained immunity-associated cytokine production during allograft rejection. We conducted nanoimmunotherapeutic studies and found that a short-term mTOR-specific high-density lipoprotein (HDL) nanobiologic treatment (mTORi-HDL) averted macrophage aerobic glycolysis and the epigenetic modifications underlying inflammatory cytokine production. The resulting regulatory macrophages prevented alloreactive CD8(+) T cell-mediated immunity and promoted tolerogenic CD4(+) regulatory T (Treg) cell expansion. To enhance therapeutic efficacy, we complemented the mTORi-HDL treatment with a CD40-TRAF6-specific nanobiologic (TRAF6i-HDL) that inhibits co-stimulation. This synergistic nanoimmunotherapy resulted in indefinite allograft survival. Together, we show that HDL-based nanoimmunotherapy can be employed to control macrophage function in vivo. Our strategy, focused on preventing inflammatory innate immune responses, provides a framework for developing targeted therapies that promote immunological tolerance.

Published
2018

24. Oncogene-induced maladaptive activation of trained immunity in the pathogenesis and treatment of Erdheim-Chester disease

Author

Molteni, Raffaella, Biavasco, Riccardo, Stefanoni, Davide, Nemkov, Travis, Domínguez-Andrés, Jorge, Arts, Rob J., Merelli, Ivan, Mazza, Davide, Zambrano, Samuel, Panigada, Maddalena, Cantoni, Eleonora, Tengesdal, Isak W., Maksud, Philippe, Piras, Francesco, Cesana, Daniela, Cassina, Laura, Distefano, Gianfranco, Loffreda, Alessia, Gnani, Daniela, De Luca, Giacomo, Tomelleri, Alessandro, Campochiaro, Corrado, Joosten, Leo A.B., Dinarello, Charles A., Kajaste-Rudnitski, Anna, Haroche, Julien, Cardaci, Simone, Cenci, Simone, Dagna, Lorenzo, Doglioni, Claudio, Ferrarini, Marina, Ferrero, Elisabetta, Boletta, Alessandra, D'Alessandro, Angelo, Montini, Eugenio, Netea, Mihai G., and Cavalli, Giulio

Abstract

Trained immunity (TI) is a proinflammatory program induced in monocyte/macrophages upon sensing of specific pathogens and is characterized by immunometabolic and epigenetic changes that enhance cytokine production. Maladaptive activation of TI (ie, in the absence of infection) may result in detrimental inflammation and development of disease; however, the exact role and extent of inappropriate activation of TI in the pathogenesis of human diseases is undetermined. In this study, we uncovered the oncogene-induced, maladaptive induction of TI in the pathogenesis of a human inflammatory myeloid neoplasm (Erdheim-Chester disease, [ECD]), characterized by the BRAFV600E oncogenic mutation in monocyte/macrophages and excess cytokine production. Mechanistically, myeloid cells expressing BRAFV600E exhibit all molecular features of TI: activation of the AKT/mammalian target of rapamycin signaling axis; increased glycolysis, glutaminolysis, and cholesterol synthesis; epigenetic changes on promoters of genes encoding cytokines; and enhanced cytokine production leading to hyperinflammatory responses. In patients with ECD, effective therapeutic strategies combat this maladaptive TI phenotype; in addition, pharmacologic inhibition of immunometabolic changes underlying TI (ie, glycolysis) effectively dampens cytokine production by myeloid cells. This study revealed the deleterious potential of inappropriate activation of TI in the pathogenesis of human inflammatory myeloid neoplasms and the opportunity for inhibition of TI in conditions characterized by maladaptive myeloid-driven inflammation.

Published
2021
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28. Rewiring monocyte glucose metabolism via C-type lectin signaling protects against disseminated candidiasis

Author

Domínguez-Andrés, Jorge, primary, Arts, Rob J. W., additional, ter Horst, Rob, additional, Gresnigt, Mark S., additional, Smeekens, Sanne P., additional, Ratter, Jacqueline M., additional, Lachmandas, Ekta, additional, Boutens, Lily, additional, van de Veerdonk, Frank L., additional, Joosten, Leo A. B., additional, Notebaart, Richard A., additional, Ardavín, Carlos, additional, and Netea, Mihai G., additional

Published
2017
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29. Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis

Author

Cheng, Shih Chin, Scicluna, Brendon P., Arts, Rob J W, Gresnigt, Mark S., Lachmandas, Ekta, Giamarellos-Bourboulis, Evangelos J., Kox, Matthijs, Manjeri, Ganesh R., Wagenaars, Jori A L, Cremer, Olaf L., Leentjens, Jenneke, van der Meer, Anne J., van de Veerdonk, Frank L., Bonten, Marc J., Schultz, Marcus J., Willems, Peter H G M, Pickkers, Peter, Joosten, Leo A B, van der Poll, Tom, Netea, Mihai G., Cheng, Shih Chin, Scicluna, Brendon P., Arts, Rob J W, Gresnigt, Mark S., Lachmandas, Ekta, Giamarellos-Bourboulis, Evangelos J., Kox, Matthijs, Manjeri, Ganesh R., Wagenaars, Jori A L, Cremer, Olaf L., Leentjens, Jenneke, van der Meer, Anne J., van de Veerdonk, Frank L., Bonten, Marc J., Schultz, Marcus J., Willems, Peter H G M, Pickkers, Peter, Joosten, Leo A B, van der Poll, Tom, and Netea, Mihai G.

Published
2016

30. Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis

Author

Medische Staf Intensive Care, Infection & Immunity, Epi Infectieziekten, JC onderzoeksprogramma Infectieziekten, MMB, Cheng, Shih Chin, Scicluna, Brendon P., Arts, Rob J W, Gresnigt, Mark S., Lachmandas, Ekta, Giamarellos-Bourboulis, Evangelos J., Kox, Matthijs, Manjeri, Ganesh R., Wagenaars, Jori A L, Cremer, Olaf L., Leentjens, Jenneke, van der Meer, Anne J., van de Veerdonk, Frank L., Bonten, Marc J., Schultz, Marcus J., Willems, Peter H G M, Pickkers, Peter, Joosten, Leo A B, van der Poll, Tom, Netea, Mihai G., Medische Staf Intensive Care, Infection & Immunity, Epi Infectieziekten, JC onderzoeksprogramma Infectieziekten, MMB, Cheng, Shih Chin, Scicluna, Brendon P., Arts, Rob J W, Gresnigt, Mark S., Lachmandas, Ekta, Giamarellos-Bourboulis, Evangelos J., Kox, Matthijs, Manjeri, Ganesh R., Wagenaars, Jori A L, Cremer, Olaf L., Leentjens, Jenneke, van der Meer, Anne J., van de Veerdonk, Frank L., Bonten, Marc J., Schultz, Marcus J., Willems, Peter H G M, Pickkers, Peter, Joosten, Leo A B, van der Poll, Tom, and Netea, Mihai G.

Published
2016

31. mTOR- and HIF-1 alpha-mediated aerobic glycolysis as metabolic basis for trained immunity

Author

Cheng, Shih-Chin Quintin, Jessica Cramer, Robert A. and Shepardson, Kelly M. Saeed, Sadia Kumar, Vinod and Giamarellos-Bourboulis, Evangelos J. Martens, Joost H. A. Rao, Nagesha Appukudige Aghajanirefah, Ali Manjeri, Ganesh R. Li, Yang Ifrim, Daniela C. Arts, Rob J. W. van der Meer, Brian M. J. W. Deen, Peter M. T. Logie, Colin O'Neill, Luke A. and Willems, Peter van de Veerdonk, Frank L. van der Meer, Jos W. M. and Ng, Aylwin Joosten, Leo A. B. Wijmenga, Cisca and Stunnenberg, Hendrik G. Xavier, Ramnik J. Netea, Mihai G.

Abstract

Epigenetic reprogramming of myeloid cells, also known as trained immunity, confers nonspecific protection from secondary infections. Using histone modification profiles of human monocytes trained with the Candida albicans cell wall constituent beta-glucan, together with a genome-wide transcriptome, we identified the induced expression of genes involved in glucose metabolism. Trained monocytes display high glucose consumption, high lactate production, and a high ratio of nicotinamide adenine dinucleotide (NAD+) to its reduced form (NADH), reflecting a shift in metabolism with an increase in glycolysis dependent on the activation of mammalian target of rapamycin (mTOR) through a dectin-1-Akt-HIF-1 alpha (hypoxia-inducible factor-1 alpha) pathway. Inhibition of Akt, mTOR, or HIF-1 alpha blocked monocyte induction of trained immunity, whereas the adenosine monophosphate-activated protein kinase activator metformin inhibited the innate immune response to fungal infection. Mice with a myeloid cell-specific defect in HIF-1 alpha were unable to mount trained immunity against bacterial sepsis. Our results indicate that induction of aerobic glycolysis through an Akt-mTOR-HIF-1 alpha pathway represents the metabolic basis of trained immunity.

Published
2014

32. Transcriptional and metabolic reprogramming induce an inflammatory phenotype in non-medullary thyroid carcinoma-induced macrophages

Author

Arts, Rob J. W., primary, Plantinga, Theo S., additional, Tuit, Sander, additional, Ulas, Thomas, additional, Heinhuis, Bas, additional, Tesselaar, Marika, additional, Sloot, Yvette, additional, Adema, Gosse J., additional, Joosten, Leo A. B., additional, Smit, Johannes W. A., additional, Netea, Mihai G., additional, Schultze, Joachim L., additional, and Netea-Maier, Romana T., additional

Published
2016
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35. Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis

Author

Cheng, Shih-Chin, primary, Scicluna, Brendon P, additional, Arts, Rob J W, additional, Gresnigt, Mark S, additional, Lachmandas, Ekta, additional, Giamarellos-Bourboulis, Evangelos J, additional, Kox, Matthijs, additional, Manjeri, Ganesh R, additional, Wagenaars, Jori A L, additional, Cremer, Olaf L, additional, Leentjens, Jenneke, additional, van der Meer, Anne J, additional, van de Veerdonk, Frank L, additional, Bonten, Marc J, additional, Schultz, Marcus J, additional, Willems, Peter H G M, additional, Pickkers, Peter, additional, Joosten, Leo A B, additional, van der Poll, Tom, additional, and Netea, Mihai G, additional

Published
2016
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40. mTOR- and HIF-1α–mediated aerobic glycolysis as metabolic basis for trained immunity

Author

Cheng, Shih-Chin, primary, Quintin, Jessica, additional, Cramer, Robert A., additional, Shepardson, Kelly M., additional, Saeed, Sadia, additional, Kumar, Vinod, additional, Giamarellos-Bourboulis, Evangelos J., additional, Martens, Joost H. A., additional, Rao, Nagesha Appukudige, additional, Aghajanirefah, Ali, additional, Manjeri, Ganesh R., additional, Li, Yang, additional, Ifrim, Daniela C., additional, Arts, Rob J. W., additional, van der Veer, Brian M. J. W., additional, Deen, Peter M. T., additional, Logie, Colin, additional, O’Neill, Luke A., additional, Willems, Peter, additional, van de Veerdonk, Frank L., additional, van der Meer, Jos W. M., additional, Ng, Aylwin, additional, Joosten, Leo A. B., additional, Wijmenga, Cisca, additional, Stunnenberg, Hendrik G., additional, Xavier, Ramnik J., additional, and Netea, Mihai G., additional

Published
2014
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42. Cellular metabolism of myeloid cells in sepsis

Author

Arts, Rob J. W., Gresnigt, Mark S., Joosten, Leo A. B., and Netea, Mihai G.

Abstract

In recent years, it has become appreciated that immune cells have different metabolic profiles depending on their activation status. During sepsis, circulating leukocytes go through a hyperinflammatory state, which can be accompanied or followed by defective antimicrobial defenses (also described as immune tolerance or paralysis). In this review, the modulation of different cellular metabolic pathways during sepsis in monocytes and macrophages will be discussed. Glycolysis is studied extensively in sepsis and is up-regulated in hyperinflammatory cells, whereas in immune tolerance, it is often down-regulated. Few data are available on other metabolic pathways in immune cells from patients with sepsis. The pentose phosphate pathway is up-regulated during acute hyperinflammatory responses, whereas fatty acid ß-oxidation is increased later during sepsis and is associated with an anti-inflammatory (M2) phenotype of macrophages. Within the amino acid metabolism we will discuss the most studied metabolites. Collectively, these data argue that exploration of the immunometabolic pathways in sepsis is an important area of research, and the targeting of metabolic pathways may represent a promising novel strategy as a therapy of sepsis. Review on the changes in immunometabolic pathways during sepsis.

Published
2017
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43. An enigma: why vitamin A supplementation does not always reduce mortality even though vitamin A deficiency is associated with increased mortality.

Author

Benn, Christine S., Aaby, Peter, Arts, Rob J. W., Jensen, Kristoffer J., Netea, Mihai G., and Fisker, Ane B

Subjects
DIETARY supplements, VITAMIN A deficiency, MORTALITY, DRUG dosage
Abstract

Background: Vitamin A deficiency (VAD) is associated with increased mortality. To prevent VAD, WHO recommends high-dose vitamin A supplementation (VAS) every 4-6 months for children aged between 6 months and 5 years of age in countries at risk of VAD. The policy is based on randomized clinical trials (RCTs) conducted in the late 1980s and early 1990s. Recent RCTs indicate that the policy may have ceased to be beneficial. In addition, RCTs attempting to extend the benefits to younger children have yielded conflicting results. Stratified analyses suggest that whereas some subgroups benefit more than expected from VAS, other subgroups may experience negative effects. Methods and Results: We reviewed the potential modifiers of the effect of VAS. The variable effect of VAS was not explained by underlying differences in VAD. Rather, the effect may depend on the sex of the child, the vaccine status and previous supplementation with vitamin A. Vitamin A is known to affect the Th1/Th2 balance and, in addition, recent evidence suggests that vitamin A may also induce epigenetic changes leading to down-regulation of the innate immune response. Thus VAS protects against VAD but has also important and long-lasting immunological effects, and the effect of providing VAS may vary depending on the state of the immune system. Conclusions: To design optimal VAS programmes which target those who benefit and avoid those harmed, more studies are needed. Work is ongoing to define whether neonatal VAS should be considered in subgroups. In the most recent RCT in older children, VAS doubled the mortality for males but halved mortality for females. Hence, we ur-gently need to re-assess the effect of VAS on older children in large-scale RCTs powered to study effect modification by sex and other potential effect modifiers, and with nested immunological studies. [ABSTRACT FROM AUTHOR]

Published
2015
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50. BCG vaccination in humans inhibits systemic inflammation in a sex-dependent manner.

Author

Koeken, Valerie A. C. M., de Bree, L. Charlotte J., Mourits, Vera P., Moorlag, Simone J. C. F. M., Walk, Jona, Cirovic, Branko, Arts, Rob J. W., Jaeger, Martin, Dijkstra, Helga, Lemmers, Heidi, Joosten, Leo A. B., Benn, Christine S., van Crevel, Reinout, Netea, Mihai G., Koeken, Valerie Acm, Moorlag, Simone Jcfm, Arts, Rob Jw, and Joosten, Leo Ab

Subjects
*BCG vaccines, *INFLAMMATION, *IMMUNOLOGIC memory, *ALLERGIES, *BLOOD cells, *ORGANIZATIONAL research, *INFLAMMATION prevention, *HUMAN reproduction, *CYTOKINES, *IN vitro studies, *MONONUCLEAR leukocytes, *HUMAN research subjects, *PROTEOMICS, *STAPHYLOCOCCUS aureus, *MYCOBACTERIUM tuberculosis, *IMMUNITY, *INFLAMMATORY mediators, *LONGITUDINAL method, *PHARMACODYNAMICS
Abstract

BACKGROUNDInduction of innate immune memory, also termed trained immunity, by the antituberculosis vaccine bacillus Calmette-Guérin (BCG) contributes to protection against heterologous infections. However, the overall impact of BCG vaccination on the inflammatory status of an individual is not known; while induction of trained immunity may suggest increased inflammation, BCG vaccination has been epidemiologically associated with a reduced incidence of inflammatory and allergic diseases.METHODSWe investigated the impact of BCG (BCG-Bulgaria, InterVax) vaccination on systemic inflammation in a cohort of 303 healthy volunteers, as well as the effect of the inflammatory status on the response to vaccination. A targeted proteome platform was used to measure circulating inflammatory proteins before and after BCG vaccination, while ex vivo Mycobacterium tuberculosis- and Staphylococcus aureus-induced cytokine responses in peripheral blood mononuclear cells were used to assess trained immunity.RESULTSWhile BCG vaccination enhanced cytokine responses to restimulation, it reduced systemic inflammation. This effect was validated in 3 smaller cohorts, and was much stronger in men than in women. In addition, baseline circulating inflammatory markers were associated with ex vivo cytokine responses (trained immunity) after BCG vaccination.CONCLUSIONThe capacity of BCG to enhance microbial responsiveness while dampening systemic inflammation should be further explored for potential therapeutic applications.FUNDINGNetherlands Organization for Scientific Research, European Research Council, and the Danish National Research Foundation. [ABSTRACT FROM AUTHOR]

Published
2020
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