524 results on '"Netea, Mihai G."'
Search Results
2. Opposing Effects of Interleukin-36γ and Interleukin-38 on Trained Immunity.
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Teufel, Lisa U., Netea, Mihai G., van de Veerdonk, Frank L., Dinarello, Charles A., Joosten, Leo A. B., and Arts, Rob J. W.
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MONOCYTES , *IMMUNITY , *IMMUNOLOGIC memory , *BONE marrow , *INTERLEUKIN-1 - Abstract
Trained immunity is the process of long-term functional reprogramming (a de facto innate immune memory) of innate immune cells such as monocytes and macrophages after an exposure to pathogens, vaccines, or their ligands. The induction of trained immunity is mediated through epigenetic and metabolic mechanisms. Apart from exogenous stimuli, trained immunity can be induced by endogenous compounds such as oxidized LDL, urate, fumarate, but also cytokines including IL-1α and IL-1β. Here, we show that also recombinant IL-36γ, a pro-inflammatory cytokine of the IL-1-family, is able to induce trained immunity in primary human monocytes, demonstrated by higher cytokine responses and an increase in cellular metabolic pathways both regulated by epigenetic histone modifications. These effects could be inhibited by the IL-36 receptor antagonist as well as by IL-38, an anti-inflammatory cytokine of the IL-1 family which shares its main receptor with IL-36 (IL-1R6). Further, we demonstrated that trained immunity induced by IL-36γ is mediated by NF-κB and mTOR signaling. The inhibitory effect of IL-38 on IL-36γ-induced trained immunity was confirmed in experiments using bone marrow of IL-38KO and WT mice. These results indicate that exposure to IL-36γ results in long-term pro-inflammatory changes in monocytes which can be inhibited by IL-38. Recombinant IL-38 could therefore potentially be used as a therapeutic intervention for diseases characterized by exacerbated trained immunity. [ABSTRACT FROM AUTHOR]
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- 2023
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3. Beyond adaptive immunity: induction of trained immunity by COVID-19 adenoviral vaccines.
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Netea, Mihai G. and Joosten, Leo A. B.
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COVID-19 vaccines , *IMMUNITY , *NATURAL immunity , *COVID-19 pandemic , *T cells - Abstract
The COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, has resulted in much human suffering and societal disruption. The ChAdOx1 nCoV-19 vaccine against COVID-19 has had a crucial role in the fight against the pandemic. While ChAdOx1 nCoV-19 has been shown to induce adaptive B and T cell responses, which protect against COVID-19, in this issue of the JCI, Murphy et al. show that this vaccine also induces trained innate immunity. This finding contributes to a better understanding of the complex immunological effects of adenoviral-based vaccines, provides the possibility of clinically relevant heterologous effects of these vaccines, and suggests that other adenoviral-based vaccines may induce trained immunity. [ABSTRACT FROM AUTHOR]
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- 2023
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4. Beneficial non-specific effects of live vaccines against COVID-19 and other unrelated infections.
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Aaby, Peter, Netea, Mihai G, and Benn, Christine S
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COVID-19 vaccines , *BCG vaccines , *COVID-19 , *RANDOMIZED controlled trials , *BOOSTER vaccines - Abstract
Live attenuated vaccines could have beneficial, non-specific effects of protecting against vaccine-unrelated infections, such as BCG protecting against respiratory infection. During the COVID-19 pandemic, testing of these effects against COVID-19 was of interest to the pandemic control programme. Non-specific effects occur due to the broad effects of specific live attenuated vaccines on the host immune system, relying on heterologous lymphocyte responses and induction of trained immunity. Knowledge of non-specific effects has been developed in randomised controlled trials and observational studies with children, but examining of whether the same principles apply to adults and older adults was of interest to researchers during the pandemic. In this Personal View, we aim to define a framework for the analysis of non-specific effects of live attenuated vaccines against vaccine-unrelated infections with pandemic potential using several important concepts. First, study endpoints should prioritise severity of infection and overall patient health rather than incidence of infection only (eg, although several trials found no protection of the BCG vaccine against COVID-19 infection, it is associated with lower overall mortality than placebo). Second, revaccination of an individual with the same live attenuated vaccine could be the most effective strategy against vaccine-unrelated infections. Third, coadministration of several live attenuated vaccines might enhance beneficial non-specific effects. Fourth, the sequence of vaccine administration matters; the live attenuated vaccine should be the last vaccine administered before exposure to the pandemic infection and non-live vaccines should not be administered afterwards. Fifth, live attenuated vaccines could modify the immune response to specific COVID-19 vaccines. Finally, non-specific effects of live attenuated vaccines should always be analysed with subgroup analysis by sex of individuals receiving the vaccines. [ABSTRACT FROM AUTHOR]
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- 2023
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5. Clinical implications of host genetic variation and susceptibility to severe or critical COVID-19.
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van der Made, Caspar I., Netea, Mihai G., van der Veerdonk, Frank L., and Hoischen, Alexander
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COVID-19 , *SARS-CoV-2 , *GENETIC variation , *COMORBIDITY , *EPINEPHRINE autoinjectors - Abstract
Since the start of the coronavirus disease 2019 (COVID-19) pandemic, important insights have been gained into virus biology and the host factors that modulate the human immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 displays a highly variable clinical picture that ranges from asymptomatic disease to lethal pneumonia. Apart from well-established general risk factors such as advanced age, male sex and chronic comorbidities, differences in host genetics have been shown to influence the individual predisposition to develop severe manifestations of COVID-19. These differences range from common susceptibility loci to rare genetic variants with strongly predisposing effects, or proven pathogenic variants that lead to known or novel inborn errors of immunity (IEI), which constitute a growing group of heterogeneous Mendelian disorders with increased susceptibility to infectious disease, auto-inflammation, auto-immunity, allergy or malignancies. The current genetic findings point towards a convergence of common and rare genetic variants that impact the interferon signalling pathways in patients with severe or critical COVID-19. Monogenic risk factors that impact IFN-I signalling have an expected prevalence between 1 and 5% in young, previously healthy individuals (<60 years of age) with critical COVID-19. The identification of these IEI such as X-linked TLR7 deficiency indicates a possibility for targeted genetic screening and personalized clinical management. This review aims to provide an overview of our current understanding of the host genetic factors that predispose to severe manifestations of COVID-19 and focuses on rare variants in IFN-I signalling genes and their potential clinical implications. [ABSTRACT FROM AUTHOR]
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- 2022
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6. Trained immunity-related vaccines: innate immune memory and heterologous protection against infections.
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Ziogas, Athanasios and Netea, Mihai G.
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IMMUNOLOGIC memory , *COVID-19 , *VACCINES , *SARS-CoV-2 , *BONE marrow , *IMMUNE response - Abstract
The innate immune system is able to build memory-like features in response to certain infections or vaccines, resulting in enhanced responsiveness upon (re)challenge with the same or an unrelated pathogen, a phenomenon termed 'trained immunity'. Compared with antigen-dependent adaptive immune responses triggered by classical vaccines against specific pathogens, trained immunity-related vaccines induce enhanced innate immune responses against unrelated pathogens and provide 'heterologous protection'. Here, we discuss the heterologous effects of vaccines against infections and detail the latest insights into the cellular and molecular mechanisms mediating trained immunity. Additionally, novel vaccine strategies are suggested for fighting new pandemics in the future by taking advantage of the heterologous memory features of trained immunity. Trained innate immune cells have improved antimicrobial function mediated by transcriptional and epigenetic rewiring. Long-lasting trained immunity is centrally regulated in hematopoietic progenitors in the bone marrow and peripherally induced in tissue-resident cells. Distinct trained immunity programs at the single cell level identify trained monocyte subpopulations. Heterologous or nonspecific protection of vaccines against unrelated pathogens can be partially explained by induction of trained immunity responses. BCG, MTBVAC, influenza, measles, and possibly the new mRNA Coronavirus 2019 (COVID-19) vaccines induce trained immunity signatures, while trained immunity inducers can act as vaccine adjuvants. Environmental factors, the microbiome, circadian rhythm, genetics, and sex influence vaccine-induced trained immunity heterogeneity. [ABSTRACT FROM AUTHOR]
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- 2022
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7. Natural resistance against infections: focus on COVID-19.
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Netea, Mihai G., Domínguez-Andrés, Jorge, van de Veerdonk, Frank L., van Crevel, Reinout, Pulendran, Bali, and van der Meer, Jos W.M.
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NATURAL immunity , *CORONAVIRUS diseases , *COVID-19 , *SARS-CoV-2 - Abstract
Not all individuals exposed to a pathogen develop illness: some are naturally resistant whereas others develop an asymptomatic infection. Epidemiological studies suggest that there is similar variability in susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. We propose that natural resistance is part of the disease history in some individuals exposed to this new coronavirus. Epidemiological arguments for natural resistance to SARS-CoV-2 are the lower seropositivity of children compared to adults, studies on closed environments of ships with outbreaks, and prevalence studies in some developing countries. Potential mechanisms of natural resistance include host genetic variants, viral interference, cross-protective natural antibodies, T cell immunity, and highly effective innate immune responses. Better understanding of natural resistance can help to advance preventive and therapeutic measures against infections for improved preparedness against potential future pandemics. Natural resistance against pathogens is described for many infections. There is no reason to believe that this might be different for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. There are discrepancies between different SARS-CoV-2 infection models and the seroprevalence of antibodies in the circulation. Differences in morbidity and mortality between countries suggest that genetic and environmental differences may influence host defense against SARS-CoV-2 infection. Studies on children, adults residing in confined environments, and on individuals residing in different geographical locations suggest that natural resistance against SARS-CoV-2 is present in human populations, and may differentially impact on the course of the pandemic in such populations. Crucial for host survival is the balance between resistance mechanisms aiming to eliminate host pathogens and tolerance mechanisms aiming to avoid collateral damage induced by inflammatory processes. [ABSTRACT FROM AUTHOR]
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- 2022
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8. BCG turns 100: its nontraditional uses against viruses, cancer, and immunologic diseases.
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Singh, Alok K., Netea, Mihai G., and Bishai, William R.
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IMMUNOLOGIC diseases , *BLADDER cancer , *MYCOBACTERIAL diseases , *VIRUS diseases , *TYPE 1 diabetes , *TUBERCULOSIS , *HISTORY of tuberculosis , *TUBERCULOSIS prevention , *MULTIPLE sclerosis treatment , *VIRAL disease treatment , *MYCOBACTERIUM , *MULTIPLE sclerosis , *HISTORY , *CELLULAR immunity , *T cells , *ANIMALS ,BLADDER tumors - Abstract
First administered to a human subject as a tuberculosis (TB) vaccine on July 18, 1921, Bacillus Calmette-Guérin (BCG) has a long history of use for the prevention of TB and later the immunotherapy of bladder cancer. For TB prevention, BCG is given to infants born globally across over 180 countries and has been in use since the late 1920s. With about 352 million BCG doses procured annually and tens of billions of doses having been administered over the past century, it is estimated to be the most widely used vaccine in human history. While its roles for TB prevention and bladder cancer immunotherapy are widely appreciated, over the past century, BCG has been also studied for nontraditional purposes, which include (a) prevention of viral infections and nontuberculous mycobacterial infections, (b) cancer immunotherapy aside from bladder cancer, and (c) immunologic diseases, including multiple sclerosis, type 1 diabetes, and atopic diseases. The basis for these heterologous effects lies in the ability of BCG to alter immunologic set points via heterologous T cell immunity, as well as epigenetic and metabolomic changes in innate immune cells, a process called "trained immunity." In this Review, we provide an overview of what is known regarding the trained immunity mechanism of heterologous protection, and we describe the current knowledge base for these nontraditional uses of BCG. [ABSTRACT FROM AUTHOR]
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- 2021
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9. Enduring echoes: Post-infectious long-term changes in innate immunity.
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Dulfer, Elisabeth A., Joosten, Leo A.B., and Netea, Mihai G.
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NATURAL immunity , *POST-infectious disorders , *IMMUNE response , *IMMUNOSUPPRESSION , *CARDIOLOGICAL manifestations of general diseases - Abstract
• Memory-like features can be induced in innate immune cells after pathogen exposure. • Trained immunity may be involved in the pathophysiology of post-infectious clinical syndromes. • Hyperinflammation or post-infectious immune paralysis are targets for treatment. Upon encountering pathogens, the immune system typically responds by initiating an acute and self-limiting reaction, with symptoms subsiding after the pathogen has been cleared. However, long-term post-infectious clinical symptoms can manifest months or even years after the initial infection. 'Trained immunity', the functional reprogramming of innate immune cells through epigenetic and metabolic rewiring, has been proposed as a key concept for understanding these long-term effects. Although trained immunity can result in enhanced protection against reinfection with heterologous pathogens, it can also contribute to detrimental outcomes. Persisting and excessive inflammation can cause tissue damage and aggravate immune-mediated conditions and cardiovascular complications. On the other hand, suppression of immune cell effector functions by long-lasting epigenetic changes can result in post-infectious immune paralysis. Distinct stimuli can evoke different trained immunity programs, potentially resulting in different consequences for the host. In this review, we provide an overview of both the adaptive and maladaptive consequences of infectious diseases. We discuss how long-term immune dysregulation in patients can be addressed by tailoring host-directed interventions and identify areas of scientific and therapeutic potential to advance further. [ABSTRACT FROM AUTHOR]
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- 2024
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10. Assessing the effect of BCG revaccination on long-term mortality.
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Netea, Mihai G and van Crevel, Reinout
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BOOSTER vaccines , *MORTALITY , *TUBERCULOSIS prevention , *IMMUNIZATION , *BCG vaccines - Published
- 2021
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11. The impact of human single nucleotide polymorphisms on Bacillus Calmette-Guérin responses.
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Messina, Nicole L., Netea, Mihai G., and Curtis, Nigel
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SINGLE nucleotide polymorphisms , *TUBERCULOSIS , *SPINAL tuberculosis - Abstract
The influence of genetic variability on human immune responses has major implications for the understanding of disease mechanisms and host-pathogen interactions. Bacillus Calmette-Guérin (BCG) vaccine, which is given globally to protect against tuberculosis, has high variability in its protective efficacy against mycobacteria and its beneficial off-target (heterologous) effects. Single nucleotide polymorphisms (SNPs) are major cause of genetic variation and have been strongly associated with susceptibility to tuberculosis and outcomes following BCG immunotherapy for cancer. This review discusses the contribution of SNPs to the variability in mycobacterial-specific and off-target BCG responses, and the implications for this on development of novel TB vaccines and strategies to harness the beneficial off-target effects of BCG. [ABSTRACT FROM AUTHOR]
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- 2020
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12. Trained Immunity: a Tool for Reducing Susceptibility to and the Severity of SARS-CoV-2 Infection.
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Netea, Mihai G., Giamarellos-Bourboulis, Evangelos J., Domínguez-Andrés, Jorge, Curtis, Nigel, van Crevel, Reinout, van de Veerdonk, Frank L., and Bonten, Marc
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SARS-CoV-2 , *VIRUS diseases , *ORAL vaccines , *POLIOMYELITIS vaccines , *INFECTION - Abstract
SARS-CoV-2 infection is mild in the majority of individuals but progresses into severe pneumonia in a small proportion of patients. The increased susceptibility to severe disease in the elderly and individuals with co-morbidities argues for an initial defect in anti-viral host defense mechanisms. Long-term boosting of innate immune responses, also termed "trained immunity," by certain live vaccines (BCG, oral polio vaccine, measles) induces heterologous protection against infections through epigenetic, transcriptional, and functional reprogramming of innate immune cells. We propose that induction of trained immunity by whole-microorganism vaccines may represent an important tool for reducing susceptibility to and severity of SARS-CoV-2. Netea and colleagues argue that we may be able to prevent or decrease the severity of SARS-CoV-2 infection through certain clinically approved live vaccines that "train" the innate immune system to be broadly vigilant against viral infection. [ABSTRACT FROM AUTHOR]
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- 2020
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13. Immune recognition of putative alien microbial structures: Host–pathogen interactions in the age of space travel.
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Netea, Mihai G., Domínguez-Andrés, Jorge, Eleveld, Marc, op den Camp, Huub J. M., van der Meer, Jos W. M., Gow, Neil A. R., and de Jonge, Marien I.
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SPACE tourism , *IMMUNE recognition , *SPACE exploration , *SCIENTIFIC apparatus & instruments , *SOLAR system , *IMMUNE system - Abstract
Human space travel is on the verge of visiting Mars and, in the future, even more distant places in the solar system. These journeys will be also made by terrestrial microorganisms (hitchhiking on the bodies of astronauts or on scientific instruments) that, upon arrival, will come into contact with new planetary environments, despite the best measures to prevent contamination. These microorganisms could potentially adapt and grow in the new environments and subsequently recolonize and infect astronauts. An even more challenging situation would be if truly alien microorganisms will be present on these solar system bodies: What will be their pathogenic potential, and how would our immune host defenses react? It will be crucial to anticipate these situations and investigate how the immune system of humans might cope with modified terrestrial or alien microbes. We propose several scenarios that may be encountered and how to respond to these challenges. [ABSTRACT FROM AUTHOR]
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- 2020
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14. Impact of Historic Migrations and Evolutionary Processes on Human Immunity.
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Domínguez-Andrés, Jorge and Netea, Mihai G.
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HUMAN evolution , *IMMUNITY , *AUTOIMMUNE diseases , *DISEASES , *DISEASE susceptibility , *IMMUNOLOGIC diseases - Abstract
The evolution of mankind has constantly been influenced by the pathogens encountered. The various populations of modern humans that ventured out of Africa adapted to different environments and faced a large variety of infectious agents, resulting in local adaptations of the immune system for these populations. The functional variation of immune genes as a result of evolution is relevant in the responses against infection, as well as in the emergence of autoimmune and inflammatory diseases observed in modern populations. Understanding how host–pathogen interactions have influenced the human immune system from an evolutionary perspective might contribute to unveiling the causes behind different immune-mediated disorders and promote the development of new strategies to detect and control such diseases. Human evolution has been constantly influenced by pathogens; therefore, a great number of human genes linked to immune functions and immunity-related disorders have evolved along with humans. The heterogeneity in the immune response to infectious diseases across different populations is under genetic control and is the result of evolutionary processes. Genetic variants that have been under evolutionary pressure can contribute to explaining the differences in the susceptibility to diseases observed across different populations. The ancestry of individuals from different populations across the globe greatly influences their possibility of developing certain autoimmune diseases and inflammatory disorders. The lifestyle of Western societies affects the symbiotic relationships between humans, viruses, and other organisms and might contribute to the rise of certain autoimmune and inflammatory diseases. [ABSTRACT FROM AUTHOR]
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- 2019
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15. Genetic and epigenetic dysregulation of innate immune mechanisms in autoinflammatory diseases.
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Merlo Pich, Laura M., Ziogas, Athanasios, and Netea, Mihai G.
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Dysregulation and hyperactivation of innate immune responses can lead to the onset of systemic autoinflammatory diseases. Monogenic autoinflammatory diseases are caused by inborn genetic errors and based on molecular mechanisms at play, can be divided into inflammasomopathies, interferonopathies, relopathies, protein misfolding, and endogenous antagonist deficiencies. On the other hand, more common autoinflammatory diseases are multifactorial, with both genetic and non‐genetic factors playing an important role. During the last decade, long‐term memory characteristics of innate immune responses have been described (also called trained immunity) that in physiological conditions provide enhanced host protection from pathogenic re‐infection. However, if dysregulated, induction of trained immunity can become maladaptive, perpetuating chronic inflammatory activation. Here, we describe the mechanisms of genetic and epigenetic dysregulation of the innate immune system and maladaptive trained immunity that leads to the onset and perpetuation of the most common and recently described systemic autoinflammatory diseases. [ABSTRACT FROM AUTHOR]
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- 2024
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16. BCG vaccination in health care providers and the protection against COVID-19.
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Netea, Mihai G., van der Meer, Jos W. M., and van Crevel, Reinout
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MEDICAL personnel , *BCG vaccines , *COVID-19 , *COVID-19 pandemic , *COVID-19 testing - Abstract
A number of coronavirus disease 2019 (COVID-19) vaccine candidates have shown promising results, but substantial uncertainty remains regarding their effectiveness and global rollout. Boosting innate immunity with bacillus Calmette Guérin (BCG) or other live attenuated vaccines may also play a role in the fight against the COVID-19 pandemic. BCG has long been known for its nonspecific beneficial effects that are most likely explained by epigenetic and metabolic reprogramming of innate immune cells, termed trained immunity. In this issue of the JCI, Rivas et al. add to these arguments by showing that BCG-vaccinated health care providers from a Los Angeles health care organization had lower rates of COVID-19 diagnoses and seropositivity compared with unvaccinated individuals. Prospective clinical trials are thus warranted to explore the effects of BCG vaccination in COVID-19. We posit that beyond COVID-19, vaccines such as BCG that elicit trained immunity may mitigate the impact of emerging pathogens in future pandemics. [ABSTRACT FROM AUTHOR]
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- 2021
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17. Trained Innate Immunity, Epigenetics, and Covid-19.
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Mantovani, Alberto and Netea, Mihai G.
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NATURAL immunity , *COVID-19 , *MEDICAL sciences , *EPIGENETICS , *MEDICAL societies - Abstract
The article presents the study presenting durable innate immune memory conferred by myeloid cells like monocytes, macrophages, and neutrophils. Topics include producing effector molecules and contributing to the activation, orientation, and regulation of adaptive immune responses; diversity and plasticity being the fundamental properties of myeloid cells particularly macrophages; and supporting the convergence of multiple regulatory layers like changes in chromatin organization.
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- 2020
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18. Cellular metabolism of tumor-associated macrophages - functional impact and consequences.
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Rabold, Katrin, Netea, Mihai G., Adema, Gosse J., and Netea‐Maier, Romana T.
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CELL metabolism , *MACROPHAGES , *TUMOR immunology , *PATHOLOGICAL physiology , *PHENOTYPES , *TUMOR microenvironment - Abstract
Macrophages are innate immune cells that play a role not only in host defense against infections, but also in the pathophysiology of autoimmune and autoinflammatory disorders, as well as cancer. An important feature of macrophages is their high plasticity, with high ability to adapt to environmental changes by adjusting their cellular metabolism and immunological phenotype. Macrophages are one of the most abundant innate immune cells within the tumor microenvironment that have been associated with tumor growth, metastasis, angiogenesis and poor prognosis. In the context of cancer, however, so far little is known about metabolic changes in macrophages, which have been shown to determine functional fate of the cells in other diseases. Here, we review the current knowledge regarding the cellular metabolism of tumor-associated macrophages (TAMs) and discuss its implications for cell function. Understanding the regulation of the cellular metabolism of TAMs may reveal novel therapeutic targets for treatment of malignancies. [ABSTRACT FROM AUTHOR]
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- 2017
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19. Interleukin-32 in chronic inflammatory conditions is associated with a higher risk of cardiovascular diseases.
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Damen, Michelle S.M.A., Netea, Mihai G., Joosten, Leo A.B., Dinarello, Charles A., and Popa, Calin D.
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INTERLEUKIN-32 , *INFLAMMATION , *CARDIOVASCULAR diseases risk factors , *ATHEROSCLEROSIS risk factors , *RHEUMATOID arthritis , *INFLAMMATORY bowel diseases , *OBSTRUCTIVE lung diseases , *GENETICS - Abstract
Cardiovascular diseases (CVD) are the most frequent cause of death in developed countries. Their prevalence is higher in several chronic inflammatory conditions. This is likely due to the substantial contribution of the inflammatory status of the patients to the development and stability of atherosclerotic plaques. Recent evidence suggests that interleukin (IL)-32 may be involved in the conditions that contribute to CVD. IL-32 not only modulates important inflammatory pathways known to contribute to the pathogenesis of both inflammatory diseases and atherosclerosis, including tumor necrosis factor (TNF)α, IL-6 or IL-1β, but it has been also suggested to modulate endothelial cell function and the serum concentration of high-density lipoprotein (HDL). In this review, we highlight the recent advances in the field of IL-32 in relation to chronic inflammatory disorders and argue for a role of IL-32 in the increased prevalence of CVD in these patients. [ABSTRACT FROM AUTHOR]
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- 2017
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20. Medical mycology and fungal immunology: new research perspectives addressing a major world health challenge.
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Gow, Neil A. R. and Netea, Mihai G.
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MYCOLOGY , *MORTALITY , *MYCOSES , *DIAGNOSIS , *IMMUNOPATHOLOGY , *DRUG development , *DISEASE risk factors - Abstract
Fungi cause more than a billion skin infections, more than 100 million mucosal infections, 10 million serious allergies and more than a million deaths each year. Global mortality owing to fungal infections is greater than for malaria and breast cancer and is equivalent to that owing to tuberculosis (TB) and HIV. These statistics evidence fungal infections as a major threat to human health and a major burden to healthcare budgets worldwide. Those patients who are at greatest risk of life-threatening fungal infections include those who have weakened immunity or have suffered trauma or other predisposing infections such as HIV. To address these global threats to human health, more research is urgently needed to understand the immunopathology of fungal disease and human disease susceptibility in order to augment the advances being made in fungal diagnostics and drug development. Here, we highlight some recent advances in basic research in medical mycology and fungal immunology that are beginning to inform clinical decisions and options for personalized medicine, vaccine development and adjunct immunotherapies. [ABSTRACT FROM AUTHOR]
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- 2016
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21. Immune defence against Candida fungal infections.
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Netea, Mihai G., Joosten, Leo A. B., van der Meer, Jos W. M., Kullberg, Bart-Jan, and van de Veerdonk, Frank L.
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The immune response to Candida species is shaped by the commensal character of the fungus. There is a crucial role for discerning between colonization and invasion at mucosal surfaces, with the antifungal host defence mechanisms used during mucosal or systemic infection with Candida species differing substantially. Here, we describe how innate sensing of fungi by pattern recognition receptors and the interplay of immune cells (both myeloid and lymphoid) with non-immune cells, including platelets and epithelial cells, shapes host immunity to Candida species. Furthermore, we discuss emerging data suggesting that both the innate and adaptive immune systems display memory characteristics after encountering Candida species. [ABSTRACT FROM AUTHOR]
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- 2015
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22. Innate immune memory: a paradigm shift in understanding host defense.
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Netea, Mihai G, Latz, Eicke, Mills, Kingston H G, and O'Neill, Luke A J
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NATURAL immunity , *IMMUNOLOGIC memory , *HOSTS (Biology) , *IMMUNE recognition , *ANTIGEN presentation , *IMMUNE response - Published
- 2015
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23. Inflammasome-Independent Regulation of IL-1-Family Cytokines.
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Netea, Mihai G., van de Veerdonk, Frank L., van der Meer, Jos W.M., Dinarello, Charles A., and Joosten, Leo A.B.
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CYTOKINES , *INTERLEUKIN-1 , *PROTEOLYTIC enzymes , *IMMUNOLOGY of inflammation , *SERINE proteinases - Abstract
Induction, production, and release of proinflammatory cytokines are essential steps to establish an effective host defense. Cytokines of the interleukin-1 (IL-1) family induce inflammation and regulate T lymphocyte responses while also displaying homeostatic and metabolic activities. With the exception of the IL-1 receptor antagonist, all IL-1 family cytokines lack a signal peptide and require proteolytic processing into an active molecule. One such unique protease is caspase-1, which is activated by protein platforms called the inflammasomes. However, increasing evidence suggests that inflammasomes and caspase-1 are not the only mechanism for processing IL-1 cytokines. IL-1 cytokines are often released as precursors and require extracellular processing for activity. Here we review the inflammasome-independent enzymatic processes that are able to activate IL-1 cytokines, paying special attention to neutrophil-derived serine proteases, which subsequently induce inflammation and modulate host defense. The inflammasome-independent processing of IL-1 cytokines has important consequences for understanding inflammatory diseases, and it impacts the design of IL-1-based modulatory therapies. [ABSTRACT FROM AUTHOR]
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- 2015
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24. BCG-induced protection: Effects on innate immune memory.
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Netea, Mihai G. and van Crevel, Reinout
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NATURAL immunity , *IMMUNOLOGIC memory , *TUBERCULOSIS vaccines , *MYCOBACTERIAL diseases , *BIOACCUMULATION - Abstract
The Bacille Calmette–Guerin (BCG) vaccine is the only vaccine proved to be effective against tuberculosis and it remains the most commonly used vaccine worldwide. In addition to its effects on mycobacterial diseases, an increasing body of epidemiological evidence accumulated since its introduction in 1921 shows that BCG also exerts beneficial non-specific effects ranging from protection against non-mycobacterial diseases, decreased incidence of allergic diseases, and treatment of certain malignancies. The biological substrate of these effects is mediated partly by heterologous effects on adaptive immunity, but also on the potentiation of innate immune responses through epigenetic mechanisms, a process termed ‘ trained immunity ’ . The process of trained immunity may also play a role in the beneficial effects of BCG against tuberculosis and Mycobacterium tuberculosis infection, and this could have important consequences for our quest for improving vaccination strategies. [ABSTRACT FROM AUTHOR]
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- 2014
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25. COVID-19: Rare variants increase the risk of severe COVID-19.
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van de Veerdonk, Frank L. and Netea, Mihai G.
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COVID-19 , *GENETIC variation - Abstract
Evidence is mounting that rare loss-of-function variants in the TLR7 gene predispose men with no medical history to severe forms of COVID-19. [ABSTRACT FROM AUTHOR]
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- 2021
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26. Influence of Lenvatinib on the Functional Reprogramming of Peripheral Myeloid Cells in the Context of Non-Medullary Thyroid Carcinoma.
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Peng, Chunying, Rabold, Katrin, Netea, Mihai G., Jaeger, Martin, and Netea-Maier, Romana T.
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MYELOID cells , *THYROID cancer , *PROTEIN-tyrosine kinase inhibitors , *IMMUNE response , *PROTO-oncogenes , *CELL physiology , *MONOCYTES - Abstract
Lenvatinib is a multitarget tyrosine kinase inhibitor (TKI) approved for the treatment of several types of cancers, including metastatic differentiated thyroid cancer (DTC). The intended targets include VEGFR 1–3, FGFR 1–4, PDGFRα, RET, and KIT signaling pathways, but drug resistance inevitably develops and a complete cure is very rare. Recent data has revealed that most of the TKIs have additional 'off-target' immunological effects, which might contribute to a protective antitumor immune response; however, human cellular data are lacking regarding Lenvatinib-mediated immunomodulation in DTC. Here, we investigated in ex vivo models the impact of Lenvatinib on the function of immune cells in healthy volunteers. We found that monocytes and macrophages were particularly susceptible to Lenvatinib, while neutrophiles and lymphocytes were less affected. In tumor-immune cell co-culture experiments, Lenvatinib exerted a broad inhibitory effect on the proinflammatory response in TC-induced macrophages. Interestingly, Lenvatinib-treated cells had decreased cellular M2 membrane markers, whereas they secreted a significantly higher level of the anti-inflammatory cytokine IL-10 upon LPS stimulation. In addition, prolonged exposure to Lenvatinib impaired macrophages survival and phenotypical differentiation, which was accompanied by remarkable morphological changes and suppressed cellular metabolic activity. These effects were mediated by myeloid cell-intrinsic mechanisms which are independent of Lenvatinib's on-target activity. Finally, using specific inhibitors, we argue that dual effects on p38 MAPK and Syk pathways are likely the underlying mechanism of the off-target immunological effects we observed in this study. Collectively, our data show the immunomodulatory properties of Lenvatinib on human monocytes. These insights could be harnessed for the future design of novel treatment strategies involving a combination of Lenvatinib with other immunotherapeutic agents. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
27. Interleukin-1β in innate inflammation, autophagy and immunity.
- Author
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Joosten, Leo A.B., Netea, Mihai G., and Dinarello, Charles A.
- Subjects
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INTERLEUKIN-1 , *INFLAMMATION , *AUTOPHAGY , *IMMUNITY , *CYTOKINES , *CARCINOGENESIS - Abstract
Abstract: Although IL-1β is the master inflammatory cytokine in the IL-1 family, after more than ten years of continuous breeding, mice deficient in IL-1β exhibit no spontaneous disease. Therefore, one concludes that IL-1β is not needed for homeostasis. However, IL-1β-deficient mice are protected against local and systemic inflammation due to live infections, autoimmune processes, tumor metastasis and even chemical carcinogenesis. Based on a large number of preclinical studies, blocking IL-1β activity in humans with a broad spectrum of inflammatory conditions has reduced disease severity and for many, has lifted the burden of disease. Rare and common diseases are controlled by blocking IL-1β. Immunologically, IL-1β is a natural adjuvant for responses to antigen. Alone, IL-1β is not a growth factor for lymphocytes; rather in antigen activated immunocompetent cells, blocking IL-1 reduces IL-17 production. IL-1β markedly increases in the expansion of naive and memory CD4T cells in response to challenge with their cognate antigen. The response occurs when only specific CD4T cells respond to IL-1β and not to IL-6 or CD-28. A role for autophagy in production of IL-1β has emerged with deletion of the autophagy gene ATG16L1. Macrophages from ATG16L1-deficient mice produce higher levels of IL-1β after stimulation with TLR4 ligands via a mechanism of caspase-1 activation. The implications for increased IL-1β release in persons with defective autophagy may have clinical importance for disease. [Copyright &y& Elsevier]
- Published
- 2013
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28. A small jab – a big effect: nonspecific immunomodulation by vaccines.
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Benn, Christine S., Netea, Mihai G., Selin, Liisa K., and Aaby, Peter
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IMMUNOREGULATION , *DRUG resistance , *VACCINATION of children , *VACCINES , *PATHOGENIC microorganisms , *DISEASE susceptibility , *NATURAL immunity - Abstract
Highlights: [•] Routine vaccines may alter resistance to unrelated pathogens in children. [•] Live vaccines are associated with increased protection to other pathogens. [•] Inactivated vaccines may increase susceptibility to other pathogens. [•] ‘Heterologous immunity’ and ‘trained innate immunity’ may explain these effects. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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29. Bacterial translocation in an experimental model of multiple organ dysfunctions.
- Author
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Louis, Konstantinos, Netea, Mihai G., Carrer, Dionyssia-Pinelopi, Kotsaki, Antigone, Mylona, Vassiliki, Pistiki, Aikaterini, Savva, Athina, Roditis, Konstantinos, Alexis, Alexandros, Van der Meer, Jos W.M., and Giamarellos-Bourboulis, Evangelos J.
- Subjects
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MULTIPLE organ failure , *ENDOTOXINS , *BACTERIAL transformation , *LABORATORY mice , *ENTEROCOCCUS , *QUANTITATIVE research - Abstract
Abstract: Background: In order to investigate the hypothesis that bacterial translocation from the intestine contributes to death after multiple organ dysfunction syndrome (MODS), a sterile MODS model was studied. Methods: MODS was induced in 139 male C57BL/6 mice by lipopolysaccharide (LPS) (endotoxin) infusion followed by zymozan infusion in four groups: Α, sham-operation; Β, LPS; C, LPS + 0.8 g/kg zymozan; and D, LPS + 1.2 g/kg zymozan. Mice were sacrificed at 24 and 48 h for quantitative tissue cultures, isolation, and stimulation of splenocytes, measurement of apoptosis of lymphocytes and macrophages, and of serum LPS and survival. Some mice with MODS were treated with the antibiotic ertapenem. Results: Enterobacteriaceae and Enterococcus spp were isolated from tissues. Group D had the highest bacterial load and the shortest survival. Release of interleukin-10, of interleukin-17, and of intgerferon-γ by splenocytes and the rate of apoptosis did not concur with immune paralysis. Serum LPS concentrations were higher in mice with MODS versus controls. Ertapenem prolonged survival and decreased the bacterial load. Conclusions: Bacterial translocation seems to be an important contributor leading from MODS to death and suggests a change in therapy towards adaptation of antimicrobial treatment upon early signs of MODS. [Copyright &y& Elsevier]
- Published
- 2013
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30. Training innate immunity: the changing concept of immunological memory in innate host defence.
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Netea, Mihai G.
- Subjects
- *
NATURAL immunity , *IMMUNOLOGY , *CELL populations , *KILLER cells , *T cells - Abstract
The inability of innate immunity to build an immunological memory is considered a main difference with adaptive immunity. This concept has been challenged by studies in plants, invertebrates and mammals. Recently, a paradigm shift in our understanding host defence has been triggered by the mounting evidence for innate immune memory, leading to increased responses to secondary infections. Important differences between the cell populations and the molecular mechanisms exist between the adaptive traits of innate host defence on the one hand and immunological memory of adaptive immunity on the other hand. The lasting state of enhanced innate immunity termed 'trained immunity' is mediated by prototypical innate immune cells such as natural killer cells and monocytes/macrophages. It provides protection against reinfection in a T/B-cell-independent manner, with both specific mechanisms and nonspecific epigenetic reprogramming mediating these effects. This concept represents a paradigm change in immunity, and its putative role in resistance to reinfection may represent the next step in the design of future vaccines. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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31. An elevated pro-inflammatory cytokine response is linked to development of amphotericin B-induced nephrotoxicity.
- Author
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Chai, Louis Y A, Netea, Mihai G, Tai, Bee Choo, Khin, Lay Wai, Vonk, Alieke G, Teo, Boon Wee, Schlamm, Haran T, Herbrecht, Raoul, Donnelly, J Peter, Troke, Peter F, and Kullberg, Bart-Jan
- Published
- 2013
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32. An elevated pro-inflammatory cytokine response is linked to development of amphotericin B-induced nephrotoxicity.
- Author
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Chai, Louis Y. A., Netea, Mihai G., Tai, Bee Choo, Khin, Lay Wai, Vonk, Alieke G., Teo, Boon Wee, Schlamm, Haran T., Herbrecht, Raoul, Donnelly, J. Peter, Troke, Peter F., and Kullberg, Bart-Jan
- Subjects
- *
CYTOKINES , *CELLULAR immunity , *AMPHOTERICIN B , *AMPHOTERICINS , *NEPHROTOXICOLOGY - Abstract
Objectives The underlying mechanism for amphotericin B-induced acute kidney injury (AKI) remains poorly understood and may be immunologically mediated. We assessed whether the development of nephrotoxicity is linked to a distinct cytokine profile in patients receiving amphotericin B deoxycholate (AmBD). Patients and methods In 58 patients who received AmBD, circulating serum interleukin (IL)-6, IL-8 and IL-10 were measured at baseline, week 1 and week 2 of antifungal treatment and correlated to the development of renal impairment. The Cox proportional hazards model approach was adopted for analysis. Results The P value was 0.026 for the overall effect of IL-6 on time to development of AKI. An increasing or non-receding IL-6 trend by week 1 of AmBD treatment (followed by a decreasing or non-receding IL-6 trend from week 1 to week 2) correlated with an increased likelihood of nephrotoxicity [hazard ratio (HR) 6.93, P value 0.005 and HR 3.46, P value 0.035, respectively]. Similarly, persistently increasing IL-8 levels were linked to a 3.84-fold increased likelihood of AKI. Conclusions In patients receiving AmBD, persistence of an elevated pro-inflammatory cytokine milieu is associated with a predisposition to drug-related kidney injury. [ABSTRACT FROM PUBLISHER]
- Published
- 2013
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33. Role of the Mycobiome in Human Acute Graft-versus-Host Disease
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van der Velden, Walter J.F.M., Netea, Mihai G., de Haan, Anton F.J., Huls, Gerwin A., Donnelly, J. Peter, and Blijlevens, Nicole M.A.
- Subjects
- *
GRAFT versus host disease , *GUT microbiome , *CANDIDA , *HEMATOPOIETIC stem cell transplantation , *HOMOGRAFTS , *GENETIC polymorphisms , *ALLELES - Abstract
Abstract: A role for gut bacteria in the pathogenesis of graft-versus-host disease (GVHD) has been firmly established; however, the role of Candida spp, which form part of the mycobiome, remains unknown. In a homogenous group of patients who underwent allogeneic stem cell transplantation (SCT), we found a significant impact of Candida colonization on the occurrence of acute GVHD. Patients colonized with Candida spp developed significantly more grade II-IV acute GVHD compared with noncolonized patients (50% vs 32%; P = .03), as well as more gastrointestinal (GI)-GVHD (33% vs 19%; P = .05). Colonization with Candida spp was more frequent in patients bearing the loss-of-function polymorphism Y238X, which results in dectin-1 dysfunction, compared with patients with the wild-type allele (73% vs 31%; P = .002). There was no direct effect of dectin-1 dysfunction on acute GVHD, although it did influence the occurrence of GVHD indirectly through Candida colonization. The exact mechanism of GVHD induction by Candida spp colonization of the mucosa is unknown, but the link might prove to be the induction of Th 17/IL-23 responses through activation of pattern recognition receptors by fungal motifs, including β-d-glucan and mannans. These data indicate a role for the mycobiome in the pathogenesis of GVHD and suggest that altering the mycobiome by antifungal drugs can help ameliorate GI-GVHD. In addition, given that the genetic constitution of patients affects susceptibility to both Candida colonization and GVHD, whether identifying gene polymorphisms will facilitate personalized treatment of SCT recipients remains to be determined. [Copyright &y& Elsevier]
- Published
- 2013
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34. Candida and Host Determinants of Susceptibility to Invasive Candidiasis.
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Lionakis, Michail S. and Netea, Mihai G.
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- *
CANDIDA , *CANDIDIASIS , *PATHOGENIC fungi , *NOSOCOMIAL infections , *IMMUNE system , *NATURAL immunity - Abstract
The article discusses the Candida which is the most common human fungal pathogen and cause of nosocomial bloodstream infection in the U.S. It outlines several questions and answers relating to Candida including how innate immune system recognized Candida, divergent roles of neutrophils, and roles of immune cell types in host defence against invasive candidiasis. It notes that invasive candidiasis is a medical condition for better understanding of its pathogenesis to improve patient outcomes.
- Published
- 2013
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35. Pattern recognition receptors and their role in invasive aspergillosis.
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Gresnigt, Mark S., Netea, Mihai G., and van de Veerdonk, Frank L.
- Subjects
- *
ASPERGILLOSIS , *MICROBIAL invasiveness , *GERM cells , *CELL receptors , *NATURAL immunity , *TOLL-like receptors ,MICROORGANISM identification - Abstract
Pattern recognition receptors (PRRs) are germline receptors that recognize conserved structures on microorganisms. Several PRRs have been identified in the recent years that are involved in the immune response against Aspergillus fumigatus. The role of PRRs in invasive pulmonary aspergillosis becomes especially apparent in the setting of an immunocompromised status of the host because of the redundancy of many PRRs in the host defense against A. fumigatus. Studies that investigated the PRRs and their effector pathways in invasive aspergillosis have led to a better understanding of the pathogenesis of invasive aspergillosis in immunocompromised patients. This knowledge may pave the way for novel diagnostic and immunomodulatory treatment strategies that are needed to overcome the high mortality associated with invasive A. fumigatus infection in immunocompromised patients. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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36. Interleukin-32: A predominantly intracellular proinflammatory mediator that controls cell activation and cell death
- Author
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Heinhuis, Bas, Netea, Mihai G., van den Berg, Wim B., Dinarello, Charles A., and Joosten, Leo A.B.
- Subjects
- *
INTERLEUKIN-32 , *CELL death , *INFLAMMATORY mediators , *CYTOKINES , *AUTOIMMUNE diseases , *RHEUMATOID arthritis - Abstract
Abstract: In this review, we will discuss the current knowledge on IL-32 and provide new insights regarding the biological function of IL-32. IL-32 is seen as a cytokine that can induce a range of proinflammatory mediators and contribute to autoimmune diseases, such as rheumatoid arthritis, however present knowledge demonstrates that IL-32 is not a classical cytokine. We present the history of this cytokine, the role of IL-32 in several diseases and discuss a possible novel role of intracellular IL-32 in cell homeostasis. Taken into account the observed biological functions of IL-32, it may belong to a class of cytokines, like IL-1α, IL-33, and IL-37, with both intracellular and extracellular functions. [Copyright &y& Elsevier]
- Published
- 2012
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37. Genetic variation in Toll-like receptors and disease susceptibility.
- Author
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Netea, Mihai G, Wijmenga, Cisca, and O'Neill, Luke A J
- Subjects
- *
TOLL-like receptors , *BIOLOGICAL variation , *DISEASE susceptibility , *NATURAL immunity , *IMMUNE response , *GENETIC polymorphisms , *AUTOIMMUNE diseases - Abstract
Toll-like receptors (TLRs) are key initiators of the innate immune response and promote adaptive immunity. Much has been learned about the role of TLRs in human immunity from studies linking TLR genetic variation with disease. First, monogenic disorders associated with complete deficiency in certain TLR pathways, such as MyD88-IRAK4 or TLR3-Unc93b-TRIF-TRAF3, have demonstrated the specific roles of these pathways in host defense against pyogenic bacteria and herpesviruses, respectively. Second, common polymorphisms in genes encoding several TLRs and associated genes have been associated with both infectious and autoimmune diseases. The study of genetic variation in TLRs in various populations combined with information on infection has demonstrated complex interaction between genetic variation in TLRs and environmental factors. This interaction explains the differences in the effect of TLR polymorphisms on susceptibility to infection and autoimmune disease in various populations. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
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38. Targeting of Toll-like receptors: a decade of progress in combating infectious diseases
- Author
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Hedayat, Mona, Netea, Mihai G, and Rezaei, Nima
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- *
COMMUNICABLE diseases , *VIRAL receptors , *IMMUNE system , *MOLECULAR recognition , *PATHOGENIC microorganisms , *CELLULAR signal transduction , *MOLECULAR structure , *CELL receptors - Abstract
Summary: Toll-like receptors (TLRs) recognise highly conserved molecular structures, collectively known as pathogen-associated molecular patterns. In the past two decades, development and clinical implementation of TLR ligands—ie, chemically modified synthetic derivatives of naturally occurring ligands and fully synthetic small molecules—have been topics of intense research. Targeted manipulation of TLR signalling has been applied clinically to boost vaccine effectiveness, promote a robust T helper 1-predominant immune response against viral infection, or dampen the exaggerated inflammatory response to bacterial infection. Use of these new therapeutic molecules as adjuncts to conventional pharmacotherapy or stand-alone treatments might offer solutions to unmet clinical needs or could replace existing partly effective therapeutic strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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39. Vildagliptin Improves Endothelium-Dependent Vasodilatation in Type 2 Diabetes.
- Author
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VAN POPPEL, PLEUN C. M., NETEA, MIHAI G., SMITS, PAUL, and TACK, CEES J.
- Subjects
- *
HYPOGLYCEMIC agents , *ENDOTHELIUM , *VASODILATION , *TYPE 2 diabetes , *DIABETES - Abstract
OBJECTIVE--To investigate whether the dipeptidyl peptidase-4 inhibitor vildagliptin improves endothelium-dependent vasodilatation in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS--Sixteen subjects with type 2 diabetes (age 59.8 ± 6.8 years, BMI 29.1 ± 4.8 kg/m², HbA1c 6.97 ± 0.61) on oral blood glucose-lowering treatment were included. Participants received vildagliptin 50 mg b.i.d or acarbose 100 mg t.i.d. for four consecutive weeks in a randomized, double-blind, cross-over design. At the end of each treatment period, we measured forearm vasodilator responses to intra-artenally administered acetylcholme (endothelium-dependent vasodilator) and sodium nitroprusside (endotheliumindependent vasodilator). RESULTS--Infusion of acetylcholine induced a dose-dependent increase in forearm blood flow in the experimental arm, which was higher during vildagliptin (3.1 ± 0.7, 7.9 -± 1.1, and 12.6 ± 1.4 mL ⋅ dL-1 ⋅ min-1 in response to three increasing dosages of acetylcholine) than during acarbose (2.0 ± 0.7, 5.0 ± 1.2, and 11.7 ± 1.6 mL ⋅ dL-1 ⋅ min-1 respectively; P = 0.01 by two-way ANOVA). Treatment with vildagliptin did not significantly change the vascular responses to sodium nitroprusside. CONCLUSIONS--Four weeks' treatment with vildagliptin improves endothelium-dependent vasodilatation in subjects with type 2 diabetes. This observation might have favorable cardiovascular implications. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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40. Defects of pattern recognition: primary immunodeficiencies of the innate immune system
- Author
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Netea, Mihai G, van de Veerdonk, Frank L, van Deuren, Marcel, and van der Meer, Jos WM
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NATURAL immunity , *IMMUNE system , *G proteins , *PATHOLOGICAL physiology , *LECTINS , *VIRAL disease treatment , *IMMUNOTHERAPY , *MICROBIAL sensitivity tests - Abstract
Genetic defects leading to impaired recognition of invading pathogens by the innate immune system, and hence to increased susceptibility to specific classes of microorganisms have been recently recognized. To date, defects have been described in three of the major families of pattern recognition receptors (PRRs): the Toll-like receptors (TLRs), the C-type lectin receptors (CLRs), and the nucleotide binding domain leucine-rich repeat containing receptors (NLRs). By contrast, defects in the viral receptors RigI helicases have not been found. PRR defects vary greatly in severity, display a narrow susceptibility profile towards specific pathogens, and when severe in infancy and childhood, often decrease in severity thereafter. Their discovery leads to crucial insight in the pathophysiology of infections, and offer therapeutic targets for future immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
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41. Inflammasome activation and IL-1β and IL-18 processing during infection
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van de Veerdonk, Frank L., Netea, Mihai G., Dinarello, Charles A., and Joosten, Leo A.B.
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- *
INTERLEUKIN-1 , *INTERLEUKINS , *INFECTION , *PHAGOCYTES , *IMMUNE response , *CYTOKINES , *SERINE proteinases , *T cells - Abstract
Interleukin-1β (IL-1β) and IL-18 contribute to host defense against infection by augmenting antimicrobial properties of phagocytes and initiating Th1 and Th17 adaptive immune responses. Protein complexes called inflammasomes activate intracellular caspase-1 autocatalytically, which cleaves the inactive precursors of IL-1β and IL-18 into bioactive cytokines. In this review, we discuss the controversies regarding inflammasome activation and the role of the inflammasome during infection. We highlight alternative mechanisms for processing IL-1β and IL-18 during infection, which involve extracellular cleavage of the inactive cytokines by neutrophil-derived serine proteases or proteases released from cytotoxic T cells. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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42. Immunodeficiency and Genetic Defects of Pattern-Recognition Receptors.
- Author
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Netea, Mihai G. and Van der Meer, Jos W.M.
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IMMUNODEFICIENCY , *CELL receptors , *LECTINS , *NUCLEOTIDES , *LEUCINE - Abstract
The article looks at the types of immunodeficiencies in which defects in pattern-recognition receptors and their downstream intracellular pathways prevail. The 4 classes of pattern-recognition receptors are toll-like receptors (TLRs), C-type lectin receptors (CLRs), nucleotide-binding oligomerization domain (NOD) leucine-rich repeat containing receptors (NLRs) and retinoic acid-inducible gene I protein (RIG-I) helicase receptors. It says that susceptibility to infection can be affected by polymorphisms in genes encoding pattern-recognition receptors.
- Published
- 2011
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43. Aspergillus fumigatus Conidial Melanin Modulates Host Cytokine Response
- Author
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Chai, Louis Y.A., Netea, Mihai G., Sugui, Janyce, Vonk, Alieke G., van de Sande, Wendy W.J., Warris, Adilia, Kwon-Chung, Kyung J., and Jan Kullberg, Bart
- Subjects
- *
ASPERGILLUS fumigatus , *MELANINS , *FUNGI imperfecti , *CYTOKINES , *ENZYME-linked immunosorbent assay , *ENDOTOXINS , *TUMOR necrosis factors - Abstract
Abstract: Melanin biopigments have been linked to fungal virulence. Aspergillus fumigatus conidia are melanised and are weakly immunogenic. We show that melanin pigments on the surface of resting Aspergillus fumigatus conidia may serve to mask pathogen-associated molecular patterns (PAMPs)-induced cytokine response. The albino conidia induced significantly more proinflammatory cytokines in human peripheral blood mononuclear cells (PBMC), as compared to melanised wild-type conidia. Blocking dectin-1 receptor, Toll-like receptor 4 or mannose receptor decreased cytokine production induced by the albino but not by the wild type conidia. Moreover, albino conidia stimulated less potently, cytokine production in PBMC isolated from an individual with defective dectin-1, compared to the stimulation of cells isolated from healthy donors. These results suggest that β-glucans, but also other stimulatory PAMPs like mannan derivatives, are exposed on conidial surface in the absence of melanin. Melanin may play a modulatory role by impeding the capability of host immune cells to respond to specific ligands on A. fumigatus. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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44. Early Proinflammatory Cytokines and C-Reactive Protein Trends as Predictors of Outcome in Invasive Aspergillosis.
- Author
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Chai, Louis Y. A., Netea, Mihai G., Teerenstra, Steven, Earnest, Arul, Vonk, Alieke G., Schlamm, Haran T., Herbrecht, Raoul, Troke, Peter F., and Kullberg, Bart-Jan
- Subjects
- *
C-reactive protein , *CYTOKINES , *ASPERGILLOSIS , *IMMUNE response , *INTERLEUKINS , *ANTIFUNGAL agents - Abstract
Background. Monitoring treatment response in invasive aspergillosis is challenging, because an immunocompromised host may not exhibit reliable symptoms and clinical signs. Cytokines play a pivotal role in mediating host immune response to infection; therefore, the profiling of biomarkers may be an appropriate surrogate for disease status. Methods. We studied, in a cohort of 119 patients with invasive aspergillosis who were recruited in a multicenter clinical trial, serum interleukin (IL)-6, IL-8, IL-10, interferon-g, and C-reactive protein (CRP) trends over the first 4 weeks of therapy and correlated these trends to clinical outcome parameters. Results. Circulating IL-6 and CRP levels were high at initiation of therapy and generally showed a downward trend with antifungal treatment. However, subjects with adverse outcomes exhibited a distinct lack of decline in IL-6 and CRP levels at week 1, compared with responders (Pp.02, for both IL-6 and CRP). Nonresponders also had significantly elevated IL-8 levels (P=.001). Conclusions. High initial IL-8 and persistently elevated IL-6, IL-8, and CRP levels after initiation of treatment may be early predictors of adverse outcome in invasive aspergillosis. Cytokine and CRP profiles could be used for early identification of patients with a poor response to antifungal treatment who may benefit from more-aggressive antimicrobial regimens. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
45. Engagement of Fatty Acids With Toll-like Receptor 2 Drives Interleukin-1β Production via the ASC/Caspase 1 Pathway in Monosodium Urate Monohydrate Crystal--Induced Gouty Arthritis.
- Author
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Joosten, Leo A. B., Netea, Mihai G., Mylona, Eleni, Koenders, Marije I., Subbarao Malireddi, R. K., Oosting, Marije, Stienstra, Rinke, van de Veerdonk, Frank L., Stalenhoef, Anton F., Giarnarellos-Bourboulis, Evangelos J., Kanneganti, Thirumala-Devi, and van der Meer, Jos W. M.
- Abstract
The article identifies the mechanism that initiates flares of gouty arthritis. The study stimulated human peripheral blood mononuclear cells (PBMC) and murine macrophages in vitro with monosodium urate monohydrate (MSU), free fatty acids (FFA) or both combined. The results showed that MSU crystals had no biologic effects on PBMC from healthy subjects. Interaction of FFA, but not alcohol, with TLR-2 synergized with MSU crystals to induce an inflammatory reaction. An important event of MSU/FFA-induced acute joint inflammation is inflammasome activation.
- Published
- 2010
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46. Novel strategies for the prevention and treatment of Candida infections: the potential of immunotherapy.
- Author
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van de Veerdonk, Frank L., Netea, Mihai G., Joosten, Leo A., van der Meer, Jos W. M., and Kullberg, Bart Jan
- Subjects
- *
CANDIDA , *CANDIDIASIS treatment , *PATIENTS , *INFECTION , *IMMUNOTHERAPY - Abstract
Infections caused by Candida spp. continue to be a substantial cause of disease burden, especially in immunocompromised patients. New approaches are needed to improve the outcome of patients suffering from Candida infections, because it seems unlikely that the established standard treatment will drastically lower the morbidity of mucocutaneous Candida infections and the high mortality associated with invasive candidiasis. New insights into the mechanisms of the anti- Candida host response have contributed to the design of novel immunotherapeutic approaches that have been proposed as adjuvant therapy in Candida infections. This review presents an overview of novel strategies in the prevention and treatment of Candida infections, with a special focus on adjuvant immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
47. Host Defense and Susceptibility to Candida Infections.
- Author
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Netea, Mihai G., Joosten, Leo A. B., van der Meer, Jos W. M., and Kullberg, Bart Jan
- Subjects
- *
MYCOSES , *CANDIDA , *CANDIDIASIS , *IMMUNE system , *GENETICS , *DISEASES - Abstract
Candida spp. are the most common cause of fungal infections, affecting either body surfaces (mucocutaneous infections) or the bloodstream and deep organs (candidemia and invasive candidiasis, respectively). Recognition of Candida by the cells of the immune system may result either in rapid elimination of the pathogen in the immunocompetent host or in persistence of the pathogen in the immunocompromised host. There is good evidence that the genetic make-up of the host is important for the susceptibility to infections in general, and to fungal infections in particular. Recent research has shed fight on the innate genetic defects that may specifically predispose patients to inborn clinical syndromes associated with fungal infections such as chronic mucocutaneous candidiasis, hyperimmunoglobulinemia E syndrome, dectin-1 deficiency, and caspase recruitment domain-containing protein-9 deficiency. An overview of the known genetic factors influencing disseminated candidiasis, with an emphasis on Toll-like receptors, is presented in this article. [ABSTRACT FROM AUTHOR]
- Published
- 2010
48. Innate immune mechanisms for recognition and uptake of Candida species
- Author
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Netea, Mihai G. and Maródi, László
- Subjects
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NATURAL immunity , *CANDIDIASIS , *CELL receptors , *CELLULAR signal transduction , *IMMUNOLOGY , *INFLAMMATION - Abstract
Candida species are major causes of infections affecting either body surfaces or the deep tissues. Candida is a complex pathogen and the immune system uses various cells, cell surface receptors and signalling pathways to trigger an efficient host defence. Host–Candida interaction can result either in rapid elimination of the pathogen or the persistence of the pathogen in immunocompromised patients, leading to either chronic mucocutanous candidiasis or invasive candidiasis. Here, we discuss the molecular basis of receptor-mediated recognition and uptake of non-opsonized Candida and we describe the relative role of these receptors in initiating inflammation. In addition, the consequence of genetic defects in dectin-1 and dectin-1-mediated signalling and the role of Th17-dependent mechanisms for the mucosal antifungal defence are discussed. [Copyright &y& Elsevier]
- Published
- 2010
- Full Text
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49. IL-1β Processing in Host Defense: Beyond the Inflammasomes.
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Netea, Mihai G., Simon, Anna, van de Veerdonk, Frank, Kullberg, Bart-Jan, Van der Meer, Jos W. M., and Joosten, Leo A. B.
- Subjects
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CYTOKINE genetics , *IMMUNOREGULATION , *DEFENSE reaction (Physiology) , *TRANSCRIPTION factors , *PATHOLOGICAL physiology , *PATHOGENIC microorganisms - Abstract
Stimulation and release of proinflammatory cytokines is an essential step for the activation of an effective innate host defense, and subsequently for the modulation of adaptive immune responses. Interleukin-1β (IL-1β) and IL-18 are important proinflammatory cytokines that on the one hand activate monocytes, macropages, and neutrophils, and on the other hand induce Th1 and Th17 adaptive cellular responses. They are secreted as inactive precursors, and the processing of pro-IL-1β and pro-IL-18 depends on cleavage by proteases. One of the most important of these enzymes is caspase-1, which in turn is activated by several protein platforms called the inflammasomes. Inflammasome activation differs in various cell types, and knock-out mice defective in either caspase-1 or inflammasome components have an increased susceptibility to several types of infections. However, in other infections and in models of sterile inflammation, caspase-1 seems to be less important, and alternative mechanisms such as neutrophil-derived serine proteases or proteases released from microbial pathogens can process and activate IL-1β. In conclusion, IL-1β/IL-18 processing during infection is a complex process in which the inflammasomes are only one of several activation mechanisms. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
50. The role of Toll-like receptors and C-type lectins for vaccination against Candida albicans
- Author
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Ferwerda, Gerben, Netea, Mihai G., Joosten, Leo A., van der Meer, Jos W.M., Romani, Luigina, and Kullberg, Bart Jan
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VIRAL receptors , *LECTINS , *CANDIDA albicans , *CELLULAR immunity , *BACTERIAL diseases , *CYTOKINESIS , *PATHOGENIC microorganisms , *THERAPEUTICS - Abstract
Abstract: Recent progress has provided important novel insights in the processes driving the adaptive immune responses. Central to these developments is the discovery of pattern recognition receptors like TLRs and CLRs that not only induce innate immune responses, but also modulate cellular and humoral adaptive immunity. As vaccination is one of the great achievements in medicine and probably the most powerful tool to protect human and animals against infectious disease, further vaccine development and optimization of current strategies can improve health status of large groups of people. Development of a vaccine against Candida spp. should induce both cellular and humoral immune responses. While the TLRs are strong inducers of inflammatory responses, it seems that the CLRs have the potential to modulate these responses by enhancement or inhibition of cytokine production. Understanding the natural host defense mechanisms against pathogens like C. albicans therefore helps to identify the proper targets for inducing a strong adjuvant effect, in order to stimulate an effective adaptive immune response and protection. [Copyright &y& Elsevier]
- Published
- 2010
- Full Text
- View/download PDF
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