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Item does not contain fulltext OBJECTIVE: To determine whether a gout polygenic risk score (PRS) is associated with age at gout onset and tophaceous disease in European, East Polynesian, and West Polynesian men and women with gout. METHODS: A 19-variant gout PRS was produced in 7 European gout cohorts (N = 4,016), 2 East Polynesian gout cohorts (N = 682), and 1 West Polynesian gout cohort (N = 490). Sex-stratified regression models were used to estimate the relationship between the PRS and age at gout onset and tophaceous disease. RESULTS: The PRS was associated with earlier age at gout onset in men (β = -3.61 in years per unit PRS [95% confidence interval (95% CI) -4.32, -2.90] in European men; β = -6.35 [95% CI -8.91, -3.80] in East Polynesian men; β = -3.51 [95% CI -5.46, -1.57] in West Polynesian men) but not in women (β = 0.07 [95% CI -2.32, 2.45] in European women; β = 0.20 [95% CI -7.21, 7.62] in East Polynesian women; β -3.33 [95% CI -9.28, 2.62] in West Polynesian women). The PRS showed a positive association with tophaceous disease in men (odds ratio [OR] for the association 1.15 [95% CI 1.00, 1.31] in European men; OR 2.60 [95% CI 1.66, 4.06] in East Polynesian men; OR 1.53 [95% CI 1.07, 2.19] in West Polynesian men) but not in women (OR for the association 0.68 [95% CI 0.42, 1.10] in European women; OR 1.45 [95% CI 0.39, 5.36] in East Polynesian women). The PRS association with age at gout onset was robust to the removal of ABCG2 variants from the PRS in European and East Polynesian men (β = -2.42 [95% CI -3.37, -1.46] and β = -6.80 [95% CI -10.06, -3.55], respectively) but not in West Polynesian men (β = -1.79 [95% CI -4.74, 1.16]). CONCLUSION: Genetic risk variants for gout also harbor risk for earlier age at gout onset and tophaceous disease in European and Polynesian men. Our findings suggest that earlier gout onset involves the accumulation of gout risk alleles in men but perhaps not in women, and that this genetic risk is shared across multiple ancestral groups.

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.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.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.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.

Contains fulltext : 286849.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Trained Immunity (TI) refers to the long-term modulation of the innate immune response, based on previous interactions with microbes, microbial ligands, or endogenous substances. Through metabolic and epigenetic reprogramming, monocytes, macrophages, and neutrophils develop an enhanced capacity to mount innate immune responses to subsequent stimuli and this is persistent due to alterations at the myeloid progenitor compartment. AREAS COVERED: The purpose of this article is to review the current understanding of the TI process and to discuss its potential clinical implications in the near future. We address the evidence of TI involvement in various diseases, the currently developed new therapy, and discuss how TI may lead to new clinical tools to improve existing standards of care. EXPERT OPINION: The state of the art in this domain has made considerable progress, linking TI-related mechanisms in multiple immune-mediated pathologies, starting with infections to autoimmune disorders and cancers. As a relatively new area of immunology, it has seen fast progress with many of its applications ready to be investigated in clinical settings.

BackgroundTrained immunity – or innate immune memory – can be described as the long-term reprogramming of innate immune cells towards a hyperresponsive state which involves intracellular metabolic changes. Trained immunity has been linked to atherosclerosis. A subgroup of patients with primary Sjögren’s syndrome (pSS) exhibits systemic type I interferon (IFN) pathway activation, indicating innate immune hyperactivation. Here, we studied the link between type I IFNs and trained immunity in an in vitro monocytic cell model and peripheral blood mononuclear cells (PBMCs) from pSS patients.MethodsThe training stimuli heat killed Candida albicans, muramyl dipeptide, IFNβ, and patient serum were added to THP-1 cells for 24 hours, after which the cells were washed, rested for 48 hours and subsequently re-stimulated with LPS, Pam3Cys, poly I:C, IFNβ or oxLDL for 4-24 hours. PBMCs from pSS patients and healthy controls were stimulated with LPS, Pam3Cys, poly I:C or IFNβ for 0.5-24 hours.ResultsTraining with IFNβ induced elevated production of pro-atherogenic cytokines IL-6, TNFα and CCL2, differential cholesterol- and glycolysis-related gene expression, and increased glucose consumption and oxLDL uptake upon re-stimulation. Type I IFN production was increased in Candida albicans- and IFNβ-trained cells after LPS re-stimulation, but was reduced after poly I:C re-stimulation. Training with muramyl dipeptide and IFNβ, but not Candida albicans, affected the IFN-stimulated gene expression response to IFNβ re-stimulation. PBMCs from pSS patients consumed more glucose compared with healthy control PBMCs and tended to produce more TNFα and type I IFNs upon LPS stimulation, but less type I IFNs upon poly I:C stimulation.ConclusionsType I IFN is a trainer inducing a trained immunity phenotype with pro-atherogenic properties in monocytes. Conversely, trained immunity also affects the production of type I IFNs and transcriptional response to type I IFN receptor re-stimulation. The phenotype of pSS PBMCs is consistent with trained immunity. This connection between type I IFN, trained immunity and cholesterol metabolism may have important implications for pSS and the pathogenesis of (subclinical) atherosclerosis in these patients.

Sub-Saharan Africa currently experiences an unprecedented wave of urbanization, which has important consequences for health and disease patterns. This study aimed to investigate and integrate the immune and metabolic consequences of rural or urban lifestyles and the role of nutritional changes associated with urban living. In a cohort of 323 healthy Tanzanians, urban as compared to rural living was associated with a pro-inflammatory immune phenotype, both at the transcript and protein levels. We identified different food-derived and endogenous circulating metabolites accounting for these differences. Serum from urban dwellers induced reprogramming of innate immune cells with higher tumor necrosis factor production upon microbial re-stimulation in an in vitro model of trained immunity. These data demonstrate important shifts toward an inflammatory phenotype associated with an urban lifestyle and provide new insights into the underlying dietary and metabolic factors, which may affect disease epidemiology in sub-Sahara African countries.Rapid urbanization can be associated with adverse health implications. de Mast and colleagues compare urban and rural Tanzanian populations using multi-omics and observe that urbanization is associated with an elevated but reversible inflammatory state.

Intergenerational inheritance of immune traits linked to epigenetic modifications has been demonstrated in plants and invertebrates. Here we provide evidence for transmission of trained immunity across generations to murine progeny that survived a sublethal systemic infection with Candida albicans or a zymosan challenge. The progeny of trained mice exhibited cellular, developmental, transcriptional and epigenetic changes associated with the bone marrow-resident myeloid effector and progenitor cell compartment. Moreover, the progeny of trained mice showed enhanced responsiveness to endotoxin challenge, alongside improved protection against systemic heterologous Escherichia coli and Listeria monocytogenes infections. Sperm DNA of parental male mice intravenously infected with the fungus C. albicans showed DNA methylation differences linked to immune gene loci. These results provide evidence for inheritance of trained immunity in mammals, enhancing protection against infections. Transgenerational transmission of acquired immunological traits has been demonstrated in invertebrates and plants but not mammals. Katzmarski et al. demonstrate that trained immunity that protects against heterologous infections can be transmitted to F2 offspring.

The similarities and differences between trained immunity and other immune processes are the subject of intense interrogation. Therefore, a consensus on the definition of trained immunity in both in vitro and in vivo settings, as well as in experimental models and human subjects, is necessary for advancing this field of research. Here we aim to establish a common framework that describes the experimental standards for defining trained immunity.

IL-38 is a recently discovered cytokine and member of the IL-1 Family. In the IL-1 Family, IL-38 is unique because the cytokine is primarily a B lymphocyte product and functions to suppress inflammation. Studies in humans with inflammatory bowel disease (IBD) suggest that IL-38 may be protective for ulcerative colitis or Crohn’s disease, and that IL-38 acts to maintain homeostasis in the intestinal tract. Here we investigated the role of endogenous IL-38 in experimental colitis in mice deficient in IL-38 by deletion of exons 1-4 in C57 BL/6 mice. Compared to WT mice, IL-38 deficient mice subjected to dextran sulfate sodium (DSS) showed greater severity of disease, more weight loss, increased intestinal permeability, and a worse histological phenotype including increased neutrophil influx in the colon. Mice lacking IL-38 exhibited elevated colonic Nlrp3 mRNA and protein levels, increased caspase-1 activation, and the concomitant increased processing of IL-1β precursor into active IL-1β. Expression of IL-1α, an exacerbator of IBD, was also upregulated. Colonic myleloperoxidase protein and Il17a, and Il17f mRNA levels were higher in the IL-38 deficient mice. Daily treatment of IL-38 deficient mice with an NLRP3 inhibitor attenuated diarrhea and weight loss during the recovery phase. These data implicate endogenous IL-38 as an anti-inflammatory cytokine that reduces DSS colitis severity. We propose that a relative deficiency of IL-38 contributes to IBD by disinhibition of the NLRP3 inflammasome.

Recent genome-wide association studies (GWASs) of COVID-19 patients of European ancestry have identified genetic loci significantly associated with disease severity. Here, we employed the detailed clinical, immunological and multi-omics dataset of the Human Functional Genomics Project (HFGP) to explore the physiological significance of the host genetic variants that influence susceptibility to severe COVID-19. A genomics investigation intersected with functional characterization of individuals with high genetic risk for severe COVID-19 susceptibility identified several major patterns: i. a large impact of genetically determined innate immune responses in COVID-19, with ii. increased susceptibility for severe disease in individuals with defective cytokine production; iii. genetic susceptibility related to ABO blood groups is probably mediated through the von Willebrand factor (VWF) and endothelial dysfunction. We further validated these identified associations at transcript and protein levels by using independent disease cohorts. These insights allow a physiological understanding of genetic susceptibility to severe COVID-19, and indicate pathways that could be targeted for prevention and therapy.

The IL‐1 family member IL‐38 (IL1F10) suppresses inflammatory and autoimmune conditions. Here, we report that plasma concentrations of IL‐38 in 288 healthy Europeans correlate positively with circulating memory B cells and plasmablasts. IL‐38 correlated negatively with age (p = 0.02) and was stable in 48 subjects for 1 year. In comparison with primary keratinocytes, IL1F10 expression in CD19+ B cells from PBMC was lower, whereas cell‐associated IL‐38 expression was comparable. In vitro, IL‐38 is released from CD19+ B cells after stimulation with rituximab. Intravenous LPS in humans failed to induce circulating IL‐38, compared to 100‐fold induction of IL‐6 and IL‐1 receptor antagonist. In a cohort of 296 subjects with body mass index > 27 at high risk for cardiovascular disease, IL‐38 plasma concentrations were significantly lower than in healthy subjects (p < 0.0001), and lowest in those with metabolic syndrome (p < 0.05). IL‐38 also correlated inversely with high sensitivity C‐reactive protein (p < 0.01), IL‐6, IL‐1Ra, and leptin (p < 0.05). We conclude that a relative deficiency of the B cell product IL‐38 is associated with increased systemic inflammation in aging, cardiovascular and metabolic disease, and is consistent with IL‐38 as an anti‐inflammatory cytokine., We propose that circulating B cells are a major source of the anti‐inflammatory cytokine interleukin 38 (IL‐38). Circulating IL‐38 concentrations are reduced by old age, being overweight and having metabolic syndrome. In overweight subjects, a relative IL‐38 deficiency is associated with chronic inflammation and increased cardiovascular disease risk.

ObjectiveGout is characterised by severe interleukin (IL)-1-mediated joint inflammation induced by monosodium urate crystals. Since IL-37 is a pivotal anti-inflammatory cytokine suppressing the activity of IL-1, we conducted genetic and functional studies aimed at elucidating the role of IL-37 in the pathogenesis and treatment of gout.MethodsVariant identification was performed by DNA sequencing of all coding bases of IL37 using molecular inversion probe-based resequencing (discovery cohort: gout n=675, controls n=520) and TaqMan genotyping (validation cohort: gout n=2202, controls n=2295). Predictive modelling of the effects of rare variants on protein structure was followed by in vitro experiments evaluating the impact on protein function. Treatment with recombinant IL-37 was evaluated in vitro and in vivo in a mouse model of gout.ResultsWe identified four rare variants in IL37 in six of the discovery gout patients; p.(A144P), p.(G174Dfs*16), p.(C181*) and p.(N182S), whereas none emerged in healthy controls (Fisher’s exact p-value=0.043). All variants clustered in the functional domain of IL-37 in exon 5 (p-value=5.71×10−5). Predictive modelling and functional studies confirmed loss of anti-inflammatory functions and we substantiated the therapeutic potential of recombinant IL-37 in the treatment of gouty inflammation. Furthermore, the carrier status of p.(N182S)(rs752113534) was associated with increased risk (OR=1.81, p-value=0.031) of developing gout in hyperuricaemic individuals of Polynesian ancestry.ConclusionHere, we provide genetic as well as mechanistic evidence for the role of IL-37 in the pathogenesis of gout, and highlight the therapeutic potential of recombinant IL-37 for the treatment of gouty arthritis.

Contains fulltext : 248727.pdf (Publisher’s version ) (Closed access)

Contains fulltext : 286870.pdf (Publisher’s version ) (Open Access) Previous studies have shown that monocytes can be 'trained' or tolerized by certain stimuli to respond stronger or weaker to a secondary stimulation. Rewiring of glucose metabolism was found to be important in inducing this phenotype. As we previously found that Borrelia burgdorferi (B. burgdorferi), the causative agent of Lyme borreliosis (LB), alters glucose metabolism in monocytes, we hypothesized that this may also induce long-term changes in innate immune responses. We found that exposure to B. burgdorferi decreased cytokine production in response to the TLR4-ligand lipopolysaccharide (LPS). In addition, B. burgdorferi exposure decreased baseline levels of glycolysis, as assessed by lactate production. Using GWAS analysis, we identified a gene, microfibril-associated protein 3-like (MFAP3L) as a factor influencing lactate production after B. burgdorferi exposure. Validation experiments proved that MFAP3L affects lactate- and cytokine production following B. burgdorferi stimulation. This is mediated by functions of MFAP3L, which includes activating ERK2 and through activation of platelet degranulation. Moreover, we showed that platelets and platelet-derived factors play important roles in B. burgdorferi-induced cytokine production. Certain platelet-derived factors, such chemokine C-X-C motif ligand 7 (CXCL7) and (C-C motif) ligand 5 (CCL5), were elevated in the circulation of LB patients in comparison to healthy individuals.

Contains fulltext : 252005.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 248720.pdf (Publisher’s version ) (Open Access) Trained immunity is the long-term memory of innate immune cells, characterised by increased pro-inflammatory responses towards homo- and heterologous secondary stimuli. Interleukin (IL)-1 signalling plays an essential role in the induction of trained immunity, also called innate immune memory. As such, certain anti-inflammatory members of the IL-1 family of cytokines (IL-1F) which interfere with the inflammatory process have the potential to regulate the induction of a trained phenotype. The aim of this review is to provide an update on the role of IL-1F members in the context of trained immunity, emphasising the role of anti-inflammatory cytokines from the IL-1F to inhibit the induction of trained immunity, and touching upon their potential as therapeutics in IL-1-driven inflammatory disorders.

The ongoing Coronavirus Disease 2019 (COVID-19) pandemic is caused by the highly infectious Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). There is an urgent need for biomarkers that will help in better stratification of patients and contribute to personalized treatments. We performed targeted proteomics using the Olink platform and systematically investigated protein concentrations in 350 hospitalized COVID-19 patients, 186 post-COVID-19 individuals, and 61 healthy individuals from 3 independent cohorts. Results revealed a signature of acute SARS-CoV-2 infection, which is represented by inflammatory biomarkers, chemokines and complement-related factors. Furthermore, the circulating proteome is still significantly affected in post-COVID-19 samples several weeks after infection. Post-COVID-19 individuals are characterized by upregulation of mediators of the tumor necrosis (TNF)-α signaling pathways and proteins related to transforming growth factor (TGF)-ß. In addition, the circulating proteome is able to differentiate between patients with different COVID-19 disease severities, and is associated with the time after infection. These results provide important insights into changes induced by SARS-CoV-2 infection at the proteomic level by integrating several cohorts to obtain a large disease spectrum, including variation in disease severity and time after infection. These findings could guide the development of host-directed therapy in COVID-19.

Contains fulltext : 248704.pdf (Publisher’s version ) (Open Access) Innate immune cells are able to build memory characteristics via a process termed "trained immunity." Host factors that influence the magnitude of the individual trained immunity response remain largely unknown. Using an integrative genomics approach, our study aimed to prioritize and understand the role of specific genes in trained immunity responses. In vitro-induced trained immunity responses were assessed in two independent population-based cohorts of healthy individuals, the 300 Bacillus Calmette-Guérin (300BCG; n = 267) and 200 Functional Genomics (200FG; n = 110) cohorts from the Human Functional Genomics Project. Genetic loci that influence cytokine responses upon trained immunity were identified by conducting a meta-analysis of QTLs identified in the 300BCG and 200FG cohorts. From the identified QTL loci, we functionally validated the role of PI3K-Akt signaling pathway and two genes that belong to the family of Siglec receptors (Siglec-5 and Siglec-14). Furthermore, we identified the H3K9 histone demethylases of the KDM4 family as major regulators of trained immunity responses. These data pinpoint an important role of metabolic and epigenetic processes in the regulation of trained immunity responses, and these findings may open new avenues for vaccine design and therapeutic interventions.

Interleukin (IL)-38 is the latest discovered member of the interleukin-1 family, which has anti-inflammatory properties similar to IL-36Ra. Several studies compared circulating IL-38 concentrations in healthy and diseased populations to characterize its role in both auto-immune and inflammatory pathologies, with both higher and lower concentrations being associated with certain diseases. However, in order to use IL-38 as a biomarker, a reference range in healthy adults is needed. To establish a reference IL-38 circulating concentration, accessible data from 25 eligible studies with IL-38 concentrations in healthy adults was collected. To validate the values found in literature, we measured IL-38 concentrations by enzyme-linked immunosorbent assay (ELISA) in several cohorts from our own institute. Additionally, the effect of blood collection techniques, freeze thawing cycles, and hemolysis on IL-38 measurements was assessed. To evaluate the importance of the genetic background of individuals as confounding factor of IL-38 synthesis, we used publicly available eQTL databases with matched data on allele frequencies in individuals of different ethnicities. Mean IL-38 concentrations in the various studies were weighted by their corresponding sample size, resulting in a weighted mean, and weighted upper and lower limits were calculated by mean ± 2 SD. Differences of over 10.000-fold were found in the weighted means between studies, which could not be attributed to the blood collection method or assessment of IL-38 in plasma or serum. Although IL-38 concentrations were markedly higher in Chinese then in European population studies, we could not show an association with the genetic background. From our analysis, a reference range for circulating IL-38 in healthy adults could thus not yet be established.

The majority of COVID-19 patients experience mild to moderate disease course and recover within a few weeks. An increasing number of studies characterized the long-term changes in the specific anti-SARS-CoV-2 immune responses, but how COVID-19 shapes the innate and heterologous adaptive immune system after recovery is less well known. To comprehensively investigate the post-SARS-CoV-2 infection sequelae on the immune system, we performed a multi-omics study by integrating single-cell RNA-sequencing, single-cell ATAC-sequencing, genome-wide DNA methylation profiling, and functional validation experiments in 14 convalescent COVID-19 and 15 healthy individuals. We showed that immune responses generally recover without major sequelae after COVID-19. However, subtle differences persist at the transcriptomic level in monocytes, with downregulation of the interferon pathway, while DNA methylation also displays minor changes in convalescent COVID-19 individuals. However, these differences did not affect the cytokine production capacity of PBMCs upon different bacterial, viral, and fungal stimuli, although baseline release of IL-1Ra and IFN-γ was higher in convalescent individuals. In conclusion, we propose that despite minor differences in epigenetic and transcriptional programs, the immune system of convalescent COVID-19 patients largely recovers to the homeostatic level of healthy individuals.

AimsPeriodontitis is an independent risk factor for cardiovascular disease, but the mechanistic link is not fully understood. In atherosclerotic cardiovascular disease, monocytes can adopt a persistent hyperresponsive phenotype, termed trained immunity. We hypothesized that periodontitis-associated bacteria can induce trained immunity in monocytes, which subsequently accelerate atherosclerosis development.Materials and MethodsWe combined in vitro experiments on human primary monocytes and in vivo techniques in patients with periodontitis to test this hypothesis. Adherent peripheral blood mononuclear cells (PBMCs) were transiently exposed in vitro to Porphyromonas gingivalis for 24 hours, and restimulated with lipopolysaccharide (LPS) or Pam3CysK4 (P3C) six days later, to measure interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) production. In an exploratory observational study, patients with severe periodontitis (63 ± 6 years, n=14) and control subjects with no-to-mild periodontitis (54 ± 10 years, n=14) underwent venipuncture and 2’-deoxy-2’-[18F]fluoro-D-glucose positron-emission-tomography ([18F]FDG PET/CT) scanning.ResultsWhen adherent peripheral blood mononuclear cells (PBMCs) were transiently exposed in vitro to Porphyromonas gingivalis for 24 hours, and restimulated with LPS or P3C six days later, IL-6 and TNFα production was significantly increased (TNFα/P3C, p18F]FDG PET/CT imaging showed a trend for increased [18F]FDG-uptake in the periodontium [mean standard uptake value (SUVmean), p=0.11] and in femur bone marrow (SUVmean, p=0.06), but no differences were observed for vascular inflammation. Positive correlations between severity of periodontitis, measured by The Dutch Periodontal Screening Index and pocket depth, with circulating inflammatory markers and tissue inflammation were found.ConclusionsP. gingivalis induces long-term activation of human monocytes in vitro (trained immunity). Patients with severe periodontitis did have signs of increased systemic inflammation and hematopoietic tissue activation. However, their circulating monocytes did not show a hyperresponsive phenotype. Together we suggest that trained immunity might contribute to local periodontal inflammation which warrants further investigation.

Contains fulltext : 206797.pdf (Publisher’s version ) (Closed access) BACKGROUND: Rewiring cellular metabolism is important for activation of immune cells during host defense against Mycobacterium tuberculosis. Glutamine has been implicated as an immunomodulatory nutrient, but its role in the response to M. tuberculosis is unknown. METHODS: We assessed expression of glutamine pathway genes in M. tuberculosis-infected macrophages and blood transcriptomic profiles of individuals with latent M. tuberculosis infection or tuberculosis. Subsequently, we studied the effect of blocking glutaminolysis on M. tuberculosis-induced cytokines. Finally, we examined whether polymorphisms in genes involved in the glutamine pathway influence M. tuberculosis-induced cytokines in a cohort of 500 individuals. RESULTS: Glutamine pathway genes were differentially expressed in infected macrophages and patients with tuberculosis. Human peripheral blood mononuclear cells stimulated with M. tuberculosis displayed decreased cytokine (ie, interleukin 1beta, interferon gamma, and interleukin 17) responses when medium was devoid of glutamine. Specific inhibitors of the glutamine pathway led to decreased cytokine responses, especially T-cell cytokines (ie, interferon gamma, interleukin 17, and interleukin 22). Finally, genetic polymorphisms in glutamine metabolism genes (including GLS2, SLC1A5, and SLC7A5) influenced ex vivo cytokine responses to M. tuberculosis, especially for T-cell cytokines. CONCLUSIONS: Cellular glutamine metabolism is implicated in effective host responses against M. tuberculosis. Targeting immunometabolism may represent new strategies for tuberculosis prevention and/or treatment.

IntroductionPatients with clinical malaria have an increased risk for bacterial bloodstream infections. We hypothesized that asymptomatic malaria parasitemia increases susceptibility for bacterial infections through an effect on the innate immune system. We measured circulating cytokine levels and ex-vivo cytokine production capacity in asymptomatic malaria and compared with controls.MethodsData were collected from asymptomatic participants ex-vivo stimulated with S. aureus, E. coli LPS and Salmonella Typhimurium; cytokine concentrations (TNF-α, IFN-γ, IL-1β, IL-6, IL-10) were measured on supernatants using ELISA.ResultsIncluded were children with clinical malaria (n=118), bacteremia (n=22), malaria and bacteremia co-infection (n=9), asymptomatic malaria (n=125), and asymptomatic controls (n=237). Children with either clinical or asymptomatic malaria had higher plasma cytokine concentrations than controls. Cytokine concentrations correlated positively with malaria parasite density with the strongest correlation for IL-10 in both asymptomatic (r=0.63) and clinical malaria (r=0.53). Patients with bacteremia had lower circulating IL-10, TNF-α and IFN-γ and higher IL-6 concentrations, compared to clinical malaria. Ex-vivo whole blood cytokine production to LPS and S. aureus was significantly lower in asymptomatic malaria compared to controls. Whole blood IFN-γ and IL-10 production in response to Salmonella was also lower in asymptomatic malaria.InterpretationIn children with asymptomatic malaria, cytokine responses upon ex-vivo bacterial stimulation are downregulated. Further studies are needed to explore if the suggested impaired innate immune response to bacterial pathogens also translates into impaired control of pathogens such as Salmonella spp.

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 facto nonspecific 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 vivo in their bone marrow cells. IL‐38 blocked mTOR signaling and prevented the epigenetic and metabolic changes induced by β‐glucan. In healthy subjects, the IL1F10 associated 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., Graphical Abstract IL‐38 inhibits the induction of innate immune memory

Tumors evade the immune system by inducing inflammation. In melanoma, tumor-derived IL-1β drives inflammation and the expansion of highly immunosuppressive myeloid-derived suppressor cells (MDSCs). Similar in many tumors, melanoma is also linked to the downstream IL‐6/STAT3 axis. In this study, we observed that both recombinant and tumor-derived IL-1β specifically induce pSTAT3(Y705), creating a tumor-autoinflammatory loop, which amplifies IL-6 signaling in the human melanoma cell line 1205Lu. To disrupt IL-1β/IL-6/STAT3 axis, we suppressed IL-1β-mediated inflammation by inhibiting the NOD-like receptor protein 3 (NLRP3) using OLT1177, a safe-in-humans specific NLRP3 oral inhibitor.In vivo, using B16F10 melanoma, OLT1177 effectively reduced tumor progression (p< 0.01); in primary tumors, OLT1177 decreased pSTAT3(Y705) by 82% (pII6expression by 53% (pPdcd1l1,Arg1,Il10andTgfb1. In conclusion, the data presented here show that the inhibition of NLRP3 reduces IL-1β induction of pSTAT3(Y705) preventing expression of immunosuppressive genes as well as activity in PMN-MDSCs.

Contains fulltext : 235365.pdf (Publisher’s version ) (Open Access) Traditionally, the innate and adaptive immune systems are differentiated by their specificity and memory capacity. In recent years, however, this paradigm has shifted: Cells of the innate immune system appear to be able to gain memory characteristics after transient stimulation, resulting in an enhanced response upon secondary challenge. This phenomenon has been called trained immunity. Trained immunity is characterized by nonspecific increased responsiveness, mediated via extensive metabolic and epigenetic reprogramming. Trained immunity explains the heterologous effects of vaccines, which result in increased protection against secondary infections. However, in chronic inflammatory conditions, trained immunity can induce maladaptive effects and contribute to hyperinflammation and progression of cardiovascular disease, autoinflammatory syndromes, and neuroinflammation. In this review we summarize the current state of the field of trained immunity, its mechanisms, and its roles in both health and disease.

BackgroundMale sex and old age are risk factors for COVID-19 severity, but the underlying causes are unknown. A possible explanation for this might be the differences in immunological profiles in males and the elderly before the infection. Given the seasonal profile of COVID-19, the seasonal response against SARS-CoV-2 could also be different in these groups.MethodsThe abundance of circulating proteins and immune populations associated with severe COVID-19 was analyzed in 2 healthy cohorts. PBMCs of female, male, young, and old subjects in different seasons of the year were stimulated with heat-inactivated SARS-CoV-2.ResultSeveral T cell subsets, which are known to be depleted in severe COVID-19 patients, were intrinsically less abundant in men and older individuals. Plasma proteins increasing with disease severity, including HGF, IL-8, and MCP-1, were more abundant in the elderly and males. The elderly produced significantly more IL-1RA and had a dysregulated IFNγ response with lower production in the summer compared with young individuals.ConclusionsThe immune characteristics of severe COVID-19, described by a differential abundance of immune cells and circulating inflammatory proteins, are intrinsically present in healthy men and the elderly. This might explain the susceptibility of men and the elderly to SARS-CoV-2 infection.SummaryImmunological profile of severe COVID-19, characterized by altered immune cell populations and inflammatory plasma proteins is intrinsically present in healthy men and the elderly. Different age and sex groups show distinct seasonal responses to SARS-CoV-2.

The last few years have witnessed an increasing body of evidence that challenges the traditional view that immunological memory is an exclusive trait of the adaptive immune system. Myeloid cells can show increased responsiveness upon subsequent stimulation with the same or a different stimulus, well after the initial challenge. This de facto innate immune memory has been termed "trained immunity" and is involved in infections, vaccination and inflammatory diseases. Trained immunity is based on two main pillars: the epigenetic and metabolic reprogramming of cells. In this review we discuss the latest insights into the epigenetic mechanisms behind the induction of trained immunity, as well as the role of different cellular metabolites and metabolic networks in the induction, regulation and maintenance of trained immunity.

Contains fulltext : 235031.pdf (Publisher’s version ) (Closed access) Behçet's disease (BD) is an inflammatory disease mainly affecting men along the ancient Silk Route. In the present study we describe a Dutch family suffering from BD-like disease with extreme pathergic responses, but without systemic inflammation. Genetic assessment revealed a combination of the human leukocyte antigen (HLA)-B*51 risk-allele together with a rare heterozygous variant in the CSF2 gene (c.130A>C, p.N44H) encoding for granulocyte-macrophage colony-stimulating factor (GM-CSF) found by whole exome sequencing. We utilized an over-expression vector system in a human hepatocyte cell line to produce the aberrant variant of GM-CSF. Biological activity of the protein was measured by signal transducer and activator of transcription 5 (STAT-5) phosphorylation, a downstream molecule of the GM-CSF receptor, in wild-type peripheral mononuclear cells (PBMCs) using flow cytometry. Increased STAT-5 phosphorylation was observed in response to mutated GM-CSF when compared to the wild-type or recombinant protein. CSF2 p.N44H results in disruption of one of the protein's two N-glycosylation sites. Enzymatically deglycosylated wild-type GM-CSF also enhanced STAT-5 phosphorylation. The patient responded well to anti-tumor necrosis factor (TNF)-α treatment, which may be linked to the capacity of TNF-α to induce GM-CSF in phorbol 12-myristate 13-acetate (PMA)-treated PBMCs, while GM-CSF itself only induced dose-dependent interleukin (IL)-1Ra production. The identified CSF2 pathway could provide novel insights into the pathergic response of BD-like disease and offer new opportunities for personalized treatment.

The clinical spectrum of COVID-19 varies and the differences in host response characterizing this variation have not been fully elucidated. COVID-19 disease severity correlates with an excessive proinflammatory immune response and profound lymphopenia. Inflammatory responses according to disease severity were explored by plasma cytokine measurements and proteomics analysis in 147 COVID-19 patients. Furthermore, peripheral blood mononuclear cell cytokine production assays and whole blood flow cytometry were performed. Results confirm a hyperinflammatory innate immune state, while highlighting hepatocyte growth factor and stem cell factor as potential biomarkers for disease severity. Clustering analysis revealed no specific inflammatory endotypes in COVID-19 patients. Functional assays revealed abrogated adaptive cytokine production (interferon-γ, interleukin-17, and interleukin-22) and prominent T-cell exhaustion in critically ill patients, whereas innate immune responses were intact or hyperresponsive. Collectively, this extensive analysis provides a comprehensive insight into the pathobiology of severe to critical COVID-19 and highlights potential biomarkers of disease severity.

Summary The endocrine and the immune systems interact by sharing receptors for hormones and cytokines, cross‐control and feedback mechanisms. To date, no comprehensive study has assessed the impact of thyroid hormones on immune homeostasis. By studying immune phenotype (cell populations, antibody concentrations, circulating cytokines, adipokines and acute‐phase proteins, monocyte–platelet interactions and cytokine production capacity) in two large independent cohorts of healthy volunteers of Western European descent from the Human Functional Genomics Project (500FG and 300BCG cohorts), we identified a crucial role of the thyroid hormone thyroxin (T4) and thyroid‐stimulating hormone (TSH) on the homeostasis of lymphocyte populations. TSH concentrations were strongly associated with multiple populations of both effector and regulatory T cells, whereas B‐cell populations were significantly associated with free T4 (fT4). In contrast, fT4 and TSH had little impact on myeloid cell populations and cytokine production capacity. Mendelian randomization further supported the role of fT4 for lymphocyte homeostasis. Subsequently, using a genomics approach, we identified genetic variants that influence both fT4 and TSH concentrations and immune responses, and gene set enrichment pathway analysis showed enrichment of fT4‐affected gene expression in B‐cell function pathways, including the CD40 pathway, further supporting the importance of fT4 in the regulation of B‐cell function. In conclusion, we show that thyroid function controls the homeostasis of the lymphoid cell compartment. These findings improve our understanding of the immune responses and open the door for exploring and understanding the role of thyroid hormones in the lymphocyte function during disease., TSH and T4 both influence lymphocyte homeostasis and subpopulations while components of the myeolid lineage and the innate immune system remained rather uneffected.

Circulatory inflammatory proteins play a significant role in anti-Candidahost immune defence. However, little is known about the genetic variation that contributes to the variability of inflammatory responses in response toC. albicans. To systematically characterize inflammatory responses inCandidainfection, we profiled 91 circulatory inflammatory proteins in peripheral blood mononuclear cells (PBMCs) stimulated withC. albicansyeast isolated from 378 individuals of European origin from the 500 Functional Genomics (500FG) cohort of the Human Functional Genomics Project (HFGP) and Lifelines Deep cohort. To identify the genetic factors that determine variation in inflammatory protein responses, we correlated genome-wide single nucleotide polymorphism (SNP) genotypes with protein abundance (protein quantitative trait loci, pQTLs) produced by theCandida-stimulated PBMCs. Furthermore, we investigated whether differences in survival of candidaemia patients can be explained by modulating levels of inflammatory proteins. We identified five genome-wide significant pQTLs that modulate IL-8, MCP-2, MMP-1, and CCL3 in response toC. albicans. In addition, our genetic analysis suggested thatGADD45Gfrom rs10114707 locus that reached genome-wide significance could be a potential core gene that regulates a cytokine network uponCandidainfection. Last but not least, we observed that a trans-pQTL marked from SNP rs7651677 at chromosome 3 that influences urokinase plasminogen activator (uPA) is strongly associated with patient survival (Psurvival= 3.52 x 10-5, OR 3). Overall, our genetic analysis showed that genetic variation determines the abundance of circulatory proteins in response toCandidainfection.

In the version of this article initially published, author Raphael Duivenvoorden’s last name was spelt incorrectly as Duivenwoorden. The error has been corrected in the HTML and PDF versions of the article.

Different components of the immune response show large variability between individuals, but they also vary within the same individual because of host and environmental factors. In this study, we report an extensive analysis of the immune characteristics of 56 individuals over four timepoints in 1 single year as part of the Human Functional Genomics Project. We characterized 102 cell subsets using flow cytometry; quantified production of eight cytokines and two chemokines in response to 20 metabolic, bacterial, fungal, and viral stimuli; and measured circulating markers of inflammation. Taking advantage of the longitudinal sampling, both seasonal and nonseasonal sources of variability were studied. The circulating markers of inflammation IL-18, IL-18 binding protein, and resistin displayed clear seasonal variability, whereas the strongest effect was observed for α-1 antitrypsin. Cytokine production capacity also showed strong seasonal changes, especially after stimulation with the influenza virus, Borrelia burgdorferi, and Escherichia coli. Furthermore, we observed moderate seasonality effects on immune cell counts, especially in several CD4+/CD8+ T cell subpopulations. Age of the volunteers was an important factor influencing IFN-γ and IL-22 production, which matched the strong impact of age on several T cell subsets. Finally, on average, genetics accounted for almost 50% of the interindividual variance not already explained by age, sex, and body mass index, although this varies strongly for different parameters. In conclusion, seasonality is an important environmental factor that influences immune responses, in addition to specific genetic and nongenetic host factors, and this may well explain the seasonal variation in the incidence and severity of immune-mediated diseases.

Objectives Histone methyltransferase G9a, also known as Euchromatic Histone Lysine Methyltransferase 2 (EHMT2), mediates H3K9 methylation which is associated with transcriptional repression. It possesses immunomodulatory effects and is overexpressed in multiple types of cancer. In this study, we investigated the role of G9a in the induction of trained immunity, a de facto innate immune memory, and its effects in non‐muscle‐invasive bladder cancer (NMIBC) patients treated with intravesical Bacillus Calmette‐Guérin (BCG). Methods EHMT2 expression was assessed upon induction of trained immunity by RNA sequencing and Western blotting. G9a inhibitor BIX‐01294 was used to investigate the effect on trained immunity responses in vitro. Subsequent cytokine production was measured by ELISA, epigenetic modifications were measured by ChIP‐qPCR, Seahorse technology was used to measure metabolic changes, and a luminescence assay was used to measure ROS release. RNA sequencing was performed on BIX‐01294‐treated monocytes ex vivo. Results The expression of EHMT2 mRNA and protein decreased in monocytes during induction of trained immunity. G9a inhibition by BIX‐01294 induced trained immunity and amplified trained immunity responses evoked by various microbial ligands in vitro. This was accompanied by decreased H3K9me2 at the promoters of pro‐inflammatory genes. G9a inhibition was also associated with amplified ex vivo trained immunity responses in circulating monocytes of NMIBC patients. Additionally, altered RNA expression of inflammatory genes in monocytes of NMIBC patients was observed upon ex vivo G9a inhibition. Furthermore, intravesical BCG therapy decreased H3K9me2 at the promoter of pro‐inflammatory genes. Conclusion Inhibition of G9a is important in the induction of trained immunity, and G9a may represent a novel therapeutic target in NMIBC patients., In this study, we show that G9a inhibits induction of trained immunity in human monocytes. Pharmacological G9a inhibition enhances trained immunity responses, accompanied by decreased H3K9me2 marks at pro‐inflammatory genes. Additionally, ex vivo G9a inhibition was associated with amplified trained immunity responses in monocytes derived from non‐muscle‐invasive bladder cancer patients and altered RNA expression of inflammatory genes.

Interleukin (IL)–38 belongs to the IL–1 family and is part of the IL–36 subfamily due to its binding to the IL–36 Receptor (IL–1R6). In the current study, we assessed the anti-inflammatory properties of IL–38 in murine models of arthritis and systemic inflammation. First, the anti-inflammatory properties of mouse and human IL–38 precursors were compared to forms with a truncated N–terminus. In mouse bone marrow derived dendritic cells (BMDC), human and mouse IL–38 precursors with a truncation of the two N-terminal amino acids (3–152) suppressed LPS-induced IL–6. Recombinant human IL–38 (3–152) was further investigated for its immunomodulatory potential using four murine models of inflammatory disease: streptococcal cell wall (SCW)-induced arthritis, monosodium urate (MSU) crystal-induced arthritis, MSU crystal-induced peritonitis, and systemic endotoxemia. In each of these models IL–38 significantly reduced inflammation. In SCW and MSU crystal-induced arthritis, joint swelling, inflammatory cell influx, and synovial levels of IL–1β, IL–6, and KC were reduced by 50% or greater. These suppressive properties of IL–38 in SCW-induced arthritis were independent of the anti-inflammatory co-receptor IL–1R8, as IL–38 reduced arthritis equally in IL–1R8 deficient and WT mice. In MSU crystal-induced peritonitis, IL–38 reduced hypothermia, while plasma IL–6 and KC and peritoneal KC levels were reduced by 65–70%. In the LPS endotoxemia model, IL–38 pretreatment reduced systemic IL–6, TNFα and KC. Furthermore, in ex vivo cultured bone marrow, LPS-induced IL–6, TNFα and KC were reduced by 75–90%. Overall, IL–38 exhibits broad anti-inflammatory properties in models of systemic and local inflammation and therefore may be an effective cytokine therapy.

Long-term changes in the immune system of successfully treated people living with HIV (PLHIV) remain incompletely understood. In this study, we assessed 108 white blood cell (WBC) populations in a cohort of 211 PLHIV on stable antiretroviral therapy and in 56 HIV-uninfected controls using flow cytometry. We show that marked differences exist in T cell maturation and differentiation between PLHIV and HIV-uninfected controls: PLHIV had reduced percentages of CD4+ T cells and naïve T cells and increased percentages of CD8+ T cells, effector T cells, and T helper 17 (Th17) cells, together with increased Th17/regulatory T cell (Treg) ratios. PLHIV also exhibited altered B cell maturation with reduced percentages of memory B cells and increased numbers of plasmablasts. Determinants of the T and B cell composition in PLHIV included host factors (age, sex, and smoking), markers of the HIV reservoir, and CMV serostatus. Moreover, higher circulating Th17 percentages were associated with higher plasma concentrations of interleukin (IL) 6, soluble CD14, the gut homing chemokine CCL20, and intestinal fatty acid binding protein (IFABP). The changes in circulating lymphocytes translated into functional changes with reduced interferon (IFN)- γ responses of peripheral blood mononuclear cells to stimulation with Candida albicans and Mycobacterium tuberculosis. In conclusion, this comprehensive analysis confirms the importance of persistent abnormalities in the number and function of circulating immune cells in PLHIV on stable treatment.

Reports suggest a role of endothelial dysfunction and loss of endothelial barrier function in COVID-19. It is well established that the endothelial glycocalyx-degrading enzyme heparanase contributes to vascular leakage and inflammation. Low molecular weight heparins (LMWH) serve as an inhibitor of heparanase. We hypothesize that heparanase contributes to the pathogenesis of COVID-19, and that heparanase may be inhibited by LMWH. Heparanase activity and heparan sulfate levels were measured in plasma of healthy controls (n=10) and COVID-19 patients (n=48).Plasma heparanase activity and heparan sulfate levels were significantly elevated in COVID-19 patients. Heparanase activity associated with disease severity including the need for intensive care and mechanical ventilation, lactate dehydrogenase levels and creatinine levels. Use of prophylactic LMWH in non-ICU patients was associated with a reduced heparanase activity. Since there is no other clinically applied heparanase inhibitor currently available, therapeutic treatment of COVID-19 patients with low molecular weight heparins should be explored.

SUMMARY: BACKGROUND: Gout flares are driven by interleukin (IL)-1β. Dapansutrile inhibits the NLRP3 inflammasome and subsequent activation of IL-1β. In this study we aimed to investigate the safety and efficacy of orally administered dapansutrile in patients with a gout flare. METHODS: In this open-label, proof-of-concept, phase 2a trial, adult patients (aged 18–80 years) with a monoarticular monosodium urate crystal-proven gout flare were enrolled at an outpatient clinic in the Netherlands and sequentially assigned using a dose-adaptive design to receive 100 mg/day, 300 mg/day, 1000 mg/day, or 2000 mg/day oral dapansutrile for 8 days. The coprimary outcomes were change in patient-reported target joint pain from baseline to day 3 and from baseline to day 7, assessed in the per-protocol population (all patients who received at least 80% of the study drug and had no major protocol deviations). Safety was assessed in the intention-to-treat population. This trial is registered with the EU Clinical Trials Register, EudraCT 2016-000943-14, and is completed. FINDINGS: Between May 18, 2017, and Jan 21, 2019, 144 patients were assessed for eligibility, of whom 34 were enrolled and 29 were included in the per-protocol population (three patients were excluded due to receiving

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. Inflammatory pathways contribute to disease pathogenesis; however, regulation of the underlying mechanism is not completely understood. IL-1β, a pro-inflammatory cytokine, participates in the development and progression of NAFLD. To become bioactive, IL-1β requires enzymatic processing. Mechanisms that activate IL-1β include the classical NLRP3 inflammasome-caspase-1 and the neutrophil serine proteases, neutrophil elastase, and proteinase-3. Several studies have shown that both caspase-1 and the neutrophil serine proteases are important for NAFLD development. However, it is unknown whether these pathways interact and if they have a synergistic effect in promoting NAFLD. In the present study, we developed a novel and unique mouse model by intercrossing caspase-1/11 knockout mice with neutrophil elastase/proteinase-3 double knockout mice. Subsequently, these mice were examined regarding the development of high-fat diet–induced NAFLD. Our results show that mice deficient in caspase-1, neutrophil elastase, and proteinase-3 were protected from developing diet-induced weigh gain, liver steatosis, and adipose tissue inflammation when compared with controls. We conclude that pathways that process pro-IL-1β to bioactive IL-1β play an important role in promoting the development of NAFLD and obesity-induced inflammation. Targeting these pathways could have a therapeutic potential in patients with NAFLD. Electronic supplementary material The online version of this article (10.1007/s10753-020-01190-4) contains supplementary material, which is available to authorized users.

Studies in IL‐32 transgenic mice and in vitro suggest that IL‐32 may have protective effects against Mycobacterium tuberculosis, but so far there are barely any studies in humans. We studied the role of IL‐32 and its splice variants in tuberculosis (TB) in vivo and in vitro. Blood transcriptional analysis showed lower total IL‐32 mRNA levels in pulmonary TB patients compared to patients with latent TB infection and healthy controls. Also, among Indonesian household contacts who were heavily exposed to an infectious TB patient, IL‐32 mRNA levels were higher among those who remained uninfected compared to those who became infected with M. tuberculosis. In peripheral blood mononuclear cells from healthy donors, we found that IL‐32γ, the most potent isoform, was down‐regulated upon M. tuberculosis stimulation. This decrease in IL‐32γ was mirrored by an increase of another splice variant, IL‐32β. Also, a higher IL‐32γ/IL‐32β ratio correlated with IFN‐γ production, whereas a lower ratio correlated with production of IL‐1Ra, IL‐6, and IL‐17. These data suggest that IL‐32 contributes to protection against M. tuberculosis infection, and that this effect may depend on the relative abundance of different IL‐32 isoforms., IL‐32 is associated with resistance against M. tuberculosis infection. Mycobacterium tuberculosis induces IL‐32 splicing into different isoforms, which correlates with specific cytokine profiles.

Low-grade inflammation is associated with the development of insulin resistance in obese individuals. The present study aims to provide additional evidence strengthening the role of interleukin (IL)-32 in this key process. Using an IL-32 transgenic (IL-32tg) mouse model, we observed that IL-32tg fed a normal diet had greater body weight, due to greater accumulation of white adipose tissue (WAT) along with larger sized adipocytes. This led to metabolic consequences, with significant higher leptin levels and a trend towards hyperinsulinemia, indicating a phenotype resembling the metabolic syndrome. Adipocytes of IL-32tg mice were more prone to induce a pro-inflammatory response locally, which would be expected when predisposed to insulin resistance and type2 diabetes mellitus (T2D). In conclusion, our study provides novel evidence of a direct contribution of IL-32 to pathophysiological perturbations within the adipose tissue, possibly contributing to the metabolic syndrome that precedes frank insulin resistance and T2D. Future research should focus on the role of IL-32 in the obesity epidemic.

Contains fulltext : 218114.pdf (Publisher’s version ) (Open Access) Articular joints are a major target of Borrelia burgdorferi, the causative agent of Lyme arthritis. Despite antibiotic treatment, recurrent or persistent Lyme arthritis is observed in a significant number of patients. The host immune response plays a crucial role in this chronic arthritic joint complication of Borrelia infections. During the early stages of B. burgdorferi infection, a major hinder in generating a proper host immune response is the lack of induction of a strong adaptive immune response. This may lead to a delayed hyperinflammatory reaction later in the disease. Several mechanisms have been suggested that might be pivotal for the development of Lyme arthritis and will be highlighted in this review, from molecular mimicry of matrix metallopeptidases and glycosaminoglycans, to autoimmune responses to live bacteria, or remnants of Borrelia spirochetes in joints. Murine studies have suggested that the inflammatory responses are initiated by innate immune cells, but this does not exclude the involvement of the adaptive immune system in this dysregulated immune profile. Genetic predisposition, via human leukocyte antigen-DR isotype and microRNA expression, has been associated with the development of antibiotic-refractory Lyme arthritis. Yet the ultimate cause for (antibiotic-refractory) Lyme arthritis remains unknown. Complex processes of different immune cells and signaling cascades are involved in the development of Lyme arthritis. When these various mechanisms are fully been unraveled, new treatment strategies can be developed to target (antibiotic-refractory) Lyme arthritis more effectively.

BCG vaccination protects not only against tuberculosis but also against heterologous infections. This effect differs between individuals, yet the factors responsible for this variation are unknown. BCG-induced nonspecific protection is, at least partially, mediated by innate immune reprogramming (trained immunity), which can be induced by the muramyl dipeptide (MDP) component of peptidoglycans. We aimed to study whether differential release of MDP in healthy individuals may explain variability of their response to BCG vaccination. Circulating MDP concentrations were increased up to three months after BCG vaccination. MDP concentrations at baseline, but not their increase postvaccination, positively correlated with the induction of trained immunity and not with mycobacteria-induced T-cell responses. Interestingly, MDP concentrations correlated with inflammatory markers in the circulation. In conclusion, circulating MDP concentrations are associated with the strength of trained immunity responses and thus influence the biological effects of BCG vaccination. This study increases our understanding about the role of MDP in BCG-induced trained immunity, which might help to optimize vaccine efficacy and explore novel applications of BCG vaccination.

Contains fulltext : 218322.pdf (Publisher’s version ) (Open Access) Toll-like receptor 10 (TLR10) is the only member of the human Toll-like receptor family with an inhibitory function on the induction of innate immune responses and inflammation. However, its role in the modulation of trained immunity (innate immune memory) is unknown. In the present study, we assessed whether TLR10 modulates the induction of trained immunity induced by beta-glucan or bacillus Calmette-Guerin (BCG). Interleukin 10 receptor antagonist production was increased upon activation of TLR10 ex vivo after BCG vaccination, and TLR10 protein expression on monocytes was increased after BCG vaccination, whereas anti-TLR10 antibodies did not significantly modulate beta-glucan or BCG-induced trained immunity in vitro. A known immunomodulatory TLR10 missense single-nucleotide polymorphism (rs11096957) influenced trained immunity responses by beta-glucan or BCG in vitro. However, the in vivo induction of trained immunity by BCG vaccination was not influenced by TLR10 polymorphisms. In conclusion, TLR10 has a limited, non-essential impact on the induction of trained immunity in humans.

The fourth Innate Immune Memory meeting was held in the historic city of Nijmegen, in the eastern-central part of the Netherlands, to discuss the basic and translational aspects of innate immune memory, popularly known as ‘trained immunity’.

The anti-tuberculosis vaccine Bacillus Calmette-Guérin (BCG) is a well-known immune modulator that induces nonspecific protective effects against heterologous infections through induction of innate immune memory, also termed “trained immunity.” In randomized trials in low weight newborns, BCG vaccination reduced neonatal mortality due to decreased incidence of sepsis and respiratory infections. In many studies, sex-differential nonspecific effects of vaccines have been observed, but the mechanisms behind these differential effects are unknown. We investigated whether the important sex hormones estrogen and dihydrotestosterone (DHT) influence BCG-induced trained immunity in human primary monocytes. Although addition of estradiol and DHT to BCG inhibited the production of proinflammatory cytokines after direct stimulation of human monocytes, they did not influence the induction of trained immunity by BCG. In addition, estradiol or DHT did not induce training or tolerance in monocytes themselves. We conclude that these important sex hormones are unlikely to explain the sex-differential effects after BCG vaccination. Future studies should focus on the investigation of alternative mechanisms as an explanation for sex-differential nonspecific effects of BCG vaccination.

Contains fulltext : 190802.pdf (Publisher’s version ) (Closed access) Immunological memory was long considered a trait exclusive to cells of the adaptive immune system. However, recent studies have shown that after activation of the innate immune system, innate immune cells may undergo long-term functional reprogramming characterized by the ability to mount either a stronger or attenuated inflammatory response upon reactivation. This phenomenon, which has been termed trained immunity and is a de facto innate immune memory, is regulated by a network of integrated metabolic and epigenetic rewiring. The endogenous mediators that modulate trained immunity in the host are only partially understood, but increasing evidence supports the concept that the interleukin (IL)-1 family of cytokines plays an important role. In this review, we will highlight key findings from studies that provide insight into the multifaceted roles of members of the IL-1 family for trained immunity. Finally, we will discuss how the recent advances of our understanding on the role of IL-1 cytokines in this field may lead to new therapeutic strategies for treatment of common conditions, such as IL-1-driven autoinflammatory diseases. 12 p.

Contains fulltext : 182561.pdf (Publisher’s version ) (Closed access) Cancer immunotherapy has steadily progressed during the past decades, with checkpoint inhibitor therapy becoming the latest and one of the most promising treatments. Despite the progress, most of the patients do not respond or develop resistance, and novel additional approaches are needed to improve the clinical effectiveness of immunotherapy. Trained immunity (TI) has been described recently as a process of epigenetic and metabolic reprogramming that induces a long-term enhanced function of innate immune cells. TI is considered to have beneficial effects in improving host response to infections and vaccination, and increasing evidence suggests that TI-mediated mechanisms also have useful and potent antitumor effects. We hypothesized that novel and more effective approaches for immunotherapy in cancer may involve induction of TI, alone or in combination with current immunotherapies.