IL-18 and IL-18 binding protein are related to disease severity and parasitemia during falciparum malaria

Background - Several inflammatory molecules participate in the immune response to malaria. Interleukin (IL)-18 is an inflammatory cytokine activated by NLRP3 inflammasomes. In clinical falciparum malaria, with and without HIV co-infection, data on IL-18 and in particular on its binding protein, IL-18bp, is scarce. Methods - Clinical data and blood samples were collected from adults in Mozambique with P. falciparum infection, with (n = 70) and without (n = 61) HIV co-infection, from HIV-infected patients with similar symptoms without malaria (n = 58) and from healthy controls (n = 52). In vitro studies were performed in endothelial cells using hemozoin crystals. Results - (i) IL-18 and IL-18bp were markedly up-regulated during falciparum malaria with particular high levels in malaria patients co-infected with HIV and severe malaria disease. (ii) In the malaria group as a whole, both IL-18 and IL-18bp were positively correlated with disease severity, parasitemia, and endothelial cell activation as assessed by vWF in plasma. (iii) Whereas there was no change in IL-18 levels in malaria patients co-infected with HIV during follow-up, the patients with malaria only had slightly increased IL-18 levels. Further, the IL-18pb levels declined and thereby contributed to an increase in IL-18/IL-18bp ratio in all subgroups of malaria patients. (iv) IL-27, previously shown to be up-regulated in this malaria cohort, markedly induced a release of IL-18bp from endothelial cells in vitro, and notably, this presumably anti-inflammatory effect was counteracted by hemozoin. Conclusions - Our findings suggest that the IL-18 system could be an important mediator in the immune pathogenesis during falciparum malaria, potentially also representing a target for therapy

Potential anti-inflammatory role of activin A in acute coronary syndromes

AbstractObjectivesWe sought to investigate whether activin A could be involved in the immunopathogenesis of acute coronary syndromes.BackgroundInflammatory mechanisms seem to play a pathogenic role in atherosclerosis and acute coronary syndromes, but the actual mediators have not been fully identified. Activin A, a pleiotropic member of the transforming growth factor-beta cytokine family, has recently been suggested to play a role in inflammation.MethodsWe examined the role of activin A and its endogenous inhibitor follistatin in patients with stable (n = 26) and unstable angina (n = 20) and healthy control subjects (n = 20) by different experimental approaches.Results1) Patients with stable angina had raised activin A concentrations, as assessed by protein levels in serum and messenger ribonucleic acid levels in peripheral blood mononuclear cells (PBMCs). 2) Although several activin A–related mediators were upregulated in PBMCs from patients with stable angina compared with controls (i.e., activin A and Smad3), no changes or even downregulation (i.e., Smad2) were seen in unstable disease. 3) The activin type II receptors, representing the primary ligand-binding proteins, were downregulated in unstable compared with stable angina. 4) Percutaneous coronary intervention induced a decrease in the activin A/follistatin ratio, suggesting downregulatory effects on activin A activity. 5) Although activin A dose-dependently suppressed the release of inflammatory cytokines from PBMCs in angina patients, an opposite effect was found in healthy controls.ConclusionsOur findings suggest an anti-inflammatory potential of activin A in angina patients, and such effects may be of particular relevance in unstable angina in which several of the activin parameters were downregulated

Gut microbiota-dependent trimethylamine N-oxide associates with inflammation in common variable immunodeficiency

A substantial proportion of patients with common variable immunodeficiency (CVID) have inflammatory and autoimmune complications of unknown etiology. We have previously shown that systemic inflammation in CVID correlates with their gut microbial dysbiosis. The gut microbiota dependent metabolite trimethylamine N-oxide (TMAO) has been linked to several metabolic and inflammatory disorders, but has hitherto not been investigated in relation to CVID. We hypothesized that TMAO is involved in systemic inflammation in CVID. To explore this, we measured plasma concentrations of TMAO, inflammatory markers, and lipopolysaccharide (LPS) in 104 CVID patients and 30 controls. Gut microbiota profiles and the bacterial genes CutC and CntA, which encode enzymes that can convert dietary metabolites to trimethylamine in the colon, were examined in fecal samples from 40 CVID patients and 86 controls. Furthermore, a food frequency questionnaire and the effect of oral antibiotic rifaximin on plasma TMAO concentrations were explored in these 40 patients. We found CVID patients to have higher plasma concentrations of TMAO than controls (TMAO 5.0 [2.9–8.6] vs. 3.2 [2.2–6.3], p = 0.022, median with IQR). The TMAO concentration correlated positively with tumor necrosis factor (p = 0.008, rho = 0.26), interleukin-12 (p = 0.012, rho = 0.25) and LPS (p = 0.034, rho = 0.21). Dietary intake of meat (p = 0.678), fish (p = 0.715), egg (p = 0.138), dairy products (p = 0.284), and fiber (p = 0.767) did not significantly impact on the TMAO concentrations in plasma, nor did a 2-week course of the oral antibiotic rifaximin (p = 0.975). However, plasma TMAO concentrations correlated positively with gut microbial abundance of Gammaproteobacteria (p = 0.021, rho = 0.36). Bacterial gene CntA was present in significantly more CVID samples (75%) than controls (53%), p = 0.020, potentially related to the increased abundance of Gammaproteobacteria in these samples. The current study demonstrates that elevated TMAO concentrations are associated with systemic inflammation and increased gut microbial abundance of Gammaproteobacteria in CVID patients, suggesting that TMAO could be a link between gut microbial dysbiosis and systemic inflammation. Gut microbiota composition could thus be a potential therapeutic target to reduce systemic inflammation in CVID

Выявление и идентификация карантинных объектов на хризантеме в Республике Карелия

BACKGROUND: Co-infection with malaria and HIV increases the severity and mortality of both diseases, but the cytokine responses related to this co-infection are only partially characterised. The aim of this study was to explore cytokine responses in relation to severity and mortality in malaria patients with and without HIV co-infection. METHODS: This was a prospective cross-sectional study. Clinical data and blood samples were collected from adults in Mozambique. Plasma was analysed for 21 classical pro- and anti-inflammatory cytokines, including interleukins, interferons, and chemokines. RESULTS: We included 212 in-patients with fever and/or suspected malaria and 56 healthy controls. Falciparum malaria was diagnosed in 131 patients, of whom 70 were co-infected with HIV-1. The malaria patients had marked increases in their cytokine responses compared with the healthy controls. Some of these changes, particularly interleukin 8 (IL-8) and interferon-γ-inducing protein 10 (IP-10) were strongly associated with falciparum malaria and disease severity. Both these chemokines were markedly increased in patients with falciparum malaria as compared with healthy controls, and raised levels of IL-8 and IP-10 were associated with increased disease severity, even after adjusting for relevant confounders. For IL-8, particularly high levels were found in malaria patients that were co-infected with HIV and in those who died during hospitalization. INTERPRETATIONS: Our findings underscore the complex role of inflammation during infection with P. falciparum, and suggest a potential pathogenic role for IL-8 and IP-10. However, the correlations do not necessarily mean any causal relationship, and further both clinical and mechanistic research is necessary to elucidate the role of cytokines in pathogenesis and protection during falciparum malaria

LIGHT/TNFSF14 is increased in patients with type 2 diabetes mellitus and promotes islet cell dysfunction and endothelial cell inflammation in vitro

Published version. Source at http://dx.doi.org/10.1007/s00125-016-4036-y Aims/hypothesis: Activation of inflammatory pathways is involved in the pathogenesis of type 2 diabetes mellitus. On the basis of its role in vascular inflammation and in metabolic disorders, we hypothesised that the TNF superfamily (TNFSF) member 14 (LIGHT/TNFSF14) could be involved in the pathogenesis of type 2 diabetes mellitus. Methods: Plasma levels of LIGHT were measured in two cohorts of type 2 diabetes mellitus patients (191 Italian and 40 Norwegian). Human pancreatic islet cells and arterial endothelial cells were used to explore regulation and relevant effects of LIGHT in vitro. Results: Our major findings were: (1) in both diabetic cohorts, plasma levels of LIGHT were significantly raised compared with sex- and age-matched healthy controls (n = 32); (2) enhanced release from activated platelets seems to be an important contributor to the raised LIGHT levels in type 2 diabetes mellitus; (3) in human pancreatic islet cells, inflammatory cytokines increased the release of LIGHT and upregulated mRNA and protein levels of the LIGHT receptors lymphotoxin β receptor (LTβR) and TNF receptor superfamily member 14 (HVEM/TNFRSF14); (4) in these cells, LIGHT attenuated the insulin release in response to high glucose at least partly via pro-apoptotic effects; and (5) in human arterial endothelial cells, glucose boosted inflammatory response to LIGHT, accompanied by an upregulation of mRNA levels of HVEM (also known as TNFRSF14) and LTβR (also known as LTBR). Conclusions/interpretation: Our findings show that patients with type 2 diabetes mellitus are characterised by increased plasma LIGHT levels. Our in vitro findings suggest that LIGHT may contribute to the progression of type 2 diabetes mellitus by attenuating insulin secretion in pancreatic islet cells and by contributing to vascular inflammation

Increased expression of the homeostatic chemokines CCL19 and CCL21 in clinical and experimental Rickettsia conorii infection

Background Based on their essential role in concerting immunological and inflammatory responses we hypothesized that the homeostatic chemokines CCL19 and CCL21 may play a pathogenic role in rickettsiae infection. Methods Serum levels of CCL19 and CCL21 in patients with R. africae and R. conorii infection were analyzed by enzyme immunoassays. Lungs from R. conorii infected mice were examined for CCL19, CCL21 and CCR7 expression by immunohistochemistry. Results We found that patients with R. africae infection (n = 15) and in particular those with R. conorii infection (n = 16) had elevated serum levels of CCL19 on admission, with a decline during follow-up. While a similar pattern was seen for CCL21 in R. africae infection, patients with R. conorii infection showed persistently increased CCL21 levels during follow-up. In experimental R. conorii infection, we found strong immunostaining of CCL19 and CCL21 in the lungs, particularly in individuals that had received lethal doses. Immunofluorescence showed co-localization of CCR7 to endothelial cells, macrophages and fibroblasts within the lung tissue of R. conorii infected mice. Conclusions Our findings suggest that the CCL19/CCL21/CCR7 axis is up-regulated during R. africae and in particular during R. conorii infection, which may potentially contribute to the pathogenesis of these disorders

A Complex Interaction between Rickettsia conorii and Dickkopf-1-Potential Role in Immune Evasion Mechanisms in Endothelial Cells

The pathophysiological hallmark of spotted fever group rickettsioses comprises vascular inflammation. Based on the emerging importance of the wingless (Wnt) pathways in inflammation and vascular biology, we hypothesized that Dickkopf-1 (DKK-1), as a major modulator of Wnt signaling, could be involved in the pathogenesis in rickettsial infections. Our major findings were: (i) While baseline concentration of DKK-1 in patients with R. conorii infection (n = 32) were not different from levels in controls (n = 24), DKK-1 rose significantly from presentation to first follow-up sample (median 7 days after baseline). (ii) In vitro experiments in human umbilical vein endothelial cells (HUVECs) showed that while heat-inactivated R. conorii enhanced the release of interleukin-6 (IL-6) and IL-8, it down-regulated the release of endothelial-derived DKK-1 in a time- and dose-dependent manner. (iii) Silencing of DKK-1 attenuated the release of IL-6, IL-8 and growth-related oncogene (GRO)α in R. conorii-exposed HUVECs, suggesting inflammatory effects of DKK-1. (iv) Silencing of DKK-1 attenuated the expression of tissue factor and enhanced the expression of thrombomodulin in R. conorii-exposed HUVECs suggesting pro-thrombotic effects of DKK-1. The capacity of R. conorii to down-regulate endothelial-derived DKK-1 and the ability of silencing DKK-1 to attenuate R. conorii-induced inflammation in endothelial cells could potentially reflect a novel mechanism by which R. conorii escapes the immune response at the site of infection. © Astrup et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Lasting Immunological Imprint of Primary Epstein-Barr Virus Infection With Associations to Chronic Low-Grade Inflammation and Fatigue

Background: Epstein-Barr virus (EBV) causes infectious mononucleosis (IM) that can lead to chronic fatigue syndrome. The CEBA-project (Chronic fatigue following acute EBV infection in Adolescents) has followed 200 patients with IM and here we present an immunological profiling of adolescents with IM related to clinical characteristics. Methods: Patients were sampled within 6 weeks of debut of symptoms and after 6 months. Peripheral blood mononuclear cells (PBMC) were cultured and stimulated in vitro (n=68), and supernatants analyzed for cytokine release. Plasma was analyzed for inflammatory markers (n=200). The Chalder Fatigue Questionnaire diagnosed patients with and without chronic fatigue at 6 months (CF+ and CF- group, respectively) (n=32 and n=91, in vitro and plasma cohorts, respectively. Results: Broad activation of PBMC at baseline, with high levels of RANTES (Regulated on activation, normal T-cell expressed and secreted) in the CF+ group, and broad inflammatory response in plasma with high levels of T-cell markers was obeserved. At 6 months, there was an increased b-agonist response and RANTES was still elevated in cultures from the CF+ group. Plasma showed decrease of inflammatory markers except for CRP which was consistently elevated in the CF+ group. Conclusion: Patients developing chronic fatigue after IM have signs of T-cell activation and low-grade chronic inflammation at baseline and after 6 months

Soluble markers of neutrophil, T-cell and monocyte activation are associated with disease severity and parasitemia in falciparum malaria

BACKGROUND: The immune response during P. falciparum infection is a two-edged sword, involving dysregulation of the inflammatory responses with several types of immune cells participating. Here we examined T-cell, monocyte/macrophage and neutrophil activation during P. falciparum infection by using soluble activation markers for these leukocyte subsets. METHODS: In a prospective cross-sectional study clinical data and blood samples were collected from adults in Mozambique with P. falciparum infection, with (n = 70) and without (n = 61) co-infection with HIV-1, as well as HIV-infected patients with similar symptoms but without malaria (n = 58) and healthy controls (n = 52). Soluble (s)CD25, sCD14, sCD163 and myeloperoxidase (MPO) as markers for T-cell, monocyte/macrophage and neutrophil activation, respectively as well as CX3CL1, granzyme B and TIM-3 as markers of T-cell subsets and T-cell exhaustion, were analyzed. RESULTS: All patient groups had raised levels of activation markers compared with healthy controls. Levels of sCD25 and MPO increased gradually from patient with HIV only to patient with malaria only, with the highest levels in the HIV/malaria group. In the malaria group as a whole, MPO, sCD14 and in particular sCD25 were correlated with disease severity. sCD163, sCD25 and in particular MPO correlated with the degree of parasitemia as assessed by qPCR. Patients with falciparum malaria also had signs of T-cell subset activation (i.e. increased granzyme B and CX3CL1) and T-cell exhaustion as assessed by high levels of TIM-3 particularly in patients co-infected with HIV. CONCLUSION: Our data support a marked immune activation in falciparum malaria involving all major leukocyte subsets with particular enhanced activation of neutrophils and T-cells in patients co-infected with HIV. Our findings also support a link between immune activation and immune exhaustion during falciparum malaria, particularly in relation to T-cell responses in patients co-infected with HI

Plasma levels of interleukin 27 in falciparum malaria is increased independently of co-infection with HIV: potential immune-regulatory role during malaria

Background The immune response during falciparum malaria mediates both harmful and protective effects on the host; however the participating molecules have not been fully defined. Interleukin (IL)-27 is a pleiotropic cytokine exerting both inflammatory and anti-inflammatory effects, but data on IL-27 in malaria patients are scarce. Methods Clinical data and blood samples were collected from adults in Mozambique with P. falciparum infection, with (n = 70) and without (n = 61) HIV-1 co-infection, from HIV-infected patients with similar symptoms without malaria (n = 58) and from healthy controls (n = 52). In vitro studies were performed in endothelial cells and PBMC using hemozoin crystals. Samples were analyzed using enzyme immunoassays and quantitative PCR. Results (i) IL-27 was markedly up-regulated in malaria patients compared with controls and HIV-infected patients without malaria, showing no relation to HIV co-infection. (ii) IL-27 was correlated with P. falciparum parasitemia and von Willebrand factor as a marker of endothelial activation, but not with disease severity. (iii) In vitro, IL-27 modulated the hemozoin-mediated cytokine response in endothelial cells and PBMC with enhancing effects on IL-6 and attenuating effects on IL-8. Conclusion Our findings show that IL-27 is regulated during falciparum malaria, mediating both inflammatory and anti-inflammatory effects, potentially playing an immune-regulatory role during falciparum malaria