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Biomedical subjects

M G Netea

Publications and source records attributed to M G Netea.

At least 19 recordsLinked to original sources
PubMed2006

Critical aneurysmal dilatation of the thoracic aorta in young adolescents with variant hyperimmunoglobulin E syndrome.

The autosomal-dominant (AD) form of the hyperimmunoglobulin E syndrome (HIES) has been described as a multisystem disorder including immune, skeletal and dental abnormalities. Recently, the evaluation of patients from families in which HIES was inherited in a manner more consistent with autosomal-recessive (AR) inheritance, showed that AR-HIES is a clinically distinct disease entity. In addition to classical immunologic findings of AD-HIES, the AR form presents with severe recurrent fungal and viral infections with herpes zoster, herpes simplex and characteristic mollusca contagiosa. Furthermore, cerebral vascular sequelae, including vasculitis, infarction and haemorrhage were noted. In this report, we describe the clinical picture of two patients who showed remarkable resemblance to the description of AR-HIES, but also developed fatal aneurysmal dilatation of the thoracic aorta in adolescence. This finding may further consummate the clinical picture of AR-HIES and emphasize the possibility to develop early aortitis, most likely preceding the critical aneurysm formation at older age. This process should be anticipated during childhood in cases with AR-HIES.

Adolescent↗
PubMed2006

Role of the dual interaction of fungal pathogens with pattern recognition receptors in the activation and modulation of host defence.

Recognition of pathogen-associated molecular patterns (PAMPs) of microorganisms by pathogen recognition receptors induces signals responsible for the activation of genes important for an effective host defence, especially those of pro-inflammatory cytokines. Toll-like receptors (TLRs) and lectin-like receptors are the most important classes of pattern-recognition receptors. In addition to their effects on the activation of host defence, recent studies suggest that pathogenic fungi can modulate or interfere with the pattern recognition mechanisms of innate immunity, and can use pattern recognition receptors as mechanisms of escape from host defence. Two major recognition receptor-mediated escape mechanisms have been identified during infection with fungal pathogens: immunosuppression induced by activation of certain pattern recognition receptors, especially induction of IL-10 release through TLR2; and the blockade of TLR recognition by antigen modification during the germination of yeasts into hyphae. Thus, signals mediated by recognition receptors are not only beneficial to the host, but in certain situations can be used by pathogenic fungi to escape immune recognition and promote infection.

Animals↗
PubMed2006

Prevalence and clinical characteristics of insulin-treated, anti-GAD-positive, type 2 diabetic subjects in an outpatient clinical department of a Dutch teaching hospital.

BACKGROUND: In clinical practice, type 1 and type 2 diabetic patients are sometimes difficult to distinguish. Type 1 diabetes has an immune-mediated pathogenesis, resulting in a loss of insulin-secreting beta-cells. Type 2 diabetes mellitus is characterised by a relative insulin insufficiency, without the presence of an autoimmune aetiology, initially due to insulin resistance and later also accompanied by defective insulin release. Latent autoimmune diabetes of the adult (LADA) is a subgroup of diabetes, somewhere on the borderland between type 1 and type 2 diabetes. LADA is characterised by a late-age onset and relatively mild progression, but with unmistakable signs of autoimmunity, such as the presence of the autoimmune antibodies anti-GAD65, anti-insulin antibodies, or anti-Ia-2ab. OBJECTIVE: To establish the prevalence of anti-GAD ina diabetic outpatient clinic of a Dutch, non-university,teaching hospital and to describe these patients clinical and laboratory features, especially of the metabolic syndrome. METHODS: We evaluated GAD65 antibodies and other parameters in 244 selected diabetic patients, who had been on oral therapy for at least three months before becoming insulin-dependent. RESULTS: Twenty-six patients (11.6%) were positive for GAD65 antibodies. These patients had a significantly lower BMI (27.8 +/- 4.5 vs 31.1 +/- 4.9; p<0.01); less often cerebrovascular accidents (19.2 vs 34.9%; p<0.01) and a higher HDL cholesterol (1.73 +/- 0.53 vs 1.21 +/- 0.38; p<0.05). In contrast, anti-GAD patients had a significantly higher prevalence of hypothyroidism (23.0 vs 6.6%; p<0.05). CONCLUSION: Anti-GAD-positive patients represent a sizable proportion of type 2 diabetes in a second-line outpatient clinic, and they are characterised by lower parameters of the metabolic syndrome, but higher prevalence of other autoimmune phenomena such as hypothyroidism.

Autoantibodies↗
PubMed2006

Recognition of pathogenic microorganisms by Toll-like receptors.

Toll-like receptors (TLRs) have been identified as a major class of pattern-recognition receptors. Recognition of pathogen-associated molecular patterns (PAMPs) by TLRs, either alone or in heterodimerization with other TLR or non-TLR receptors, induces signals responsible for the activation of innate immune response. Recent studies have demonstrated a crucial involvement of TLRs in the recognition of all the major classes of microbial pathogens. By studying fungal infection in knock-out mice deficient in either TLRs or TLR-associated adaptor molecules, it appeared that specific TLRs play differential roles in the activation of the various arms of the innate immune response. Recent data also suggest that TLRs offer escape mechanisms to certain pathogenic microorganisms, especially through TLR2-driven induction of antiinflammatory cytokines. These new data have substantially increased our knowledge of the recognition of microbial pathogens, and this remains one of the most active areas of research in the field of infectious diseases.

Animals↗
PubMed2005

Beneficial response to anakinra and thalidomide in Schnitzler's syndrome.

BACKGROUND: Schnitzler's syndrome is an inflammatory disorder characterised by chronic urticarial rash and monoclonal gammopathy, accompanied by periodic fever, arthralgia or arthritis, and bone pain. The cause and treatment are still unknown. OBJECTIVE: To assess treatment with thalidomide and an interleukin 1 receptor antagonist, anakinra, in Schnitzler's syndrome. CASE REPORTS: Three patients with Schnitzler's syndrome are described, one with IgM gammopathy, two with IgG type. In one patient, thalidomide induced complete remission, but was stopped because of polyneuropathy. Anakinra 100 mg daily in all three patients led to disappearance of fever and skin lesions within 24 hours. After a follow up of 6-18 months, all patients are free of symptoms. CONCLUSION: Anakinra proved to be effective in three patients with Schnitzler's syndrome. This treatment is preferable to thalidomide, which induced a complete remission in one of our patients, as it has fewer side effects.

Antirheumatic Agents↗
PubMed2005

Markers of inflammation are negatively correlated with serum leptin in rheumatoid arthritis.

BACKGROUND: Leptin regulates food intake and modulates immunity and inflammation. A positive feedback mechanism has been described between tumour necrosis factor (TNF) and leptin, and it has been suggested that leptin potentiates inflammation in patients with rheumatoid arthritis (RA). OBJECTIVE: To assess whether inflammation correlates with leptin concentrations in patients with RA, and whether anti-TNF treatment modulates leptin concentrations in these patients. METHODS: Leptin, IL6 and CRP were measured (at baseline and after 2 weeks of treatment) in the blood of 31 patients with RA starting either anti-TNF treatment or placebo, and in 18 healthy controls. RESULTS: In patients with RA, plasma leptin concentrations at baseline correlated inversely with the degree of inflammation as assessed by C reactive protein (CRP; r(s)(2) = 0.21, p<0.01) or interleukin (IL) 6 concentrations (r(s)(2) = 0.22, p<0.008). Mean (SD) leptin concentrations did not differ between patients with RA and controls (6.0 (4.6) v 4.2 (2.8) ng/ml in men; 15.1 (7.9) v 13.4 (5.2) ng/ml in women). Short course anti-TNF treatment for 2 weeks did not modify leptin concentrations, despite significant reduction of CRP and IL6. CONCLUSION: A significant inverse correlation between inflammation and leptin concentrations was found in patients with active RA, although plasma leptin concentrations did not significantly differ from those in healthy controls. This suggests that active chronic inflammation may lower plasma leptin concentrations. Two weeks' treatment with anti-TNF did not change plasma leptin concentrations and longer treatment may be needed to see an effect on leptin.

Adalimumab↗
PubMed2005

Severely impaired IL-12/IL-18/IFNgamma axis in patients with hyper IgE syndrome.

BACKGROUND: Hyperimmunoglobulin E syndrome (HIES) is an inborn disorder characterized by recurrent skin and respiratory tract infections, skeletal abnormalities, chronic eczema and elevated serum IgE. The nature of the host defence defect has yet to be established. The aim of this study was to investigate whether activation of the interleukin-12/interleukin-18/interferon-gamma axis, known to be crucial for the activation of cellular immune responses, is impaired in patients with HIES. MATERIALS AND METHODS: Cytokine production capacity of seven HIES patients and seven healthy controls was investigated in whole-blood cultures stimulated with heat-killed Staphylococcus aureus, Candida albicans, or a combination of interleukin (IL)-12/IL-18. RESULTS: Interferon (IFN)gamma production, in addition to IFNgamma/IL-10 ratios, was 10-30-fold lower in the HIES patients compared with the healthy volunteers. In contrast TNF, IL-1beta and IL-8 production was normal. CONCLUSIONS: These data revealed a severe dysbalance towards a Th2 phenotype in HIES patients which is likely to contribute to the specific pattern of infection susceptibility characteristic to HIES.

Adult↗
PubMed2005

Cytokine responses to fungal pathogens in Kupffer Cells are Toll-like receptor 4 independent and mediated by tyrosine kinases.

Disseminated fungal infections are increasing. However, the interactions between the body's largest population of tissue macrophages, the Kupffer cells and the fungal pathogens are scarcely understood. The aim of this study was to examine the involvement of Toll-like receptor 4 (TLR4) signalling in cytokine production, using primary cultures of rat and murine Kupffer cells exposed to Aspergillus fumigatus and Candida albicans hyphae and conidia. All fungal components induced the release of tumour necrosis factor-alpha (TNF-alpha), but with delayed kinetics compared with lipopolysaccharide (LPS). Candida albicans was the most potent inducer of TNF-alpha protein and mRNA and the only inducer of interleukin-10 (IL-10) in rat Kupffer cells. All fungal components induced enhanced mRNA levels of macrophage inhibitory protein-2 (MIP-2) in the cells, similar to LPS. Inhibitors of Src tyrosine kinases added to cells prior to stimulation led to attenuation in the release of both TNF-alpha (60%, P < 0.05) and IL-10 (70%, P < 0.05) induced by C. albicans conidia but did not influence the LPS-mediated cytokine release. Murine Kupffer cells (C57BL/10J) also released TNF-alpha as well as the chemokines keratinocyte-derived chemokine (KC) and MIP-2 in response to fungal component. Surprisingly, Kupffer cells from TLR4-deficient C57BL/ScCr mice exhibited significantly enhanced production of KC and MIP-2 upon stimulation by fungal components compared with control littermates (P < 0.05). Our study demonstrates that Aspergillus and Candida components induce cytokine production in rat Kupffer cells and that the response to C. albicans conidia involves Src tyrosine kinases. The experiments with TLR4-deficient Kupffer cells suggest that the cytokine response in these cells to fungal component is not mediated by TLR4.

Animals↗
PubMed2005

Side effects of anticytokine strategies.

Anticytokine strategies probably represent the most important breakthrough in the treatment of inflammatory diseases in the last decade. However, blocking the bioactivity of proinflammatory cytokines, crucial activators of host defence, has proved to be accompanied by an increased susceptibility to infections, especially with Mycobacteria, Salmonellae and fungal pathogens. Multiple mechanisms for these side effects have been proposed, such as inhibition of gamma-interferon production, decreased expression of pattern-recognition receptors, and leucocyte apoptosis. Caution is therefore warranted when these treatments are given to patients with an increased risk for infections. A range of side effects other than infection have been reported.

Adalimumab↗
PubMed2005

NOD2 3020insC mutation and the pathogenesis of Crohn's disease: impaired IL-1beta production points to a loss-of-function phenotype.

BACKGROUND: Mutations of the NOD2 gene increase the susceptibility of humans to Crohn's disease. NOD2 is a cytoplasmic receptor for the bacterial product peptidoglycan. There is considerable controversy in the literature whether the most common mutation in Crohn's disease, the 3020insC NOD2, leads to a loss of function, i.e. decreased cytokine production, or to the reverse, i.e. a gain of function. In previous papers we proposed the former, since we could show decreased cytokine production with a net proinflammatory status after exposure to muramyl dipeptide (MDP). METHODS: Because of recent data in the literature showing increased interleukin-beta (IL-1beta) production in mice with the corresponding NOD2 mutation, we investigated the production of this cytokine by cells of patients with Crohn's disease, either homozygous or heterozygous for the 3020insC mutation, and compared it with that of patients with Crohn's disease bearing the wild-type allele. RESULTS: A strongly decreased production of IL-1beta by peripheral mononuclear cells was found upon exposure to either peptidoglycan or peptidoglycan-derived MDP in homozygous patients bearing the 3020insC NOD2mutation. CONCLUSION: This sustains the hypothesis that the 3020insC mutation in the human NOD2 gene leads to a loss-of-function phenotype.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2004

Recognition of fungal pathogens by Toll-like receptors.

Toll-like receptors (TLRs) have been identified as a major class of pattern-recognition receptors. Recognition of pathogen-associated molecular patterns by TLRs, either alone or in heterodimerization with other TLR or non-TLR receptors, induces signals responsible for the activation of the innate immune response. Recent studies have demonstrated a crucial involvement of TLRs in the recognition of fungal pathogens such as Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans. Through the study of fungal infection in knock-out mice deficient in either TLRs or TLR-associated adaptor molecules, it became apparent that specific TLRs such as TLR2 and TLR4 play differential roles in the activation of the various arms of the innate immune response. Recent data also suggest that TLRs offer escape mechanisms to certain pathogenic microorganisms, especially through TLR2-driven induction of anti-inflammatory cytokines. These new data have substantially increased our knowledge of the recognition of fungal pathogens, and the study of TLRs remains one of the most active areas of research in the field of fungal infections.

Animals↗
PubMed2004

Influence of anti-tumour necrosis factor therapy on cardiovascular risk factors in patients with active rheumatoid arthritis.

BACKGROUND: Tumour necrosis factor (TNF) is known to increase the concentrations of interleukin (IL) 6 and C reactive protein (CRP) and to induce proatherogenic changes in the lipid profile and may increase the cardiovascular risk of patients with rheumatoid arthritis (RA) and other inflammatory disorders. OBJECTIVE: To assess whether anti-TNF therapy modifies the cardiovascular risk profile in patients with RA. METHODS: The lipoprotein spectrum and the inflammation markers CRP and IL6 were investigated in 33 patients with RA treated with human anti-TNF monoclonal antibodies (D2E7, adalimumab, Humira) and 13 patients with RA given placebo, before and after 2 weeks' treatment. RESULTS: In the anti-TNF treated group, the mean (SD) concentrations of HDL-cholesterol were significantly higher after 2 weeks' treatment (0.86 (0.30) mmol/l v 0.98 (0.33) mmol/l, p<0.01), whereas LDL and triglyceride levels were not significantly changed. Additionally, a significant decrease in CRP (86.1 (54.4) mg/l v 35.4 (35.0) mg/l, p<0.0001), and IL6 (88.3 (60.5) pg/ml v 42.3 (40.7) pg/ml, p<0.001) concentrations was seen in this group. No changes in lipid profile, IL6, or CRP levels were seen in the placebo group. CONCLUSIONS: TNF neutralisation with monoclonal anti-TNF antibodies increased HDL-cholesterol levels and decreased CRP and IL6 levels after 2 weeks. Therefore this treatment may improve the cardiovascular risk profile of patients with RA.

Adalimumab↗
PubMed2004

Toll-like receptor-4 Asp299Gly polymorphism does not influence progression of atherosclerosis in patients with familial hypercholesterolaemia.

BACKGROUND: Toll-like receptor-4 (TLR4) is a major receptor for inflammatory stimuli potentially involved in the pathogenesis of atherosclerosis, such as lipopolysaccharide (LPS) and heat-shock proteins. The Asp299Gly polymorphism of the TLR4 gene has been associated with a reduced intima-media thickness (IMT) of the common carotid artery in healthy individuals. We have investigated whether the presence of the Asp299Gly polymorphism in patients with familial hypercholesterolaemia (FH) has a similar protective effect, and whether it influences the effects of HMG-CoA reductase treatment. MATERIALS AND METHODS: A cohort of 293 FH patients and 200 healthy volunteers were genotyped for the presence of the Asp299Gly allele using polymerase chain reaction followed by restriction fragment length polymorphism analysis. Intima-media thickness measurements, inflammatory parameters and the effect of HMG-CoA reductase inhibitors were compared between the patients with and without Asp299Gly allele. RESULTS: The Asp299Gly allele was present in 10.6% of the FH patients and 11.0% of the healthy individuals. Whereas the FH patients carrying the Asp299Gly allele displayed a reduced absolute IMT value compared with the FH patients carrying the wild-type allelle, the difference did not reach statistical significance. In addition, the effect of treatment with HMG-CoA reductase inhibitors was not influenced by the presence of Asp299Gly allele. CONCLUSION: The presence of the Asp299Gly allele of the TLR4 gene does not seem to exert a major influence on the progression of atherosclerosis in patients with FH.

Adult↗
PubMed2004

Hypothesis: Normalisation of cytokine dysbalance explains the favourable effects of strict glucose regulation in the critically ill.

Recent trials investigating the effects of strict glucose regulation in critically ill patients have shown impressive reductions in morbidity and mortality. Although the literature focuses on the possible toxic effects of high blood glucose levels, the underlying mechanism for this improvement is unclear. We hypothesise that strict glucose regulation results in modulation of cytokine production, leading to a shift towards a more anti-inflammatory pattern. This shift in the cytokine balance accounts for the reduction in morbidity and mortality. To support our hypothesis, effects of glucose and insulin on cytokine release and effects of glucose, insulin, and cytokines on host defence, cardiac function and coagulation will be reviewed.

Blood Coagulation↗
PubMed2003

Hypoglycaemia downregulates endotoxin-induced production of tumour necrosis factor-alpha, but does not affect IL-1beta, IL-6, or IL-10.

The aim of the present study was to investigate the effect of hypoglycaemia on the production capacity of the proinflammatory cytokines tumour necrosis factor-alpha (TNFalpha) and interleukin-1beta (IL-1beta) in subjects with and without diabetes. Hyperinsulinaemic (360 pmolm(-2) x min(-1)) stepped hypoglycaemic (5.0-3.5-2.5 mmoll(-1)) glucose clamps were performed in eight diabetic patients and in six non-diabetic subjects, and hyperinsulinaemic normoglycaemia (5.0 mmoll(-1)) control experiments were performed in four non-diabetic subjects. Circulating levels of cytokines and endotoxin-induced production of TNFalpha, IL-1beta, IL-6, and IL-10 were assessed. The effects of insulin and adrenaline were measured in separate in vitro experiments. In non-diabetic subjects, hypoglycaemia downregulated the production capacity of TNFalpha in a concentration-dependent fashion (P=0.007), but not of IL-1beta, IL-6, or IL-10. Compared to controls, the production capacity of TNFalpha in diabetic patients was already suppressed at normoglycaemia (P=0.02) and only fell in response to hypoglycaemic nadir (P=0.04). The downregulation of TNFalpha could not be explained by increased insulin or adrenaline levels. We conclude that hypoglycaemia specifically downregulates TNFalpha production capacity. Diabetic patients already have a suppressed TNFalpha production capacity at non-hypoglycaemic levels.

Adult↗
PubMed2003

Successful treatment of dermatomyositis and polymyositis with anti-tumor-necrosis-factor-alpha: preliminary observations.

Tumor necrosis factor alpha neutralization seems a rational therapy for myositis because this proinflammatory cytokine has been implicated in the pathogenesis of this disorder. Until now, we have treated 2 patients with a chimeric anti-TNF-alpha monoclonal antibody (infliximab). Both patients demonstrated a marked and sustained subjective and objective improvement without the occurrence of any side effects. These preliminary results suggest that anti-TNF-alpha treatment with infliximab is a safe and rapidly effective therapy for myositis.

Adult↗