Increased indoleamine 2,3-dioxygenase (IDO) activity in idiopathic generalized epilepsy.

PURPOSE: Indoleamine 2,3-dioxygenase (IDO) is a cytokine-inducible enzyme that participates in tryptophan (trp) and serotonin metabolism with an ability to modulate neuroinflammation. Several recent studies have shown associations between cytokines and epilepsy. In this study we investigated whether activation of IDO is associated with epilepsy. METHODS: Kynurenine (kyn)/trp serum ratio, as an indicator of IDO activity was analyzed in 271 carefully classified epilepsy patients, and 309 healthy adults. RESULTS: IDO activity was increased in patients with unclassified idiopathic generalized epilepsy (IGE) (n=11; p=0.05), in juvenile myoclonic epilepsy (JME) (n=25; p=0.04) and in patients those with temporal lobe epilepsy but no hippocampal sclerosis (TLE-HS) (n=103; p=0.05) compared to the control subjects. In patients with idiopathic (but not cryptogenic or symptomatic) etiology of epilepsy, IDO activity was increased compared to the control subjects (p<0.05). Patients with extra-TLE or TLE+HS had IDO activity comparable to the control subjects. Patients who were one-month seizure-free prior to sampling had increased IDO activity compared to the control subjects (p=0.03). CONCLUSIONS: Increased IDO activity appeared to be associated with idiopathic generalized epilepsies such as unclassified IGE and JME, two of the most common types of primary generalized epilepsy. We also found a trend of increased IDO activity in patients with TLE-HS. Our results suggest that increased IDO activity may represent an adaptive metabolic phenomenon in epilepsy, which may also have a neuroprotective or anticonvulsive role by downregulating neuroinflammation in the brain.

Aging is associated with quantitative and qualitative changes in circulating cell-free DNA: the Vitality 90+ study.

As a marker of cellular death, cell-free DNA (cf-DNA) has a utility in diagnosis and prognosis of various disorders. Since aging accompanies increased cellular senescence and death, we aimed to characterize potential age-related alterations in cf-DNA. The study population consisted of 12 nonagenarian women (participants in the Vitality 90+ Study) and 11 healthy control women (aged 22-37 years). Some of the nonagenarians (n=8) were also recruited for follow-up after one year. cf-DNA was extracted using two different methods. Total cf-DNA was quantified directly in plasma and the amplifiable cf-DNA was assessed using quantitative PCR. Quality of cf-DNA was analysed with a DNA Chip assay. For all the quantification methods, the concentration of cf-DNA was significantly higher (p<0.05) in nonagenarians as compared to controls. The quality of the cf-DNA also displayed a marked difference between nonagenarians and controls; a fragmented pattern or appearance of low molecular weight cf-DNA was observed in the majority of the nonagenarians, whereas in controls, cf-DNA was intact and had a quasi-genomic, high molecular weight appearance. In nonagenarians, the quality of cf-DNA appeared similar in the original and follow-up samples. We propose that some, as yet uncharacterized, aspects of aging are reflected in the appearance of cf-DNA.

High activity of indoleamine 2,3 dioxygenase enzyme predicts disease severity and case fatality in bacteremic patients.

Indoleamine 2,3-dioxygenase (IDO), which is the rate-limiting enzyme for tryptophan (trp) catabolism, may play a critical role in various inflammatory disorders. Recent studies on trauma patients have suggested that the degradation of trp is associated with the development of sepsis. The role of IDO activity in bacteremic patients is unclear. We studied IDO activity in 132 patients with bacteremia caused by Staphylococcus aureus, Streptococcus pneumoniae, beta-hemolytic streptococcae, or Eschericia coli. The serum concentrations of trp and its metabolite kynurenine (kyn) were measured by reverse-phase high-performance liquid chromatography 1 to 4 days after the positive blood culture and on recovery. The kyn-to-trp ratio (kyn/trp), reflecting the activity of the IDO enzyme, was calculated. The maximum value in the ratio for every patient during 1 to 4 days after positive blood culture was used in analysis. The maximum kyn/trp ratio was significantly higher in nonsurvivors versus those who survived (193.7 vs. 82.4 micromol/mmol; P = 0.001). The AUC(ROC) of maximal kyn/trp in the prediction of case fatality was 0.75 (95% confidence interval, 0.64-0.87), and the kyn/trp ratio at a cutoff level of 120 micromol/mmol showed 83% sensitivity and 69% specificity for fatal disease. A kyn/trp ratio greater than 120 micromol/mmol was associated with increased risk of death versus low (

Helicobacter pylori-induced indoleamine 2,3-dioxygenase activity in vivo is regulated by TGFB1 and CTLA4 polymorphisms.

The chronic gastric infection caused by Helicobacter pylori is known to be associated with several, probably interrelated, immunomodulatory effects, such as protection from atopic diseases, induction of CD4+ CD25+ T regulatory (T(reg)) cells and increase in indoleamine-pyrrole 2,3-dioxygenase (IDO) -dependent suppressive mechanisms. As these mechanisms, as well as the strength of the infection, are very probably genetically controlled, we selected candidate genes (TGFB1, CTLA4) known to be involved in the activation of T(reg) cells. We examined the association of their polymorphisms (TGFB1 C-509T, CTLA4 A+49G) with blood IDO activity in H. pylori seropositive individuals. Genotypes were determined from 391 healthy adults. H. pylori infection was verified by detecting H. pylori IgG antibodies in sera. Concentrations of tryptophan (trp) and kynurenine (kyn), the main metabolite, were determined by reverse-phase high-performance liquid chromatography, and kyn/trp ratio was used as an indicator of IDO activity. The activity was higher in H. pylori seropositive individuals, but this increase was only detected in individuals with CTLA4+49 AA genotype or in carriers of TGFB1-509 allele T. This suggests that H. pylori induced IDO activity is regulated by TGFB1 and CTLA4, and that IDO is a mediator of the T cell suppressive effects of these genes.

Indoleamine 2,3-dioxygenase (IDO) activity is lower in atopic than in non-atopic individuals and is enhanced by environmental factors protecting from atopy.

Tryptophan catabolism activated by the indoleamine 2,3-dioxygenase (EC 1.13.11.42) (IDO) enzyme in antigen presenting cells has a central role in induction of mechanisms suppressing T cell activation or clonal expansion. There is evidence suggesting that IDO activity is mainly upregulated by typical Th1-differentiating signals such as interferon-gamma and bacterial lipopolysaccharide (LPS). Therefore, we hypothesized that IDO activity would be lower in a Th2-associated disease such as atopy and that it would be higher in the presence of environmental factors known to favor Th1 differentiation. Here we show that this was the case. Concentrations of tryptophan (trp) and kynurenine (kyn), the main metabolite, were determined by reverse phase liquid chromatography from serum samples of a cohort of 392 non-asthmatic individual of whom 149 were atopics (one or more positive skin test when tested with a panel of 22 allergens). Kyn/trp ratio, as an indicator of IDO activity, was significantly lower in atopic than in non-atopic individuals. The cohort was stratified according to two known atopy-protecting factors, presence of antibodies against Helicobacter pylori or anamnestic information about childhood on a farm environment. As expected, IDO activity was significantly higher in their presence than absence.