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PubMed1996

Are serum neopterin concentrations superior to other parameters in the differential diagnosis and prognostic assessment of Graves' disease?

There is a lack (1.) of a single criterion for the definitive differentiation between immunogenic (IH) and non-immunogenic hyperthyroidism (NIH), and (2.) also a lack of an unequivocal prognostic predictor for the individual course of patients with immunogenic hyperthyroidism. In 152 patients scheduled for iodine-131 therapy, serum neopterin concentrations were measured using a commercially available RIA, and the neopterin concentrations of IH (n = 84) and NIH (n = 42) patients were compared. Of these patients, 83 and 26 per cent respectively were treated with antithyroid drugs which did not have a significant impact on neopterin levels. In patients with IH and NIH, the concentrations [mean +/- SD] of neopterin were 1.89 +/- 0.79 milligrams and 1.98 +/- 0.9 milligrams, respectively (p = 0.4). After therapy with iodine-131, 28% of the IH-patients were euthyroid, 32% hyperthyroid, and 40% hypothyroid. In finally euthyroid patients, pretherapeutic neopterin concentrations were higher (3.1 +/- 2.8 milligrams) than in finally hyperthyroid (1.8 +/- 0.7 milligrams), or hypothyroid (1.6 +/- 0.7 milligrams) patients. These results argue against a relevant clinical role of neopterin concentrations for the differential diagnosis of IH versus NIH in these patients. However, a prognostic significance of neopterin concentrations in patients with IH is suggested.

Adult↗
PubMedDate not supplied

[Intrathecal production of neopterin in meningitis in childhood].

A major activator of antigen presenting cells (APC) is gamma interferon a product of activated T-lymphocytes. CNS is not well studied and represents a unique system with respect to the immune reactions. Neopterin is an indirect marker of gamma interferon deliberation and may give some new information on the role of APC in CNS. Neopterin in serum and cerebrospinal fluid (CSF) was determined by specific RIA in children who were lumbar punctured to exclude meningitis. Neopterin was found in various concentrations in serum and CSF of all patients (n = 47). Bacterial meningitis (group 3) was diagnosed in 12 and aseptic meningitis in 18 children (group 2). CSF was drawn in 17 children with febrile convulsions (group 1). Elevated serum neopterin in childhood was only reported in children with an atypical PKU, while data on CSF neopterin were published only in a few cases of adults with CNS involvement. The results show that the APC is stimulated rapidly in childhood similar as in adults following severe viral or bacterial infections. Furthermore neopterin in CSF is not only explained by alteration of the blood-brain barrier but also it may reflect local intrathecal response with activation of accessory cells (APC) in the CNS itself. Between the stimulation of the cellular immune system indicated by increased levels of neopterin and the severity of the disease seems to be a positive correlation.

Antigen-Presenting Cells↗
PubMed2003

Serum and salivary neopterin and interferon-gamma in primary Sjögren's syndrome. Correlation with clinical, laboratory and histopathologic features.

OBJECTIVE: To investigate serum and salivary neopterin and interferon-gamma as possible markers of immune system activation in primary Sjögren's Syndrome (pSS). METHODS: Serum and salivary neopterin and interferon-gamma concentrations were determined in 30 untreated patients with pSS and matched with several other clinical and laboratory parameters. RESULTS: The mean concentration of neopterin was significantly higher in pSS patients (8.12+/- 3.36 nmol/L in serum and 9.50 +/-7.61 nmol/L in saliva) than in normal controls (p<0.05). Significant correlations were found between serum neopterin and beta2-microglobulin, serum IgG as well as lip biopsy score. Salivary neopterin concentration was inversely related to Shirmer-I test, tear break-up time and stimulated salivary flow rate. Serum and salivary levels of interferon-gamma were normal and no correlation with the other parameters was found. CONCLUSION: In pSS patients serum neopterin may represent a useful marker of cell-mediated immunity. On the other hand, salivary neopterin seems to reflect theglandular damage.

Biomarkers↗
PubMed2006

Serum neopterin levels in children with primary nephrotic syndrome.

AIM: To assess the changes that occurs in serum neopterin levels in children with primary nephrotic syndrome. METHODS: Serum neopterin levels were measured by ELISA in 38 children with active primary nephrotic syndrome (group I) and 17 children with primary nephrotic syndrome in remission (group II) and 20 healthy controls. All patients had normal creatinine clearance. Among group I, 28 patients were steroid-sensitive while 10 patients were steroid-resistant. RESULTS: Serum neopterin levels were significantly elevated in group I patients (median = 30, 7.2-43.2 nmol/l) compared with group II (median = 6, 2-10 nmol/l, P<0.001) and controls (median = 3.2, range: 0.4-1.8 nmol/l, P<0.001). Group II patients had similar neopterin levels compared with controls (P=0.71). There was a significant positive correlation between serum neopterin levels and the degree of proteinuria in group I patients (r = 0.4, P=0.01). No significant differences in serum neopterin levels were noted between steroid-sensitive and steroid-resistant patients (P=0.4). CONCLUSION: Serum neopterin could be used as a marker of the activity of primary nephrotic syndrome but it could not be used to differentiate between steroid-sensitive and steroid-resistant patients.

Acute Disease↗
PubMed1991

Serum neopterin--possible immunological marker of myocardial inflammation in patients with dilated heart muscle disease.

Measurement of neopterin in biological fluids is a sensitive and specific tool for detecting activation of the T cell/macrophage system. Serum neopterin level, detected by radioimmunoassay, and data from morphological investigations of myocardium were compared in 29 patients with a clinical diagnosis of dilated heart muscle disease. According to the results of endomyocardial biopsy (22 cases) and autopsy (seven cases), 14 patients had morphological features of myocarditis, 13 dilated cardiomyopathy and two a fibrotic subtype of dilated cardiomyopathy (DCMP). The mean neopterin level in all patients (12 +/- 9 nM l-1) was higher than in the control group (5 +/- 2 nM l-1) (P less than 0.05). Also, the mean neopterin level was significantly higher in patients with myocarditis and fibrotic subtype of DCMP (16 +/- 11 nM l-1) than in patients with a morphological diagnosis of DCMP (9 +/- 6 nM l-1) (P less than 0.05). The highest neopterin levels in both groups were found in those who subsequently died during follow-up (mean level 23 +/- 10 nM l-1). There was a correlation between neopterin and beta 2-microglobulin (r = 0.83, P less than 0.05). Our study suggests that the raised serum neopterin level may be a marker of myocardial inflammation and unfavourable prognosis in patients with a clinical diagnosis of dilated heart muscle disease.

Adult↗
PubMed1997

Elevated serum levels of neopterin in adult patients with polymyositis/dermatomyositis.

We determined serum concentrations of neopterin, soluble tumour necrosis factor (55 kDa) receptor (sTNF-R) and soluble interleukin-2 receptor (sIL-2R) in plasma of 44 patients with polymyositis (PM)/dermatomyositis (DM), including 15 patients with primary PM, 13 patients with primary DM, and 16 patients with myositis and systemic sclerosis in overlap. Concentrations of neopterin, sTNF-R and sIL-2R were measured using commercially available immunoassays. Serum neopterin was increased in 35 of 44 PM/DM patients (80%), sTNF-R in 14 (32%) and sIL-2R in 18 (41%) patients, respectively. There were significant correlations between serum neopterin and sTNF-R, sIL-2R and erythrocyte sedimentation rate (all P < 0.001). Neopterin, as well as sTNF-R and sIL-2R, did not correlate with clinical (neuromuscular and activities of daily living scores) and laboratory (creatine kinase levels) manifestations of myositis. Increased serum levels of neopterin were associated with non-muscular manifestations of PM/DM. In conclusion, serum neopterin appears to be a useful laboratory marker for ongoing immune activation and global disease activity in PM/DM.

Adolescent↗
PubMed1994

Increased systemic, but not regional, neopterin production following intraperitoneal administration of interleukin-2 and lack of effect of pterins upon the lymphokine-activated killer cell phenomenon.

Circulating neopterin is derived from monocytes and/or macrophages that produce it upon stimulation by interferon-gamma released from activated T cells. Neopterin production has been proposed as a marker of biological response in the clinical administration of a number of cytokines. Changes in neopterin production as indicated by urinary neopterin excretion were studied in four patients with ovarian carcinoma receiving intraperitoneal interleukin-2 and lymphokine-activated killer cells. Neopterin production increased approximately threefold during treatment with interleukin-2 at doses which represent or exceed the maximum tolerated dose by this route of administration. Increased neopterin apparently was derived from systemic, not regional, tissues. The physiologic role(s) of pterins in immune responses is uncertain. In an in vitro system, the presence of neopterin or tetrahydrobiopterin or the pterin synthesis inhibitor, N-acetyl serotonin, did not modulate cytotoxic effects of lymphokine-activated killer cells.

Biopterins↗
PubMed1991

Neopterin as a marker of C hepatitis in thalassaemia major.

The authors studied serum neopterin in 106 patients with beta thalassaemia major. A good correlation was found between neopterin values and glutamic pyruvic transaminase (GPT) mean values of the last 6 months, whereas no correlation was found between neopterin values and some siderosis indexes (iron/body weight, total accumulated iron). A statistically significant correlation was found between neopterin values (greater than 10 nM/L vs. less than 10 nM/L) and histological liver findings (chronic hepatitis vs. siderosis). Neopterin values were also statistically different between splenectomized and not splenectomized patients. Moreover serum neopterin was higher in HCV-Ab positive than in HCV-Ab negative patients, and 91.6% of the HCV-Ab positive group also showed histological signs of chronic hepatitis. These data suggest that increased serum neopterin might help to identify chronic C hepatitis in thalassaemic patients.

Adolescent↗
PubMed1992

Neopterin concentrations in pediatric human immunodeficiency virus infection as predictor of disease activity.

Neopterin concentrations in 50 children with human immunodeficiency virus infection were correlated with disease course. The neopterin concentrations ranged from 4 to 70 nM with a mean of 34.7 +/- 25.1 (SD) nM compared with a mean of 6.1 +/- 1.6 nM in the human immunodeficiency virus-negative control group. Elevated neopterin concentrations above the upper range of the control group were detected as early as 5 months of age. Nineteen of 20 patients (95%) with neopterin concentrations above 20 nM either died or have severe clinical disease. Increasing neopterin concentrations were also associated with poor prognosis even though the first value was below 20 nM. Conversely neopterin concentrations less than 20 nM or declining concentrations were associated with a stable clinical course, except in terminal illness. With stepwise logistic regression analysis neopterin concentrations were predictive for disease progression. This predictive value was further improved by the addition of CD4 cell counts.

Biopterins↗
PubMed1983

Neopterin as a new biochemical marker for diagnosis of allograft rejection. Experience based upon evaluation of 100 consecutive cases.

The use of daily urinary neopterin evaluation to detect immunological complications has been tested in 96 consecutive cadaveric kidney recipients, three liver recipients, and one pancreas recipient. In 29 of these patients an immunologically uncomplicated posttransplant course was associated with stable or low neopterin levels, or both. In only 5% of daily determinations on these patients were increasing or high neopterin levels seen. On the other hand, major immunological complications, such as acute rejection episodes (38 cases), viral infections (17 cases), or both problems (8 cases), were preceded by increasing or high neopterin levels or both--on the average by one day. Withdrawal of cyclosporine was also found to be followed by increase of urinary neopterin levels. Neopterin evaluation enabled reliable and accurate prediction of immunological complications in 95% of patients with acute rejections and in 100% of patients with viral infections. It thus appears that daily assessment of urinary neopterin levels represents a useful tool for biochemical detection of immunological complications in allograft recipients.

Biopterins↗
PubMed1986

Relationship of interferon-gamma and neopterin levels during stimulation with alloantigens in vivo and in vitro.

We have recently shown that interferon-gamma is capable of activating the key enzyme of pterin biosynthesis in macrophages. This leads to excretion of the stable degradation product neopterin. In this article we present experimental evidence suggesting that stimulation of T cells by alloantigens is associated with release of interferon-gamma--which, in the case of rejection, is locally restricted and not always detectable in the bloodstream. Neopterin induced by this lymphokine, however, readily penetrates tissue barriers and is detectable in the serum. This conclusion is based on two different sets of observations: (1) If supernatants of MLCs are compared with sera from patients with documented acute rejection episodes for their interferon-gamma and neopterin levels, a marked gradient is observed to exist between interferon levels measured in vitro and in vivo; this is not the case for neopterin for which comparable levels were seen. (2) Detection of interferon-gamma in sera of allograft recipients invariably precedes an increase of neopterin; on the other hand, increasing neopterin counts are also seen in the absence of detectable interferon-gamma levels in the serum. It thus appears that although interferon-gamma release during allograft rejection is primarily restricted to the tissue, evaluation of certain metabolites of interferon-dependent metabolic pathways enables definition of its endogenous release. Whereas interferon gamma represents a less reliable marker in the monitoring of rejection episodes, it might offer an additional means to differentiate rejection from systemic infections. Such a discrimination can not be achieved with the neopterin marker.

Acute Disease↗
PubMed1992

Increased urine neopterin levels in psoriasis.

The production of neopterin closely reflects activation of T-lymphocyte-mediated immunity. Oxidized and reduced forms of urine neopterin were measured by reversed-phase ion-pair high-performance liquid chromatography in patients with moderate to severe chronic plaque psoriasis (n = 40), and in a heterogeneous group of patients (n = 14) with cutaneous T-cell malignancies (CTCM). Results were compared with healthy non-psoriatic control subjects (n = 30). Neopterin levels were repeated after a course of ultraviolet B therapy (UVB) plus topical tar or dithranol, or photochemotherapy (PUVA), in 12 psoriatic patients. Fully oxidized urine neopterin levels and neopterin/creatinine ratios were significantly elevated in the psoriatic group compared with controls (P < 0.002, P < 0.05) but not in the CTCM group. Both neopterin and its creatinine ratio were significantly reduced by treatment (P < 0.05, P < 0.01). Psoriasis area and severity index scores (PASI) correlated strongly with urine neopterin levels (P < 0.001). These findings indicate that urine neopterin concentrations may be a marker of psoriatic disease activity, and further support the importance of activated T lymphocytes in the pathogenesis of psoriasis.

Adolescent↗
PubMed1990

Macrophage activation in falciparum malaria as measured by neopterin and interferon-gamma.

Macrophage activation during acute falciparum malaria in 71 Thai adults was investigated by measuring urinary neopterin and serum interferon-gamma (IFN-gamma). Neopterin, a product of IFN-gamma-activated macrophages, was elevated in 94% of patients upon admission (day 0, prior to treatment) and in all at some time during the period of study. Neopterin levels tended to rise further (days 1-5) before falling back towards the normal range as patients recovered following effective chemotherapy (days 6-8). IFN-gamma was measured in 32 patients and found to be directly related to neopterin concentration. Both neopterin and IFN-gamma values were highest in patients experiencing a first malaria infection. Among those with histories of prior malaria, neopterin and IFN-gamma levels were inversely related to the number of previous infections. Morbidity, as assessed by degree and duration of fever, was directly related to neopterin concentration. This longitudinal study quantitatively describes the extent and duration of macrophage activation in falciparum malaria. The data also suggest that with repeated malaria infection and antigen exposure, there is a progressive decrease or possibly suppression of the T cell-macrophage interaction mediated by IFN-gamma.

Adult↗
PubMed2006

Neopterin induces pro-atherothrombotic phenotype in human coronary endothelial cells.

BACKGROUND: Inflammation plays a pivotal role in atherothrombosis. Recent data indicate that serum levels of neopterin, a marker of inflammation and immune modulator secreted by monocytes/macrophages, are elevated in patients with acute coronary syndromes and seem to be a prognostic marker for major cardiovascular events. The aim of the present study was to determine whether neopterin might affect the thrombotic and atherosclerotic characteristics of human coronary artery endothelial cells (HCAECs). METHODS AND RESULTS: In HCAECs, neopterin induced TF-mRNA transcription as demonstrated by real time polymerase chain reaction and expression of functionally active tissue factor (TF) as demonstrated by procoagulant activity assay, and of cellular adhesion molecules (CAMs) as demonstrated by FACS analysis, in a dose-dependent fashion. These neopterin effects were prevented by lovastatin, a HMG-CoA reductase inhibitor. Neopterin-induced TF and CAMs expression was mediated by oxygen free radicals through the activation of the transcription factor, nuclear factor-kappa B (NF-kappaB), as demonstrated by electrophoretic mobility shift assay and by suppression of CAMs and TF expression by superoxide dismutase and by NF-kappaB inhibitor, pyrrolidine-dithio-carbamate ammonium. CONCLUSIONS: These data indicate that neopterin exerts direct effects on HCAECs by promoting CAMs and TF expression and support the hypothesis that neopterin, besides representing a marker of inflammation, might be an effector molecule able to induce a pro-atherothrombotic phenotype in cells of the coronary circulation.

Cell Adhesion↗
PubMed1994

Urine neopterin: a new parameter for serial monitoring of disease activity in patients with systemic lupus erythematosus.

OBJECTIVE: To investigate the role of serial measurement of urine neopterin concentration in monitoring the progression of systemic lupus erythematosus (SLE) disease activity scored using the British Isles Lupus Assessment Group (BILAG) index. METHODS: We followed prospectively 68 unselected SLE patients for a total of 464 patient months during which 233 separate assessments were carried out. At each assessment, urine neopterin, determined by high performance liquid chromatography, together with erythrocyte sedimentation rate (ESR) and plasma C3, C4, and C3d were measured and the SLE disease activity scored by a single observer. Serial data sets were analysed using time series modelling techniques. RESULTS: Single time point analysis showed a significant increase in urine neopterin concentrations in 14 patients who suffered flares of their disease during the study period (p = 0.02). Thirty patients with active disease went into disease remission with significant decreases in their urine neopterin values (p = 0.02). In the time series analysis, a statistically significant association was found between serial concentrations of urine neopterin and BILAG score (r = 0.6, p < 0.05); no other study parameter (ESR and serum C3, C4, and C3d) mirrored SLE disease activity as effectively. CONCLUSIONS: This study provides initial evidence that changes in urine concentrations of neopterin are significantly correlated with fluctuations in disease activity over time, scored using the BILAG index, amongst individual patients with SLE. Consequently, serial urine neopterin measurements appear to be clinically useful for monitoring disease activity and may contribute substantially to therapeutic decision making in these patients.

Adult↗
PubMed2005

Urinary neopterin levels in the different stages of pregnancy.

BACKGROUND/AIMS: Neopterin is a biochemical marker of activated cell-mediated immune response which increases in pathological conditions associated with cellular immune activation as well as in pregnancy where cellular immune response is predominant. The aim of this study was to determine the urinary neopterin level in each trimester of pregnancy and to determine if it can be used as a marker. METHODS: 104 healthy pregnant women (mean age 22.10 +/- 4.39 years; 36 in the first, 30 in the second and 38 in the third trimester) and 16 non-pregnant healthy women (mean age 20.94 +/- 4.48 year) were included. RESULTS: The mean urinary neopterin concentration of all pregnant women was higher than that of non-pregnant women (166.4 +/- 31.7 and 103.1 +/- 27.5 micromol/mol creatinine respectively, p < 0.01). The mean urinary neopterin levels in each trimester and non-pregnant women were 139.8 +/- 49.6, 131 +/- 40.2, 227.9 +/- 86.5 and 103.1 +/- 27.5 micromol/mol creatinine, respectively. Urinary neopterin levels were not significantly different between non-pregnant, first and second trimester groups, but were significantly higher in the third trimester than each of these groups (p < 0.05, p < 0.01 and p < 0.01 respectively). CONCLUSION: Urinary neopterin levels increase significantly in the third trimester probably due to more predominated cellular immunity. The pathologies causing cellular immune activation, especially in the first two trimesters can be predicted with urinary neopterin levels.

Adult↗
PubMed1992

Effects of interferons beta or gamma on neopterin biosynthesis and tryptophan degradation by human alveolar macrophages in vitro: synergy with lipopolysaccharide.

Interferons can induce neopterin biosynthesis and tryptophan degradation in monocytic cells. Indoleamine 2,3-dioxygenase (IDO), an inducible cellular enzyme, metabolizes tryptophan to N-formyl-L-kynurenine. Tryptophan degradation has been linked to interferon-mediated inhibition of replication by intracellular pathogens and inhibition of cancer cell proliferation. We evaluated the ability of the recombinant human interferons beta ser and gamma to stimulate neopterin production and tryptophan degradation in vitro by alveolar macrophages (AM) obtained from normal volunteers by bronchoalveolar lavage. Additionally, because other biologic response modifiers such as lipopolysaccharide (LPS) can also stimulate monocytic cells to produce increased amounts of neopterin and degrade tryptophan, we evaluated the effects of LPS on interferon-induced neopterin production and tryptophan degradation by AM. Both interferon-gamma (IFN-gamma) and interferon-beta (IFN-beta) induced neopterin production and tryptophan degradation by AM with corresponding inhibition of intracellular replication by Chlamydia psittaci in AM, but IFN-gamma was a more potent inducer of these responses than IFN-beta. LPS enhanced neopterin production and tryptophan degradation by interferon-exposed cells. This effect was particularly evident at lower concentrations of interferon, and LPS synergy was more pronounced with IFN-beta than IFN-gamma. Concentrations of LPS that alone had no stimulatory effect on tryptophan degradation synergistically enhanced the induction of IDO activity by lower concentrations of interferon. These studies suggest that IFN-gamma stimulates human AM to produce neopterin and degrade tryptophan more potently than IFN-beta, and that low concentrations of LPS can synergistically enhance such effects of interferons on tissue macrophage metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2004

Evidence of cellular immune activation in children with opsoclonus-myoclonus: cerebrospinal fluid neopterin.

To evaluate cellular immune activation in opsoclonus-myoclonus syndrome, we measured the inflammatory marker neopterin in the cerebrospinal fluid of 16 children with opsoclonus-myoclonus and neuroblastoma, 24 children with opsoclonus-myoclonus but no tumor, and 19 age-matched controls. The mean concentration in opsoclonus-myoclonus was 2.3-fold higher than in controls (P = .008). Neopterin was greatly elevated in four of the most neurologically severe cases, up to 8.3-fold above the highest control level. Thirteen of the 40 children with opsoclonus-myoclonus but no controls had a neopterin concentration >2 SD above the control mean (P = .005). In this high neopterin subgroup, neurologic severity was significantly greater and the duration of neurologic symptoms was less. In 16 children re-examined on immunotherapy, including adrenocorticotropic hormone (ACTH) combination therapy, treatment was associated with a significant reduction in both neopterin and neurologic severity. Neopterin did not differ significantly between the tumor and non-tumor opsoclonus-myoclonus etiologies. No abnormalities of tetrahydrobiopterin were found. Although cerebrospinal fluid neopterin lacked the sensitivity to be a biomarker of disease activity in opsoclonus-myoclonus, elevated concentrations do support a role for T-cell activation and cell-mediated immunity in its pathophysiology.

Adolescent↗