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The authors explore the therapeutic and prophylactic efficacies of Immunopterin (calcium pterin-6-carboxylate chelate) against coronavirus colds and as a therapy against COVID-19.

The naturally occurring stilbenoid oxyresveratrol was shown to influence inflammatory and metabolic processes. During cellular immune activation, tryptophan breakdown and neopterin formation via the enzymes indoleamine 2,3-dioxygenase-1 (IDO-1) and GTP-cyclohydrolase, respectively, are induced. Neopterin and the kynurenine to tryptophan ratio are reliable and pertinent biomarkers of Th1-type immune response and are also used in vitro to monitor effects of active plant ingredients on peripheral blood mononuclear cells (PBMCs). We investigated the effects of oxyresveratrol on the activity of the above-mentioned pathways in mitogen-stimulated human PBMC and in the myelomonocytic cell line THP-1. Oxyresveratrol exerted suppressive effects on tryptophan breakdown in both stimulated cell models. Of note, in PBMC, tryptophan breakdown was induced at lower concentrations (5–20 µM) and suppressed at higher treatment concentrations only. Neopterin formation was decreased dose-dependently in stimulated PBMC. In unstimulated PBMC similar, albeit lesser effects were observed. Data indicate that oxyresveratrol exerts distinct and concentration-dependent effects on different immune cell types. IDO-1 is targeted by oxyresveratrol and its activity can be modulated in both directions. Detailed investigations of the interactions would be interesting to fully explore the activity of this phytocompound.

The new coronavirus SARS-CoV-2 was identified to be responsible for the COVID-19 pandemic. There are striking differences in the response to infection, some people develop no or mild symptoms, while other outcomes are severe of even fatal. For those COVID-19 patients who require hospitalization, prognostic markers could help clinicians to identify patients with a poor outcome early. The serum levels of the immune activation marker neopterin have already been shown to be of prognostic value in patients with SARS-CoV-1 and a similar pattern can be observed for SARS-CoV-2. This comment discusses the biochemical circuits that support the clinical value of neopterin measurements in COVID-19 patients.

Background: Soluble P-selectin (sP-selectin) is associated with risk factors for cardiovascular disease (CVD) but this association has not been evaluated in patients with schizophrenia. This study primarily evaluated the association of sP-selectin with plasma lipids and nitrite (NO2-) respectively in overweight/obese adults with schizophrenia.

Immune activation coincides with disturbances in iron and vitamin D metabolism in patients with cardiomyopathy. In this study, we investigated whether there are differences regarding immune activation, iron and vitamin D metabolism between the different cardiomyopathy aetiologies.

Background: Evidence links Toxoplasma gondii (T. gondii), a neurotropic parasite, with schizophrenia, mood disorders and suicidal behavior, all of which are associated and exacerbated by disrupted sleep. Moreover, low-grade immune activation and dopaminergic overstimulation, which are consequences of T. gondii infection, could alter sleep patterns and duration. Methods: Sleep data on 833 Amish participants [mean age (SD) = 44.28 (16.99) years; 59.06% women] were obtained via self-reported questionnaires that assessed sleep problems, duration and timing. T. gondii IgG was measured with ELISA. Data were analyzed using multivariable logistic regressions and linear mixed models, with adjustment for age, sex and family structure. Results: T. gondii seropositives reported less sleep problems (p < 0.005) and less daytime problems due to poor sleep (p < 0.005). Higher T. gondii titers were associated with longer sleep duration (p < 0.05), earlier bedtime (p < 0.005) and earlier mid-sleep time (p < 0.05). Conclusions: It seems unlikely that sleep mediates the previously reported associations between T. gondii and mental illness. Future longitudinal studies with objective measures are necessary to replicate our findings.

Background: Interferon-γ (IFN- γ) regulates the degradation of tryptophan to kynurenine via induction of indoleamine- 2,3-dioxygenase (IDO). Local tryptophan depletion and accumulation of toxic metabolites might impair the proliferative capacity of lymphocytes. The aim of this study was to assess the actual status of immune system activation of patients with bacterial infection in the acute phase and during convalescence in vivo and in vitro. Parameters of systemic immune system activation were evaluated for associations with proliferative responsiveness of immune cells, and compared with healthy controls. Methods: 24 patients with various acute bacterial infections were included in the group of acutely ill patients. Sixteen patients participated in a follow-up examination after convalescence. The control group consisted of 6 healthy people. To assess the status of immune system activation in vivo, inflammation parameters C-reactive protein and differential blood counts were determined. Neopterin concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Tryptophan and kynurenine measurements were performed with high pressure liquid chromatography (HPLC). Peripheral blood mononuclear cells (PBMCs) were isolated from the patients’ blood and stimulated with concanavalin A (Con A), phytohemagglutinin (PHA) and pokeweed mitogen (PWM) in vitro proliferation rates were evaluated by ³H-thymidine incorporation and neopterin production and tryptophan degradation were determined in supernatants of mitogen stimulated PBMCs. Results: Patients with acute bacterial infections showed reduced tryptophan and elevated neopterin concentrations, which did not normalize after convalescence period. Higher plasma neopterin values and increased IDO-activity were associated with reduced proliferative responses in vitro after stimulation with PHA. Associations were observed during acute infection as well as convalescence. Conclusions: Results of this study show that increased immune system activation in vivo is associated with impaired proliferative responsiveness of immune cells in vitro in acute bacterial infections as well as during convalescence.

Seasonal changes in non-human animals and seasonal affective disorder (SAD) in humans are associated with immune activation in winter relative to summer. We intended to measure seasonal variation in neopterin, a marker of cellular immunity, and its interactions with gender and seasonality of mood. We studied 320 Amish from Lancaster, PA, USA (men=128; 40%) with an average age [Standard deviation (SD)] of 56.7 (13.9) years. Blood neopterin level was measured with enzyme-linked immunosorbent assay (ELISA). Seasonality was measured with Seasonal Pattern Assessment Questionnaire (SPAQ). Statistical analysis included analysis of covariance (ANCOVAs) and multivariate linear regression. We also investigated interactions of seasonal differences in neopterin with gender, seasonality scores and estimation of SAD diagnosis. We found a significantly higher neopterin level in winter than in summer (p=0.006). There were no significant gender or seasonality interactions. Our study confirmed the hypothesized higher neopterin level in winter. A cross sectional design was our major limitation. If this finding will be replicated by longitudinal studies in multiple groups, neopterin could be used to monitor immune status across seasons in demographically diverse samples, even if heterogeneous in gender distribution, and degree of seasonality of mood.

Toxoplasma gondii (T. gondii) infects central nervous tissue and is kept in relative dormancy by a healthy immune system. Sleep disturbances have been found to precipitate mental illness, suicidal behavior and car accidents, which have been previously linked to T. gondii as well. We speculated that if sleep disruption, particularly insomnia, would mediate, at least partly, the link between T. gondii infection and related behavioral dysregulation, then we would be able to identify significant associations between sleep disruption and T. gondii. The mechanisms for such an association may involve dopamine (DA) production by T. gondii, or collateral effects of immune activation necessary to keep T. gondii in check. Sleep questionnaires from 2031 Old Order Amish were analyzed in relationship to T. gondii-IgG antibodies measured by enzyme-linked immunosorbent assay (ELISA). Toxoplasma gondii seropositivity and serointensity were not associated with any of the sleep latency variables or Epworth Sleepiness Scale (ESS). A secondary analysis identified, after adjustment for age group, a statistical trend toward shorter sleep duration in seropositive men (p=0.07). In conclusion, it is unlikely that sleep disruption mediates links between T. gondii and mental illness or behavioral dysregulation. Trending gender differences in associations between T. gondii and shorter sleep need further investigation.

In our individual and collaborative studies, we have played a part in pioneering investigations on the usefulness of biomarkers – red blood cell distribution width (RDW) and neopterin. This mini review includes historical data on the topic and is related to the first contributions in this field, as well as to the possibilities for further improvement and simultaneous application of RDW and neopterin measurements in the prevention, prognosis and treatment of a great number of socially important disease conditions (arterial, cardiovascular, brain vascular, peripheral artery diseases, inflammations, autoimmune states, cancers and leukemias, addictions, etc.). When comparing the results obtained with the immunobiochemical biomarker neopterin with RDW, they are reported to be very similar as independent predictors of the same pathological states in the human body although their biomedical origins are very different. Both the parameters were until now successfully, but only separately used in medical practice. The combined use of these two biomarkers can shed some more light on their interrelationships and provide some clues as to how the interaction between immune system activation and red blood cells biology are intertwined.

As the disease-free 5-year-survival of late stage laryngeal carcinoma patients is extremely low, indoleamine-2,3-dioxygenase-1 (IDO)-induced tryptophan degradation may represent an immune escape mechanism which plays an important role in cancer spreading in advanced stage laryngeal cancers. We examined whether the late stage laryngeal cancer enhances tumor immune evasion by the expression of systemic IDO activities and chronic cellular immune activation. Twenty-two of 42 male laryngeal cancer patients were classified as late stage cancer according to American Joint Committee on Cancer (AJCC) criteria. Their serum neopterin, tryptophan and kynurenine concentrations were compared with 30 cancer-free individuals. IDO activity was approved by correlation between serum neopterin and kynurenine/tryptophan. Late stage cancer patients preoperatively showed a significantly higher IDO activity compared to controls and early stage cancer cases. Six months after tumor removal, late stage cancer patients although having higher serum neopterin concentration compared to early stage patients or controls, they showed a significant decrease in IDO activity and tryptophan consumption. Increased systemic IDO activity may provoke the escape of tumor cells from the immune surveillance of the host. High IDO activity is due to the presence of tumor mass. Persistence of high serum neopterin levels despite tumor removal may indicate poor prognosis.

We previously reported that trait aggression, proposed as an endophenotype for suicidal behavior, is positively associated with Toxoplasma gondii (T. gondii) seropositivity in females, but not in males. Additionally, older males seropositive for T. gondii had lower scores on measures of trait aggression, including self-aggression. Trait aggression may be influenced by dopaminergic signaling, which is known to be moderated by gender and age, and potentially enhanced in T. gondii positives through the intrinsic production of dopamine by the microorganism. Therefore, we investigated associations between trait aggression and interactions between T. gondii enzyme-linked immunoabsorbant assay (ELISA) IgG titer-determined seropositivity and high-performance liquid chromatography- (HPLC-) measured blood levels of dopamine precursors phenylalanine (Phe), tyrosine (Tyr), and their ratio in a sample of 1000 psychiatrically healthy participants. Aggressive traits were assessed using the questionnaire for measuring factors of aggression (FAF), the German version of the Buss-Durkee hostility questionnaire. We found that 1) the decrease in trait aggression scores in T. gondii-positive older males was only present in individuals with a low Phe:Tyr ratio, and 2) that there was a positive correlation between Phe:Tyr ratio and total aggression and selected subscales of aggression in T. gondii-positive males, but not in T. gondii-negative males. These findings point toward a gender-specific reciprocal moderation by Phe:Tyr ratio and T. gondii seropositivity of their associations with aggression scores, and lead to experimental interventions geared to manipulating levels of dopamine precursors in selected T. gondii positive individuals with increased propensity for aggression.

Gender differences in tryptophan (TRP) breakdown in obese individuals have been previously reported. This could be both contributory to, as well as a consequence of, gender differences in mood changes among obese people. To exclude the potential effect of depression on TRP breakdown and its levels in obesity, we replicated analyses in psychiatrically healthy individuals. In 1000 participants, plasma kynurenine (KYN), TRP, and the KYN/TRP ratio were compared between overweight/obese and normal-weight individuals using analysis of covariance, with adjustment for age and gender. Bivariate post hoc tests were also conducted. There were no significant relationships between KYN, TRP, or the KYN/TRP ratio and overall overweight/obese status. However, a significant gender by weight category interaction was identified for TRP only, with overweight/obese women having lower TRP than overweight/obese men (p=0.02). No gender differences in TRP were found in non-obese participants. Our study in psychiatrically healthy individuals suggested that lower TRP levels in obese women were not secondary to depression, strengthening the possibility that TRP levels could mediate depression in vulnerable women. Thus experimental manipulations of TRP levels could be used to advance theoretical knowledge, prevention, and clinical control of depression in obese women.

Formation of neopterin, a biomarker of the activated human immune system, is linked with tryptophan (TRP) and phenylalanine (PHE) metabolism. To obtain normal values, in this study, serum concentrations of neopterin as well as of TRP, PHE and their respective metabolites kynurenine (KYN) and tyrosine (TYR) were investigated in 100 successive blood donor serum specimens from the University Clinics of Innsbruck, Austria. In addition, nitrite concentrations were determined. Donors had passed anamnestic examination at entry and were therefore considered as healthy. The mean age of participants was 49±11.4 (mean±SD) years; 18% were older than 60 years. Both genders were included in the analysis. Neopterin concentrations measured by enzyme-linked immunosorbent assay were 5.9±1.6 nmol/L (mean±SD). Levels of amino acids and metabolites were determined by HPLC. Mean KYN and TRP concentrations were 1.78±0.42 μmol/L and 67.4±10.2 μmol/L, respectively. KYN to TRP ratio (KYN/TRP), an estimate for the activity of tryptophan-degrading enzyme indoleamine 2,3-dioxygenase, was 26.7±6.2 μmol/mmol. Mean PHE and TYR concentrations were 65.2±11.1 μmol/L and 90.6±22.9 μmol/L. PHE to TYR ratio (PHE/TYR), an estimate for the activity of PHE-converting enzyme phenylalanine hydroxylase, was 0.75±0.14 μmol/μmol. Nitrite concentrations, estimated by Griess-Ilosvay reagent, were 44.9±32.0 μmol/L. Males were taller and heavier than females (both p

Phenylalanine hydroxylase (PAH) is the key enzyme in phenylalanine metabolism, catalyzing its oxidative breakdown to tyrosine. Its function in the committed step of amino acid metabolism requires strict regulation. Thus, several regulatory mechanisms are central for an understanding of PAH at the atomistic level. The enzyme is activated by incubation with phenylalanine and inhibited by tetrahydrobiopterin binding. Furthermore, phosphorylation of Ser-16 in the regulatory domain influences enzyme turnover. All major regulatory processes in PAH are connected to the conformational changes within a protein and its oligomeric assembly. The underlying dynamic processes in the enzyme are tackled by a variety of experimental and computational approaches. We especially emphasize the computational approaches, aiming to unravel the changes in the molecular dynamics of PAH that govern allosteric regulation. State-of-the-art molecular dynamics simulations provide access to the conformational transitions in biological macromolecules at the microsecond time scale and beyond. Thus, in silico strategies are promising for the identification of the complex allosteric mechanisms governing PAH activity in vivo.

The effects of cytokine and mitogen stimulation on homocysteine (HCY) metabolism in different cells were investigated: in human dermal microvascular endothelial cells (HDMEC), T lymphocytes, mature and immature dendritic cells, and myelomonocytic (THP-1) and monocytic cell lines (U-937). Furthermore, the influence of supplementation of cells with folate acid, methionine and the combination of both on HCY metabolism was investigated. Unstimulated HDMEC and dendritic cells only produced very little amounts of HCY, and stimulation did not change HCY formation significantly either. However, higher HCY concentrations were detected in HDMEC and dendritic cells under supplementation with methionine and slightly less under supplementation with folate. Proliferating T lymphocytes showed an increase in HCY production on stimulation with increasing doses of mitogens; proliferative activity was associated with HCY formation. THP-1 and U-937 cells produced significantly more HCY than endothelial cells; U-937 cells produced most HCY, which was mainly due to their high proliferation rate. Stimulation of both cell lines with lipopolysaccharide and interferon-γ, respectively, showed a significant effect on HCY production of cells; in THP-1 cells, stimulation with IFN-γ and lipopolysaccharide induced neopterin formation. Methionine supplementation strongly increased and folate supplementation slightly decreased HCY formation in both cell lines. Thus, inflammation may play a role in moderate hyperhomocysteinemia.

In vitro, large amounts of neopterin are released from human monocyte-derived macrophages and dendritic cells primarily upon stimulation with Th1-type cytokine interferon-γ (IFN-γ). IFN-γ also induces the enzyme indoleamine 2,3-dioxygenase (IDO), which degrades tryptophan (TRP) to form kynurenine (KYN). IDO-mediated TRP catabolism is very effective in suppressing the proliferation of T lymphocytes as well as of pathogens in vitro and in vivo. In this study, we investigated whether exogenously added neopterin may influence IDO activity in resting and in stimulated peripheral blood mononuclear cells (PBMC). PBMC were isolated from healthy donors, and neopterin was added in a concentration range from 0.01 to 50 μmol/L. After 30 min, PBMC were stimulated or not with 10 μg/mL of mitogen phytohemagglutinin (PHA). After 48 h, culture supernatants were collected, KYN and TRP concentrations were measured by high-performance liquid chromatography, and the ratio of KYN vs. TRP was calculated as an estimate of IDO activity. Spontaneous as well as PHA-induced TRP breakdown was suppressed by exogenously added neopterin in a dose-dependent way; the lowest active concentration of neopterin was

Survival of neurons is dependent on the presence of trophic and non-trophic factors. We have previously observed the protective capacity of purine nucleosides in hypoxic neuronal cell cultures. Guanosine appeared especially interesting with respect to its remarkable neurite-stimulating aptitude. Here we report the effect of ischemic stress and guanosine on the concentration of the essential amino acids phenylalanine and tyrosine, in culture supernatants of PC12 cells. In ischemic neuronal cultures, a substantial rise of phenylalanine and tyrosine levels was observed, indicating inhibition of cellular metabolism due to neuronal stress. Elevated phenylalanine and tyrosine concentrations were reduced by the addition of guanosine. Guanosine even down-regulated the ratio of phenylalanine to tyrosine. Results may support current efforts to propagate guanosine as a neuroprotective and neuroregenerative substance.

Pro-inflammatory cytokines like interferon-γ (IFN-γ) play dominant roles in pathophysiologic conditions like infections, cardiovascular and neurodegenerative disorders and autoimmune syndromes. As part of its antimicrobial and immunomodulatory armature, the tryptophan-degrading enzyme indoleamine (2,3)-dioxygenase (IDO) is mainly up-regulated in dendritic cells (DCs) and phagocytes by pro-inflammatory stimuli, most notably IFN-γ. By the breakdown of the essential amino acid l-tryptophan along the kynurenine pathway, IDO plays a key role in the inhibition of cell proliferation including that of activated T cells, thereby supporting immune tolerance in mammalian pregnancy, tumor development, allergic inflammation and allotransplantation. IFN-γ-induced tryptophan deprivation also seems to be involved in the pathogenesis of anemia and cachexia when erythroid progenitor cells suffer from insufficient amino acid supply or when protein biosynthesis of the organism is restricted by diminished tryptophan availability. This biochemical cascade seems also to be involved in the production of potentially neurotoxic tryptophan catabolites such as quinolinic acid, which ultimately leads to the development of neuropsychiatric symptoms like cognitive impairment and depression especially in patients suffering from severe and chronic infections.

Higher serum neopterin concentrations and kynurenine-to-tryptophan (Kyn/Trp) ratios are associated with increased mortality in patients with coronary artery disease (CAD). Preferentially, Th1-type cytokine interferon-γ stimulates tryptophan breakdown and neopterin production by GTP cyclohydrolase I (GCH-I) in parallel in monocyte-derived macrophages and dendritic cells. In other cells, activation of GCH-I leads to the formation of 5,6,7,8-tetrahydrobiopterin (BH4), the necessary cofactor of amino acid hydroxylases such as phenylalanine 4-hydroxylase (PAH) and nitric oxide synthases. In 31 CAD patients (70.3±9.9 years; 21 males, 10 females), we determined serum concentrations of phenylalanine, tyrosine, and Kyn/Trp by HPLC, neopterin by ELISA, and nitrite by the colorimetric Griess assay. The phenylalanine-to-tyrosine ratio (Phe/Tyr) served as an estimate of PAH enzyme activity. Elevated Phe/Tyr concentrations were detected in a subgroup of CAD patients and correlated with Kyn/Trp (r=0.396, p

The proinflammatory cytokine interferon (IFN) γ activates GTP-cyclohydrolase I. In turn, the production of neopterin in human monocytic cells and of 5,6,7,8-tetrahydrobiopterin (BH4) in other human cells and cells of other species is markedly upregulated. BH4 is cofactor for the biosynthesis of the neurotransmitters 5-hydroxytryptamine (serotonin) and the catecholamines dopamine, epinephrine (adrenaline), and norepinephrine (noradrenaline). The finding of increased neopterin concentrations in patients with viral infections, autoimmune syndromes, malignant tumors, and during treatment with specific cytokines corresponds well with its immunobiological background. However, there is no clear information about BH4 concentrations in these patients. Furthermore, higher blood phenylalanine (Phe)-to-tyrosine (Tyr) ratios have been described in patients with ovarian cancer, after multiple trauma and with sepsis, in patients with HIV-1 infection, in elderly individuals, and in patients with HCV infection under IFN-α therapy. Recent studies already showed that the alterations of Phe metabolism are associated with mood changes and depression. Results point to an impaired hydroxylation of Phe when the enzyme phenylalanine 4-hydroxylase (PAH) is less efficient. As the decrease of PAH activity might result from a diminished availability of BH4, the determination of the Phe/Tyr ratio may serve as an indirect measure of BH4 availability.

Neopterin, as a non-conjugated pteridine, is synthesized from guanosine triphosphate and its production is upregulated upon the activation of cellular immune response. Alterations of pteridines in body fluids are known to correlate well with existing diseases and stages, prognosis, clinical outcomes and survival data. It is of advantage to have a pteridine database of healthy volunteers to determine normal values. Thereby, especially in children there is no detailed study on pteridine levels. The aim of this study is to initiate the establishment of pteridine database of healthy children in our country. Serum neopterin levels were analysed by enzyme-linked immunosorbent assay. Urinary neopterin and biopterin levels and serum kynurenine, tryptophan levels and kynurenine/tryptophan ratio as an estimate of tryptophan breakdown were assessed with high-pressure liquid chromatography in serum and urine samples of 55 children aged between 3 months and 10 years. The results were evaluated within the subgroups of different ages and sex. Pteridine pathway components were found to be higher in children compared to adults. Higher levels of pteridine pathway components observed within the first years of life may reflect the rapid maturation of the immune system, and environmental adaptation and/or insufficiency of defence systems. On the other hand, it may also relate to a higher frequency of infections not (yet) manifested clinically.

HIV-1 persists as a latent reservoir in people receiving suppressive antiretroviral therapy (ART). When ART is interrupted (treatment interruption/TI), rebound virus re-initiates systemic infection in the lymphoid system. During TI, HIV-1 is also detected in cerebrospinal fluid (CSF), although the source of this rebound virus is unknown. To investigate whether there is a distinct HIV-1 reservoir in the central nervous system (CNS), we compared rebound virus after TI in the blood and CSF of 11 participants. Peak rebound CSF viral loads vary and we show that high viral loads and the appearance of clonally amplified viral lineages in the CSF are correlated with the transient influx of white blood cells. We found no evidence of rebound macrophage-tropic virus in the CSF, even in one individual who had macrophage-tropic HIV-1 in the CSF pre-therapy. We propose a model in which R5 T cell-tropic virus is released from infected T cells that enter the CNS from the blood (or are resident in the CNS during therapy), with clonal amplification of infected T cells and virus replication occurring in the CNS during TI.

Immune system activation and inflammation accompanies immune dysfunction in trauma and sepsis patients. Tryptophan degradation via the kynurenine pathway by the cytokine-inducible enzyme indoleamine 2,3-dioxygenase (IDO) could contribute to the deficient responsiveness of immunocompetent cells. Activated IDO in patients after trauma and with sepsis is indicated by an increased kynurenine to tryptophan ratio (kyn/trp), which was found to be associated with poor outcome of patients. In this study, tryptophan and kynurenine concentrations in 18 patients post trauma or with sepsis during 12-14 days of follow up (up to 84 specimens were available) were compared to concentrations of neopterin and cytokines tumor necrosis factor-α (TNF-α) and interleukin- 6 (IL-6) and the in vitro response of lipopolysaccharide-stimulated monocytes. Compared to healthy controls, average kyn/trp and kynurenine, TNF-α, IL-6 and neopterin concentrations were increased in patients, and tryptophan concentrations were decreased. During follow-up, only kyn/trp, kynurenine and neopterin concentrations (all p

In recent years, interest has been growing regarding the role of alcohol intake on systemic lupus erythematosus (SLE) disease activity. This integrative single-case study investigated the dynamic interdependencies between alcohol consumption, various emotional states and cellular immune activity in SLE using time series analysis (i.e., ARIMA modeling, cross-correlational analysis). We determined neopterin concentrations (HPLC) in a 52-year-old woman suffering from SLE, who collected her entire urine on a twice-daily basis for a period of 56 days (total: 112 time-points). Aside from the central interest of our studies, i.e., the impact of everyday incidents on cellular immune system dynamics, the patient also provided daily information on intake of alcoholic beverages (type and quantity) and various emotional state variables (mental activity, irritation, mood). Cross-correlational analyses revealed that moderate alcohol consumption had different effects on urinary neopterin levels depending on whether time series data were analyzed before or after the occurrence of an inflammatory event (acute paranasal sinusitis) that had taken place halfway through the study period (time-points 45-54). Before sinusitis (1-44), increases in alcohol consumption were parallelized by decreases in urinary neopterin levels (lag0: r = -0.371; p< 0.05) whereas after sinusitis (55-112), increases in alcohol intake preceded increases in urinary neopterin levels with a temporal delay of 12 hours (lag1: r = +0.308; p< 0.05). The emotional states under study did not interfere with the associations between alcohol intake and neopterin levels. These findings show that even within the same patient with SLE the relationship between alcohol intake and neopterin levels might not always be stable suggesting a possible reason for inconsistent evidence from cross-correlational studies.

Nigella sativa, commonly known as black cumin seed, belongs to the botanical family of Ranunculaceae. The active antioxidant components of Nigella sativa display a remarkable array of biochemical, immunological and pharmacological actions, including bronchodilatory, anti-inflammatory, antibacterial, hypoglycaemic, antitumoural and immunopotentiating effects. Effects of Nigella sativa seeds extracts were investigated in freshly isolated human peripheral blood mononuclear cells stimulated with the mitogens phytohaemagglutinin and concanavalin A in vitro. Tryptophan degradation and neopterin production were monitored in culture supernatants, both these immunobiochemical pathways are induced by pro-inflammatory cytokine interferon-γ. Compared to unstimulated cells, the mitogens enhanced degradation of tryptophan and production of neopterin. Nigella sativa seeds extracts significantly suppressed both pathways in a dose-dependent way. Suppression of tryptophan degradation and neopterin formation by Nigella sativa seeds extracts demonstrates an inhibitory influence on activated T-cells and macrophages. Data are in line with an anti-inflammatory activity of the extracts.

The profiles of unconjugated pteridines such as neopterin and biopterin and of tryptophan metabolism change in many pathologic conditions such as rheumatoid arthritis, malignancies and autoimmune diseases and are related to the release of pro-inflammatory cytokines. However, studies on potential effects of drugs are very limited. This study investigates whether meloxicam, a non-steroidal anti-inflammatory drug, may cause any alteration of the pteridine pathway and tryptophan metabolism in 22 patients who admitted to the Physical and Rehabilitation Medicine outpatient clinic in the Hacettepe University Hospital and suffering from various musculoskeletal pain conditions without systemic inflammation. Urine concentrations of neopterin, biopterin and xanthopterin, and serum concentrations of neopterin, tryptophan, and kynurenine, and the activity of dihydropteridine reductase were measured at the beginning of the therapy and after a 15 days treatment with meloxicam. Average urine concentrations (± S.E.M.) of pterins before therapy (neopterin: 263 ± 15.6 μmol/mol creatinine, biopterin: 72.4 ± 13.4 μmol/mol creatinine, and xanthopterin: 675 ± 93.0 μmol/mol creatinine) were not changed during meloxicam therapy (neopterin: 230 ± 30.7 μmol/mol creatinine = 88% of baseline, biopterin 115 ± 26.5 μmol /mol creatinine = 159% of baseline, and xanthopterin 684 ± 88.0 μmol/mol creatinine = 101% of baseline; all differences not significant). The activity of dihydropteridine reductase was 6.02 ± 0.21 nmol/cytochrome C reduced/min/5 mm disc before and 6.28 ± 0.18 nmol/cytochrome C reduced/min/5 mm after treatment (= 104% of baseline; p = 0.088). Serum concentrations of neopterin 6.04 ± 0.33 nmol/L before treatment increased to 6.89 ± 0.48 nmol/L after treatment (= 114% of baseline; p

Acute infectious diseases of the respiratory tract are regularly associated with increased concentrations of neopterin in serum and/or urine. Most likely, the pteridine compound is not only a marker of an activated cellular immune system but may exert distinct biochemical functions in the process of infections as well. In response to viral contact, macrophages located in the nasal mucosa may represent a source for neopterin in the nasal cavity with potential hazardous effects on ciliary beat frequency (CBF), thus promoting chronic infectious processes. The aim of the present study was to investigate the effects of neopterin at different concentrations (10 nM, 100 nM, and 100 μM) on CBF in human nasal epithelial cells in vitro. Samples were taken from the inferior nasal turbinate and incubated with neopterin dissolved in either aqua destillata or in sodium chloride (0.9%) at the given amounts for 2, 5, 10, and 20 min. In a preliminary set of experiments, neopterin inhibited CBF following the 5 and 10 min. incubation protocol, respectively. However, analyses of pooled data from 28 experiments using sodium chloride (0.9%) as solvent could not confirm these findings: in no setting a significant reduction of CBF was detected at the end of the 20 min. experimental procedure. Therefore, we conclude that neopterin most likely does not affect the mucociliary clearance defense mechanisms in the course of infections of the nasal respiratory tract.

Immune system activation has been observed during endurance exercise, but its relevance is largely unclear. We evaluated urinary neopterin excretion in an athlete competing in the Race Across America (RAAM), to determine whether neopterin excretion would indicate that immune system activation occurs during extreme endurance sport. Urinary samples were collected at the day before the race, during the whole RAAM, and, without a physical strain, seven days after the race. Neopterin normalized to creatinine concentration was determined by reversed-phase high-pressure liquid chromatography (HPLC). Data were analysed by repeated-measured analysis of variance (ANOVA). In the athlete, urinary neopterin concentration started to increase consistently after the start of the race until day four, followed by a decline thereafter, reaching values close to the starting value. The lowest average neopterin concentration was observed at day seven; this concentration was significantly lower than mean values at days 2- 6 (all p

This study on a patient with prior breast cancer investigated the cause-effect relations between immune system activation, fatigue and mood under real-life conditions. The 60-year old woman (primary diagnosis 5 years ago, relapse one year ago, currently no signs of recurrence) collected her entire urine for 31 days in 12 hour intervals for the determination of immune activation marker neopterin and creatinine concentrations by HPLC. This study used only the daytime urinary neopterin concentrations (from approx. 8 a.m. to 8 p.m.) and cross-correlated them with daily data from mood (3-Skalen-EWL) and fatigue (VAS) questionnaires which the patient filled in for 31 days. Serial dependencies were controlled for by applying moving average smoothing. When averaged over the whole observation period, daily fatigue, daily mood and daily urinary neopterin (average 173 μmol per mol creatinine) were within normal limits. Cross-correlational analyses revealed that increases in urinary neopterin significantly preceded increases in fatigue by 24 hours (lag 1: r = +0.424; p

Inflammation and immune system activation seem to play an important role in the development and progression of dementia. Also concentrations of immune activation marker neopterin are increased in serum and cerebrospinal fluid of some patients with dementia, and a significant relationship is found between concentrations of neopterin and homocysteine. Β vitamin supplementation is able to rapidly slow-down homocysteine formation in patients. However, no change of neopterin was found within one month of such therapy. In this study, scrum concentrations of neopterin and homocysteine were investigated in 58 patients with Alzheimer's disease (n=30), vascular dementia (n=12) and mild cognitive impairment (n=16) during 1 -3 months of supplementation with Β vitamins (Beneitran compositum®)with monthly increasing dose ( 1 - 6 tablets a day). No change of neopterin concentrations was observed In the patients groups throughout the whole study period (all ρ >0.05). As was reported earlier, a rapid decline of homocysteine concentrations was achieved already within the first month of supplementation (p

Prolonged physical exercise is associated with multiple changes in the immune status indicating an acute phase response and an activation of the immune system. Eccentric muscle activation (e.g. downhill running) induces micro-trauma of skeletal muscles thus inducing an inflammatory response. At present there are no data to which extent the immune system is activated after a downhill marathon run and if there arc any correlations between immune activation and markers for muscle damage or functional impairment of leg muscles. As model for severe eccentric exercise we selected the Tyrolean Speed Marathon (42 km downhill run, 795 m vertical difference). 13 volunteers (12 male, 1 female; mean running time 224 min [range 193 - 266 min.]) finished the run. Blood from antecubital veins was collected 3-4 days before (T1 ), 3-4 hrs before (T2) and immediately after the marathon (T3) as well as on the morning after the run (T4). We measured serum neopterin concentrations, white blood cell count. C-reactive protein (CRP), creatine kinase (CK), myoglobin (Mb), cardiac troponin I (cTnl) and troponin Τ (cTnT). Moreover, isokinetic muscle tests were performed. Following significant changes were found (before vs. after the run): increase in neopterin, CRP, total leukocyte count, CK. Mb, cTnl, cTnT, whereas isokinetic dynamometry showed a reduction in peak hamstring torque of both thighs after the marathon. There were no significant correlations (Spearman's rank correlation coefficient) between the observed changes in neopterin and CRP, CK, Mb. cTnT, cTnl or between neopterin concentrations and parameters of isokinetic muscle tests. We could demonstrate that a 42 km downhill marathon is associated a) with an activation of the cellular immune system, as evidenced by the increase in serum-neopterin. b) pronounced micro-skeletal muscle damage with high serum creatine kinase and myoglobin, and c) eccentric hamstring fatigue. The absolute changes in neopterin were moderate and similar to other types of exercise (flat course and bicycle marathon, mountain hiking).

Thl-type cytokine interferon-y induces neopterin production in human monocyte-derived macrophages and it stimulates enzyme indoleamine (2,3)-dioxygenase (IDO) which converts tryptophan to kynurenine in various cells. In an integrative single-case study, a healthy, 27-year-old female had collected her entire urine in 12-hour (= I lag) intervals on 56 consecutive days. Neopterin, tryptophan, kynurenine and Creatinine concentrations were determined using HPLC. The kynurenine to tryptophan ratio (kyn/trp) was calcuiated as an index for IDO activity. Within the Observation period, the woman experienced an infection episode presenting with vomiting and headache, however, not serologically verified. During this period, strong increases in both urinary kyn/trp and neopterin to Creatinine concentrations were observed, and thcrc was a significant correlation between neopterin/creatinine and kyn/trp at the same day (rs =0.334, p

Extract of traditional Tibetan herbal remedy Padma 28 revealed suppressive effects on neopterin production and tryptophan degradation in mitogen-stimulated peripheral blood mononuclear cells (PBMC). One of the questions was to asses the robustness of the Tibetan way of formulating herbal multicomponent medicines. Can small changes affect the effectiveness of the formula? In this study, effect of a derivative multicomponent mixture was investigated in stimulated and unstimulated human PBMC in vitro. Neopterin production and tryptophan degradation were measured in supernatants of PBMC in the presence or absence of mitogens phytohacmagglutinin and concanavalin A. Stimulation of PBMC induced neopterin formation and tryptophan degradation, and the herbal multicomponent mixture inhibited both immunobiochemical effects in a dose-dependent way. Higher concentrations were more effective and were able to completely block the pathways induccd upon mitogenic stimulation. When comparing the results obtained with those observed earlier using Padma 28, there was no obvious difference between the two different preparations. Data allow to conclude that Padma 28 and its modified version is equally able to suppress immunobiological effects in stimulated PBMC.

Thirty healthy individuals as well as 42 patients with coronary artery disease (CAD) verified by coronary angiography were examined before and 6 month after percutaneus transluminal coronary angioplasty followed by stent implantation and statins treatment. Such therapy positively influenced high sensitivity C-reactive protein, total cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol concentration in blood scrum as well as cholesterol to phospholipid ratio. By contrast, scrum concentration of neopterin, total homocysteine, pyridoxal-5-phosphate, triglycerol and phospholipids as well as fatty acid content of phospholipids remained unchanged or became worse. These changes were followed by restenosis or new coronary events in half of observed CAD patients. Findings suggest that cholesterol concentration has no pivotal role, neither in restenosis nor in the development of coronary events after stent implantation. Elevated serum concentration of neopterin and homocysteine before and 6 months after stent implantation appear more significant indicator of new coronary events in CAD patients. Further investigations arc necessary to substantiate these observations.

Blood serum neopterin, high sensitivity C-reactive protein (hsCRP), total homocysteine, pyridoxal-5-phosphatc ( P-5-P) and total phospholipid concentrations have been examined in 30 healthy individuals as well as in patients with coronary artery disease (CAD) verified by coronary angiography (43 patients with 1-artery disease, 24 patients with 2- or 3-artery disease, 17 patients with restenosis) before percutaneous transluminal coronary angioplasty. We have observed increased mean concentrations of neopterin, hsCRP and homocysteine as well as decreased mean concentration of P-5-P and phospholipids in all groups of CAD patients. The positive correlation between neopterin and hsCRP in all CAD patients (r = 0.536; Ρ

Neopterin is produced from human monocyte-derived macrophages and dendritic cells upon Stimulation with interferon-y, and increased neopterin concentrations thus indicate cell-mediated immune activation. In healthy individuals increasing neopterin concentrations are found with increasing age, which is also evident from the agedependency of reference values of serum neopterin concentrations. Increase of neopterin concentrations in the elderly may relate to, e.g., altered T lymphocyte differentiation with age. In this study, serum neopterin concentrations of 138 persons (median age: 34 years; interquartile range 29.0 - 67.8 years) were investigated and compared to age and to the percentage of CD28+CD45RA+ or CD28+CD45RO+ subsets among CD8+ T cells. With increasing age, the percentage of CD28+CD45RA+ in CD8+ T-cells decreased (Spearman's rank correlation coefficient: rs = -0.561; p < 0.0001) accompanied by an increase of the percentage of CD28+CD45RO+ in CD8+ T-cells (rs = +0.221; p < 0.01). Serum neopterin concentrations increased with age (rs = -+0.541; p < 0.0001). This increase of neopterin concentration was accompanied by a decreased percentage of CD28+CD45RA+ in CD8+ T-cells (r+ = -0.287; p < 0.001). Multivariate analyses revealed that the inverse relationship between the percentage of CD28+CD45RA+ in CD8+ T-cells and neopterin concentrations was at least partly independent from age. Thus, investigation allows to conclude that an increase of neopterin concentrations with older age is accompanied by a loss of naive CD28+CD45RA+ CD8+ T-cells. Data suggest that the subset of CD28+CD8+ T-cells, which is developing in states of sustained immune activation, is important for a chronic production of interferon-γ which in turn gives rise to increased neopterin concentrations.

Recent studies have shown a strong association between indices of inflammation and metabolic Syndrome. Proinflammatory mediators like tumor necrosis factor-α may act as a trigger for insulin insensitivity. Therefore, patients with metabolic Syndrome might be at higher risk of insulin resistance when confronted with additional Stimuli of the immune system. These Stimuli are not restricted to the presence of pathogens but include environmental factors like physical exercise and hypoxemia as well. With respect to these interdependencies, one may assume higher risk for patients with metabolic Syndrome who perform physical exercise in alpine regions. We investigated the effects of a 3-weeks holiday with moderate sporting activities at moderate altitude (1700 m) on the conceiitrations of neopterin, tumor necrosis factor-α, serum soluble 75kD type TNF receptor (sTNF-R75), and interleukin-6 in vacationers with metabolic Syndrome. Only serum neopterin and sTNF-R75 concentrations transiently increased during the stay at moderate altitude compared to pre-altitude levels (P

We investigated a possible involvement of nitric oxide formed by inducible nitric oxide synthase (iNOS) in the signaling cascade leading to growth inhibition and differentiation in the human neuroblastoma cell line SK-NSII. Treatment of SK-N-SH with interferon-γ (IFN-γ) plus interleukin-lß (IL-lß) led to induction of iNOS, growth inhibition and an altered cell shape. However two inhibitors of iNOS were not able to prevent cytokine induced changes. In addition, IFN-γ alone led to growth inhibition in absence of iNOS induction. Inhibition of the induced indoleamine 2,3-dioxygenase (IDO) activity also did not prevent growth inhibition. Our findings show that mechanisms other than NO and IDO can control interferon-y-induced growth inhibition of SK-N-SH cells.

Upon stimulation with the cytokine interferon-γ human monocytes/macrophages produce neopterin. Accordingly, measurement of neopterin concentrations in body fluids like blood, urine or cerebrospinal fluid provides information about activation of immune response involving type 1 Τ helper cells. Increased neopterin production is found in infections by viruses including human immunodeficiency virus (HIV), infections by intracellular living bacteria and parasites, autoimmune diseases, malignant tumor diseases and in allograft rejection episodes, but also in some neurodegenerative and in cardiovascular diseases. Major diagnostic applications of neopterin measurements are monitoring of the immune status of allograft recipients, detection of infectious diseases in blood donations and monitoring of therapy in HIV-infected individuals. Neopterin concentrations also provide prognostic information in HIV-infected individuals and in several malignant tumor diseases, high neopterin production at the moment of diagnosis is associated with poorer survival expectations. As high neopterin production is associated with increased production of reactive oxygen species and with low serum concentrations of antioxidants like α-tocopherol, neopterin can be regarded as a marker of oxidative stress caused by an activated immune system. Therefore, by neopterin measurements not only the extent of cellular immune activation, but also the extent of tissue damage caused by reactive oxygen specics may be estimated.

Population-based studies suggest moderate and regular consumption of alcoholic beverages and especially of red wine to reduce morbidity and mortality from coronary heart disease. These beverages may interfere with immune activation cascades crucial in the pathogenesis of coronary heart diseases. Neopterin concentrations in human body tluids were found to increase in the course of coronary heart disease indicating the activity of the atherogenetic process. In this study, human peripheral blood mononuclear cells (PBMC) stimulated with mitogens phytohaemagglutinin and concanavalin A were exposed to red and white wines, to ethanol and to grape juice as a non-alcoholic control in vitro. Neopterin production and tryptophan degradation were measured in supcrnalants. Both biochemical effects are induced by Th 1-type cytokine interferon-y and allow monitoring of immune actnation. In stimulated PBMC increased production of neopterin and degradation of tryptophan was observed Red and white wines, as well as grape juice inhibited these stimulation-induced effects, higher concentrations being more cffective. Ethanol had comparably small if any effect, Red and white wines as well as grape juice down regulate cytokine-mediated effects in PBMC. Most likely, antioxidant ingredients of wine and grape juice such as resveratrol are capable of interfering with immunologic pathways which appear to be of relevance, e g.. in the pathogenesis of cardiovascular disease.

Earlier neopterin was demonstrated to inhibit hypoxia-induced erythropoietin synthesis in isolated perfused rat kidneys. The present experiments were performed to gain further insight into the mode of action underlying this effect. Numerous studies provided evidence of a link between neopterin and oxidative stress as well as intraccllular calcium concentrations. Thus, neopterin (200 μM) NQS added into the perfusion medium together with either the caclium Channel blocker Verapamil (5 μM) or the anti-oxidant N-acetylcysteine (200 μM). The addition of neopterin as a Single stimulus resulted in a significant decrease in the rate of hypoxia-induced eryihropoietin release accompanied by an augmented renal vascular resistance and a reduced perfusion flow rate. Although these data point towards an involvement of calcium and/or reactive oxygen species, verapamil or Nacetyleysteine were able to abrogate the suppression of erythropoietin generation which was induced by neopterin. Therefore, the mechanisms responsible for the impact of neopterin on the production of this growih lactor in the kidney remain to be elucidated.

Neopterin is a sensitive marker of the activated cellular (= Thl-type) immune response. Neopterin concentrations in healthy children are higher compared with those of adults and are declining with increasing age. In this study, we present a follow-up of urinary neopterin to creatinine concentrations in two healthy children until adolescence. Data were available from one female (7 - 23 years) and her brother (0 - 18 years), of whom early morning urine specimens were collected on an irregular basis throughout 18 years. In total, neopterin and creatinine concentrations were measured by high pressure liquid chromatography (HPLC) in 343 urinary specimens. In both children, concentrations of urinary neopterin were highest at study entry. With increasing age neopterin concentrations decreased continuously to reach rather constant levels around the age of fifteen years. On several occasions at which individuals presented with common sickness, mostly of infectious origin, neopterin concentrations were found highly increased. In the absence of such infectious episodes, neopterin/creatinine measurements of both individuals fit well to previously established normal ranges. However this was true only for specimens collcctcd when children were older than 10 years, before that age concentrations of neopterin were frequently found to be higher than the established upper limits of the normal range.

Moderate hyperhomocysteinemia is associated with an increased risk of coronary heart disease (CHD). An inverse relationship usually exists between homocysteine and folate concentrations, and folate supplementation is often able to lower homocysteine concentrations. Thus, insufficient dietary intake of folate and/or vitamin B12 is considered to be responsible for the development of hyperhomocysteinemia. Inflammation and immune activation appear also to be important in the pathogenesis of CHD and may influence availability of folate. Blood concentrations of homocysteine, Β vitamins and neopterin were examined in 35 patients with CHD verified by coronary angiography, (2 1 patients with one-artery disease, 9 with two- or three-artery disease, 5 with restenosis). Compared to 30 healthy controls, a significant proportion of patients presented with increased homocysteine concentrations. Hyperhomocysteinemia coincided with lower folate and also with higher neopterin concentrations indicating immune system activation. In addition, correlations existed between neopterin and homocysteine (r = 0.472, ρ < 0.01) and folate (r = -0.370, ρ = 0.01). We conclude that higher homocysteine is not only associated with lower circulating folate but also with higher neopterin. Immune activation could be involved to cause an increased demand for folate resulting in hyperhomocysteinemia even when dietary folate intake is within the recommended range.

Human monocyte-derived macrophages and dendritic cells produce increased amounts of neopterin derivatives upon stimulation with interferon-γ (IFN-γ). In parallel, such stimulated cells release a record of oxidizing specics as part of their cytocidal repertoire. Production of reactive oxygen species by stimulated immunocompetent cells may be the reason for the depletion of antioxidant vitamins and the development of oxidative stress during diseases with stimulated immune system. Noteworthy also neopterin derivatives are able to interfere with reactive oxygen, chlorine, and nitrogen species, and neopterin itself could contribute to oxidative stress. In vivo, neopterin concentrations thus allow not only to monitor cell-mediated immune response, they also allow to estimate the extent of oxidative stress which emerges during immune response. In certain diseases associations between higher neopterin levels and markers of oxidative stress have been reported. In neurodegenerative diseases, neopterin concentrations in scrum and cerebrospinal fluid also correlate with the cognitive decline in patients. In this studv we compared serum concentrations of neopterin with serum concentrations of peroxides and homocysteine in patients with various forms of dementia and in 5 healthy elderly controls. In patients of either form of dementia serum concentrations of peroxides and neopterin were increased compared to controls. There existed a positive correlation between age and concentrations of peroxides, neopterin and homocysteine. The data further supportile view that increased neopterin concentrations are associated with oxidative stress which could underlie c¡r increased demand of antioxidants in neurodegenerative disorders. It appears important that such changes can h> detected in the blood of patients with dementia, albeit its pathogenesis is considered to be confined to the brain The results further suggest that aging is associated with immune system activation which may lead to the increased production of peroxides.

Increased neopterin concentrations in serum and urine indicate activation of cell-mediated immunity. In this study, urinary neopterin concentrations of a family consisting of 1 child (aged 5 years), her parents, and her grandparents were determined over a one year period and the course of neopterin levels was compared. Urine specimens were taken every second week during 1 year beginning in June. All 5 individuals lived in the same house, child and her parents separated by one floor from the grandparents. Neopterin concentrations were determined by high Performance liquid chromatography. In adults, neopterin concentrations were very stable throughout the year and peak increases occurred only rarely. In contrast, 5 sharp peaks of urinary neopterin concentrations were observed in the child, all occurring during the period when she was attending the kindergarten. Comparing the course of neopterin concentrations between the persons tested, several corresponding elevations of urinary neopterin were detected in the child and her relatives. The best association was detected between the child and her father (3 peaks of neopterin concentrations were observed, 1 of which coinciding with a peak in the child and two peaks with two weeks delay in the father). Between the child and her mother 1 corresponding neopterin peak was observed. One highly increased urinary neopterin concentration was observed in the grandmother which corresponded to a peak in the child with two weeks delay, a similar Observation was made between the child and her grandfather. In summary, high degree of correspondence in neopterin peaks was detected between child and adults. The data render it likely that the child was transmitting infectious diseases which she acquired at the kindergarten to her relatives, and the data are in line with the assumption that a dose family contact between individuals increases the risk of infectious disease transmission via household contact.

Hyperhomocysteinemia is considered to be an independent risk factor for cardiovascular diseases and atherosclerosis. Also patients with dementia, either of Alzheimer's or of vascular type, may present with elevated homocysteine levels. All these disorders are linked with older age and since hyperhomocysteinemia is also frequent in the healthy elderly, we were interested to determine homocysteine concentrations in a younger population of demented patients suffering from Huntington's disease. In 15 patients with Huntington's disease and in a control group of similar age, serum homocysteine concentrations were measured and changes were compared to concentrations of folate and neopterin, the latter being an indicator of immune activation. A subgroup of patients with Huntington's disease presented with elevated homocysteine concentrations compared to healthy controls of similar age. Moderate hyperhomocysteinemia was related to lower folate concentrations and also to higher neopterin levels which indicate increased immune activation. The correlation of homocysteine with neopterin concentrations points to a possible relationship between the development of hyperhomocysteinemia and immune activation in the patient

Upon stimulation with interferon-γ, a typical Thl cell-derived cytokine, human monocyte-dertved macrophages produce neopterin derivatives and in parallel degrade the essential amino acid L-tryptophan to L-kynurenine and subsequently to 3-hydroxyanthramlic acid and anthramlic acid. In parallel, stimulated macrophages produce reactive oxygen species such as hydrogen peroxide and hypochlorous acid. Earlier, neopterin and 7.8-dihydroneoptenn were found to enhance or decrease effects of reactive oxygen species in vitro, depending on concentration and on environmental condition. In this study, we investigated the ability of tryptophan and its metabolites to interfere with radicals in vitro by means of a chemiluminiseence-based assay system. When using hydrogen peroxide or chloramine Τ as source for radical formation. L-tryptophan and its catabolites reduced chennluminescence according to a dose-response relationship, 3-hydroxvanthranilic acid being the most efficient compound. Apart from L-kynurenme the scavenging effects of tryptophan and its metabolites were not affected by changes m pH from 5.5 to 7.5. Our data indicate that tryptophan degradation produces metabolites with a high scavenging ability for reactive oxygen and chlorine species, thereby establishing a self-regulatory mechanism to limit the tissue damage by reactive radicals produced by macrophages.