L-Tryptophan is an essential amino acid that is required for the biosynthesis of proteins and is the precursor for several important biological compounds, e.g., 5-hydroxytryptamine (serotonin). In an alternative reaction series, the so-called kynurenine pathway, tryptophan is catabolized to form nicotine amides and the vitamin niacin (1) as end products. A cytokine-inducible indoleamine-(2,3)-dioxygenase (IDO) catalyzes the first step of tryptophan degradation (2)(3)(4)(5), forming the intermediate kynurenine. Interferon-γ has been shown to be a potent stimulating cytokine for IDO in vitro (6)(7). Similarly in vivo, a decrease of serum tryptophan and an increase of kynurenine in parallel was described (8)(9)(10)(11)(12), indicating an enhanced cytokine-induced degradation of tryptophan, when the cellular immune system is activated. In particular, the ratio of kynurenine to tryptophan seems to be a sensitive indicator for interferon-γ-induced tryptophan degradation and therefore for an activated immune system (10)(13). Thus, simultaneous measurements of kynurenine and tryptophan, allowing calculation of the ratio, enables indirect examination of endogenous interferon-γ formation.

Multiple factors are involved in the etiology of cardiovascular disease (CVD). Pathological changes occur in a variety of cell types long before symptoms become apparent and diagnosis is made. Dysregulation of physiological functions are associated with the activation of immune cells, leading to local and finally systemic inflammation that is characterized by production of high levels of reactive oxygen species (ROS). Patients suffering from inflammatory diseases often present with diminished levels of antioxidants either due to insufficient dietary intake or, and even more likely, due to increased demand in situations of overwhelming ROS production by activated immune effector cells like macrophages. Antioxidants are suggested to beneficially interfere with diseases-related oxidative stress, however the interplay of endogenous and exogenous antioxidants with the overall redox system is complex. Moreover, molecular mechanisms underlying oxidative stress in CVD are not fully elucidated. Metabolic dybalances are suggested to play a major role in disease onset and progression. Several central signaling pathways involved in the regulation of immunological, metabolic and endothelial function are regulated in a redox-sensitive manner. During cellular immune response, interferon γ-dependent pathways are activated such as tryptophan breakdown by the enzyme indoleamine 2,3-dioxygenase (IDO) in monocyte-derived macrophages, fibroblasts, endothelial and epithelial cells. Neopterin, a marker of oxidative stress and immune activation is produced by GTP-cyclohydrolase I in macrophages and dendritic cells. Nitric oxide synthase (NOS) is induced in several cell types to generate nitric oxide (NO). NO, despite its low reactivity, is a potent antioxidant involved in the regulation of the vasomotor tone and of immunomodulatory signaling pathways. NO inhibits the expression and function of IDO. Function of NOS requires the cofactor tetrahydrobiopterin (BH4), which is produced in humans primarily by fibroblasts and endothelial cells. Highly toxic peroxynitrite (ONOO(-)) is formed solely in the presence of superoxide anion (O2 (-)). Neopterin and kynurenine to tryptophan ratio (Kyn/Trp), as an estimate of IDO enzyme activity, are robust markers of immune activation in vitro and in vivo. Both these diagnostic parameters are able to predict cardiovascular and overall mortality in patients at risk. Likewise, a significant association exists between increase of neopterin concentrations and Kyn/Trp ratio values and the lowering of plasma levels of vitamin-C, -E and -B. Vitamin-B deficiency is usually accompanied by increased plasma homoycsteine. Additional determination of NO metabolites, BH4 and plasma antioxidants in patients with CVD and related clinical settings can be helpful to improve the understanding of redox-regulation in health and disease and might provide a rationale for potential antioxidant therapies in CVD.

Background: Dysbiosis of intestinal microbiota in the elderly can cause a leaky gut, which may result in silent systemic inflammation and promote neuroinflammation - a relevant pathomechanism in the early course of Alzheimer’s disease. Objective: The rebalancing of the microbiome could benefically impact on gut inflammation and immune activation. Methods: In this study, routine laboratory tests in twenty outpatients (9 females, 11 males, aged 76.7 ± 9.6 years) with Alzheimer’s disease were investigated. The mean Mini Mental State Examination score was 18.5 ± 7.7. Biomarkers of immune activation – serum neopterin and tryptophan breakdown - as well as gut inflammation markers and microbiota composition in fecal specimens were analyzed in 18 patients before and after probiotic supplementation for 4 weeks. Results: After treatment a decline of fecal zonulin concentrations and an increase in Faecalibacterium prausnitzii compared to baseline were observed. At the same time, serum kynurenine concentrations increased (p <0.05). Delta values (before - after) of neopterin and the kynurenine to tryptophan ratios (Kyn/Trp) correlated significantly (p <0.05). Conclusion: Results show that the supplementation of Alzheimer’s disease patients with a multispecies probiotic influences gut bacteria composition as well as tryptophan metabolism in serum. The correlation between Kyn/Trp and neopterin concentrations points to the activation of macrophages and/or dendritic cells. Further studies are warranted to dissect the potential consequences of Probiotic supplementation in the course of Alzheimer’s disease.

HIV-1 invades the central nervous system (CNS) in the context of acute infection, persists thereafter in the absence of treatment, and leads to chronic intrathecal immunoactivation that can be measured by the macrophage activation marker, neopterin, in cerebrospinal fluid (CSF). In this review we describe our experience with CSF neopterin measurements in 382 untreated HIV-infected patients across the spectrum of immunosuppression and HIV-related neurological diseases, in 73 untreated AIDS patients with opportunistic CNS infections, and in 233 treated patients. In untreated patients, CSF neopterin concentrations are almost always elevated and increase progressively as immunosuppression worsens and blood CD4 cell counts fall. However, patients with HIV dementia exhibit particularly high CSF neopterin concentrations, above those of patients without neurological disease, though patients with CNS opportunistic infections, including CMV encephalitis and cryptococcal meningitis, also exhibit high levels of CSF neopterin. Combination antiretroviral therapy, with its potent effect on CNS HIV infection and CSF HIV RNA, mitigates both intrathecal immunoactivation and lowers CSF neopterin. However, despite suppression of plasma and CSF HIV RNA to below the detection limits of clinical assays (<50 copies HIV RNA/mL), CSF neopterin often remains mildly elevated, indicating persistent low-level intrathecal immune activation and raising the important questions of whether this elevation is driven by continued CNS infection and whether it causes continued indolent CNS injury. Although nonspecific, CSF neopterin can serve as a useful biomarker in the diagnosis of HIV dementia in the setting of confounding conditions, in monitoring the CNS inflammatory effects of antiretroviral treatment, and give valuable information to the cause of ongoing brain injury.

Reactive oxygen and nitrogen species (ROS-RNS) and other redox active molecules fulfill key functions in immunity. Beside the initiation of cytocidal reactions within the pathogen defense strategy, redox reactions trigger and shape the immune response and are further involved in termination and initialization of cellular restorative processes. Regulatory mechanisms provided by redox-activated signaling events guarantee the correct spatial and temporal proceeding of immunological processes, and continued imbalances in redox homeostasis lead to crucial failures of control mechanisms, thus promoting the development of pathological conditions. Interferon-gamma is the most potent inducer of ROS-RNS formation in target cells like macrophages. Immune-regulatory pathways such as tryptophan breakdown via indoleamine 2,3-dioxygenase and neopterin production by GTP-cyclohydrolase-I are initiated during T helper cell type 1 (Th1-type) immune response concomitant to the production of ROS-RNS by immunocompetent cells. Therefore, increased neopterin production and tryptophan breakdown is representative of an activated cellular immune system and can be used for the in vivo and in vitro monitoring of oxidative stress. In parallel, the activation of the redox-sensitive transcription factor nuclear factor-kappa B is a central element in immunity leading to cell type and stimulus-specific expression of responsive genes. Furthermore, T cell activation and proliferation are strongly dependent on the redox potential of the extracellular microenvironment. T cell commitment to Th1, Th2, regulatory T cell, and other phenotypes appears to crucially depend on the activation of redox-sensitive signaling cascades, where oxidative conditions support Th1 development while 'antioxidative' stress leads to a shift to allergic Th2-type immune responses.