Neopterin Concentrations In Body Fluids Research Articles

Neopterin as a potential biomarker in neuropsychiatry

The importance of finding predictors or biomarkers of neuropsychiatric pathology, as well as methods of its prevention, treatment and early diagnosis is beyond question. The level of neopterin in body fluids is one of the possible biomarkers. Increased levels of neopterin in biological fluids (e.g., serum, cerebrospinal fluid or urine) are closely associated with various diseases associated with cellular immune response. The data presented in the review indicate the relevance of the study of neopterin concentrations in body fluids in patients with mental illness for the development of diagnostic and prognostic tests or as a pharmacodynamic marker of drug action.

Interferon Crevicular Fluid Profile and Correlation with Periodontal Disease and Wound Healing: A Systemic Review of Recent Data.

The purpose of the present study was to see if there is a correlation between the effect of interferons in crevicular fluid and periodontitis, evaluating literature. Interferon gamma (IFN-γ) is an immunoregulatory cytokine that, when activated by its receptor, plays an important role in the activation of inflammatory processes, which are the basis of periodontal disease. Stem cells in the periodontal ligament, like stem cells from other tissues, have immunomodulatory capacity and are regulated by some cytokines such as interferon-γ (IFN-γ). The study searched MEDLINE databases from 2008 to 2018. Clinical human in vitro and in vivo studies had reported a correlation between interferon and periodontitis. The initial search obtained 359 citations. After screening and determination of eligibility, nine articles were included in the review. Significant (p < 0.05) increases in IFN-γ gene expression were observed in some studies in the chronic periodontitis group. In some cases it was suggested that molecular mechanisms underlie the possible roles of IFN-γ in the inhibition of osteoclastogenesis. Neopterin belongs to the chemical group known as pteridines. It is synthesised by human macrophages upon stimulation with the interferon-gamma. Neopterin concentrations in body fluids are high in the case of infections, immune diseases or graft rejection. In the chronic periodontitis group, this marker is significantly higher. These studies underlined the clinical evidence between interferons in the crevicular fluid and inflammatory response of periodontitis. However, there is a lack of scientific evidence that could lead the clinician to an interferon-modulated therapy because of periodontitis.

The Role of Neopterin in Atherogenesis and Cardiovascular Risk Assessment

Neopterin is produced by human and primate monocyte/macrophages upon activation by pro-inflammatory stimuli like Th1-type cytokine interferon-gamma. Neopterin has pro-oxidative properties, which have been demonstrated in vitro in physicochemical and cell culture studies and also in in vivo experiments, e.g. the Langendorff perfusion model of rat hearts. In the past several years, the measurement of neopterin concentrations in body fluids including serum, urine and cerebrospinal fluid has revealed a potential role of this molecule in the prediction of long-term prognosis in both patients with cancer and those with systemic infections such as HIV-1 infection. Moreover, elevated neopterin concentrations have been reported in patients with coronary disease compared to controls and in recent years it has become apparent that increased neopterin concentrations are an independent marker for cardiovascular disease and a predictor of future cardiovascular events in patients with coronary artery disease. Current data suggest that the diagnostic performance of neopterin testing is comparable to that of well established biomarkers such as C-reactive protein and cholesterol plasma levels. The present article reviews the role of neopterin in the pathogenesis of cardiovascular disease and as a marker of coronary artery disease progression.

Neopterin, a prognostic marker in human malignancies

Increased neopterin concentrations are established in patients with an activated cellular (= Th1-type) immune response which includes allograft rejection, viral infection and autoimmune disorders as well as various malignant tumors. In patients with several types of cancer, neopterin concentrations in body fluids like urine, serum/plasma or ascites parallel the course of the disease, and a higher neopterin concentration in patients is an independent predictor of a shorter survival period. Neopterin is released in large amounts from human monocyte-derived macrophages and dendritic cells preferentially following stimulation with the pro-inflammatory cytokine interferon-γ, thus reflecting the immune activation status. Therefore, not only as a laboratory diagnostic tool, the measurement of neopterin concentrations allows studying the immunological network and its interaction with the pathogenesis of tumor development. It contributes to a better understanding how immune activation is involved in the development of tumor-induced immune escape and tumor antigen specific tolerance.

Neopterin Concentration in Serum and Chosen Markers of Inflammatory Process in Children with Acute Diarrhea Caused by Rotavirus or Salmonella

Abstract Neopterin concentrations reflect the activation of the cellular immune system. Neopterin is released by macrophages stimulated by interferon-γ (IFN-γ), which is produced by activated T lymphocytes. Raised neopterin concentrations in body fluids are found in various disorders, e.g. viral infections (AIDS, cytomegalovirus, hepatitis), intracellular bacteria infections (Mycobacteruim tuberculosis, Mycobacterium leprae), autoimmune disorders and malignancy. Neopterin concentrations are low or not significantly increased in bacterial infections, with exception of infections with intracellular bacteria. The aim of this study was to evaluate the usefulness of neopterin in the differential diagnosis of viral (Rotavirus) and bacterial (Salmonella) origin of diarrhoea. 129 children, aged 1 month -14 years, who were hospitalized for rotavirus gastroenteritis or salmonellosis were included into the study. Rotavirus was identified by latex test and Salmonella by stool cultures and the children were divided into 2 groups: with rotavirus infection (group I (R) - 71 children) and with salmonellosis (group II (S) - 58 children). In this study it was analyzed: disease duration before hospitalization, the general condition of a child on admission, body temperature, the number of loose and bloody stools and the number of vomits. On their admission to hospital, erythrocyte sedimentation rate (ESR), leukocyte count, and in the sera of all children C-reactive protein (CRP) and neopterin concentrations were determined. The serum neopterin concentrations were analyzed by ELISA. Mean neopterin concentration was 35.0 nmol/L in patients with salmonellosis, and it was significantly higher than in patients with rotavirus infection (22.0 nmol/L; p &lt;0,001). The neopterin level that reliably discriminated between rotavirus diarrhoea and salmonellosis was 22 nmol/L: neopterin concentration higher than 22 nmol/L suggested diarrhoea caused by Salmonella, and neopterin concentrations equal or lower than 22 nmol/L suggested a rotavirus diarrhoea The combination of the results of two (neopterin &gt;10 nmol/L and CRP &gt;10mg/L) or three (neopterin &gt;10nmol/L, ESR &gt;10mm/h, CRP &gt;10mg/L) serum markers helps to achieve better results. The best specificity (100%) was obtained for CRP concentration &gt;15mg/L and neopterin concentration &gt;37 nmol/L. We conclude that serum neopterin concentrations in children with acute diarrhea are not a laboratory indicator diversifying salmonellosis and rotavirus infection, because it increases in both infections. However higher concentrations indicate salmonellosis.

Neopterin to Monitor Clinical Pathologies Involving Interferon-γ Production

Abstract 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.

Monocyte-derived dendritic cells release neopterin

Increased neopterin concentrations in body fluids are found in diseases associated with activated, cell-mediated immunity including infections, autoimmune diseases, and certain malignancies. Monocytes/macrophages are known to secrete large amounts of neopterin upon stimulation with interferon-gamma (IFN-gamma). Ontogenetically, the major part of dendritic cells (DC) belongs to the myeloid lineage. Therefore, we investigated whether cultured monocyte-derived DC can elaborate neopterin. Cells were treated with cytokines in the presence or absence of monocyte-conditioned medium as a maturation stimulus. DC secreted an average 3.5 nmol/l neopterin. In response to IFN-gamma, cells significantly increased their output of neopterin. In distinction to monocytes/macrophages, neopterin production in DC was highly sensitive to IFN-alpha and IFN-beta. Further, lipopolysaccharides (LPS) enhanced neopterin synthesis, whereas tumor necrosis factor alpha, interleukin (IL)-1beta, IL-2, IL-10, and IL-18 were ineffective. Simultaneously, tryptophan degradation by induction of indoleamine (2,3)-dioxygenase (IDO) was tested in stimulated cells. Our results showed that IFN-gamma as well as LPS are inducers of IDO in DC.

Neopterin production, tryptophan degradation, and mental depression—What is the link?

The cytokine interferon-γ stimulates human monocytes/macrophages to release large amounts of neopterin. Increased neopterin concentrations in body fluids of patients are observed during diseases with activated cellular (=TH1-type) immune response such as allograft rejection, virus infections, autoimmune disorders, or malignant tumors but also in neurodegenerative diseases or during pregnancy. In various cells interferon-γ induces indoleamine 2,3-dioxygenase (IDO) which degrades tryptophan via the kynurenine pathway. Therefore like increased neopterin formation, enhanced tryptophan degradation is observed in diseases concomitant with cellular immune activation. Disturbed metabolism of tryptophan affects biosynthesis of neurotransmitter 5-hydroxytryptamine (serotonin), and it appears to be associated with an increased susceptibility for depression. In fact, enhanced neopterin concentrations together with increased degradation of tryptophan and low serum levels of tryptophan correlate with neuropsychiatric abnormalities like cognitive decline and depressive symptoms especially in long-lasting and chronic diseases. Activation of IDO could represent an important link between the immunological network and the pathogenesis of depression.

Neopterin as a marker for immune system activation.

Increased amounts of neopterin are produced by human monocytes/macrophages upon stimulation with the cytokine interferon-y. Therefore, measurement of neopterin concentrations in body fluids like serum, cerebrospinal fluid or urine provides information about activation of T helper cell 1 derived cellular immune activation. 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 neurological and in cardiovascular diseases cellular immune activation indicated by increased neopterin production, is found. Major diagnostic applications of neopterin measurements are, e.g. monitoring of allograft recipients to recognize immunological complications early. Neopterin production provides prognostic information in patients with malignant tumor diseases and in HIV-infected individuals, high levels being associated with poorer survival expectations. Neopterin measurements are also useful to monitor therapy in patients with autoimmune disorders and in individuals with HIV infection. Screening of neopterin concentrations in blood donations allows to detect acute infections in a non-specific way and improves safety of blood transfusions. As high neopterin production is associated with increased production of reactive oxygen species and with low serum concentrations of antioxidants like alpha-tocopherol, neopterin can also be regarded as a marker of reactive oxygen species formed by the activated cellular immune system. Therefore, by neopterin measurements not only the extent of cellular immune activation but also the extent of oxidative stress can be estimated.

Correlation of body mass index with urinary neopterin in individuals infected with human immunodeficiency virus.

We assessed correlations between body mass index and plasma lipids, immune activation markers and the CD4+ T-cell count. The subjects of this cross-sectional study were randomly selected and comprised all those who attended the AIDS Out-Patient Clinic at the University Hospital in Innsbruck in March and April 1992. Patients with signs and symptoms of acute bacterial and secondary opportunistic infections were excluded. We investigated 63 individuals with HIV infection of whom 35 were asymptomatic, 8 had oral candidiasis, 4 had constitutional signs and symptoms and 16 had AIDS, for an association among body mass index, urinary neopterin, soluble tumor necrosis factor receptors (sTNFRs), plasma lipids, and the numbers of CD4+ T cells. The body mass index correlated inversely with urinary neopterin (rs = -0.42, p = 0.0009) and weakly with the numbers of CD4+ T cells (rs = 0.29, p = 0.02) but not with plasma lipids, sTNFRs and beta 2-microglobulin. The results show that body mass index correlates with immune activation. The data suggest that endogenous formation of interferon-gamma may be an important mediator of wasting in HIV infection, since this cytokine is responsible for the observed elevation of neopterin concentrations in body fluids.

Immune activation markers to predict AIDS and survival in HIV-1 seropositives

Neopterin concentrations in body fluids of HIV-1 seropositives provide predictive information. In 1986, we examined serum and urine neopterin concentrations in 29 HIV-1 seropositives. Serum levels of soluble IL-2 receptor (sIL2R), soluble CD8 (sCD8), tumour necrosis factor alpha (TNF-alpha) and circulating immune complexes (CIC) were retrospectively analysed in 1989. All individuals had increased serum and urine neopterin, sIL2R and CIC concentrations, 27/29 had increased sCD8 concentrations, whereas all had normal TNF-alpha levels. During a 3-year follow-up, high urine and serum neopterin concentrations were significantly associated with progression to AIDS and with the occurrence of AIDS-associated death. Both neopterin variables were of similar predictive value (p less than 0.001, generalized Wilcoxon test). sIL2R concentrations were of borderline significance in predicting the onset of AIDS (p = 0.05). All other parameters lacked predictive information in our study. We conclude, that chronic immune activation is detectable in almost all HIV-1 seropositives. Chronic immune activation may be associated with HIV-1 replication and may contribute to the immunopathology of HIV-1 infection.

Neopterin and viral infections: diagnostic potential in virally induced liver disease

d-erythro-neopterin is excreted in high amounts from human monocytes/macrophages responding to stimulation with gamma interferon. In vivo, the determination of neopterin offers a convenient possibility for monitoring the activation state of the cell-mediated immune system. Neopterin concentrations in body fluids also are raised with high sensitivity in viral diseases, irrespective of the specific nature of the virus. Thus, neopterin concentrations also are raised in viral diseases the causative agent of which has not yet been characterized such as non-A, non-B hepatitis. Determination of neopterin concentrations is easily accomplished by Chromatographic or immunological techniques. Clinical studies showing the behaviour of neopterin levels in viral diseases are reviewed with special emphasis laid on the behaviour of neopterin concentrations in body fluids during virus-induced liver diseases, particularly non-A, non-B hepatitis. The possibilities offered by this marker to reduce the risk of disease transmission via transfusion of blood or blood components are discussed.