Chronic Immune Cell Activation Research Articles

Integrated multi-omics analysis reveals molecular changes associated with chronic lipid accumulation following contusive spinal cord injury

Functional and pathological recovery after spinal cord injury (SCI) is often incomplete due to the limited regenerative capacity of the central nervous system (CNS), which is further impaired by several mechanisms that sustain tissue damage. Among these, the chronic activation of immune cells can cause a persistent state of local CNS inflammation and damage. However, the mechanisms that sustain this persistent maladaptive immune response in SCI have not been fully clarified yet.In this study, we integrated histological analyses with proteomic, lipidomic, transcriptomic, and epitranscriptomic approaches to study the pathological and molecular alterations that develop in a mouse model of cervical spinal cord hemicontusion.We found significant pathological alterations of the lesion rim with myelin damage and axonal loss that persisted throughout the late chronic phase of SCI. This was coupled by a progressive lipid accumulation in myeloid cells, including resident microglia and infiltrating monocyte-derived macrophages. At tissue level, we found significant changes of proteins indicative of glycolytic, tricarboxylic acid cycle (TCA), and fatty acid metabolic pathways with an accumulation of triacylglycerides with C16:0 fatty acyl chains in chronic SCI. Following transcriptomic, proteomic, and epitranscriptomic studies identified an increase of cholesterol and m6A methylation in lipid-droplet-accumulating myeloid cells as a core feature of chronic SCI.By characterizing the multiple metabolic pathways altered in SCI, our work highlights a key role of lipid metabolism in the chronic response of the immune and central nervous system to damage.

On the wake of metformin: Do anti-diabetic SGLT2 inhibitors exert anti-aging effects?

Here we propose that SGLT2 inhibitors (SGLT2i), a class of drugs primarily used to treat type 2 diabetes, could also be repositioned as anti-aging senomorphic drugs (agents that prevent the extrinsic harmful effects of senescent cells). As observed for metformin, another anti-diabetic drug with established anti-aging potential, increasing evidence suggests that SGLT2i can modulate some relevant pathways associated with the aging process, such as free radical production, cellular energy regulation through AMP-activated protein kinase (AMPK), autophagy, and the activation of nuclear factor (NF)-kB/inflammasome. Some interesting pro-healthy effects were also observed on human microbiota. All these mechanisms converge on fueling a systemic proinflammatory condition called inflammaging, now recognized as the main risk factor for accelerated aging and increased risk of age-related disease development and progression. Inflammaging can be worsened by cellular senescence and immunosenescence, which contributes to the increased burden of senescent cells during aging, perpetuating the proinflammatory condition. Interestingly, increasing evidence suggested the direct effects of SGLT-2i against senescent cells, chronic activation of immune cells, and metabolic alterations induced by overnutrition (meta-inflammation). In this framework, we analyzed and discussed the multifaceted impact of SGLT2i, compared with metformin effects, as a potential anti-aging drug beyond diabetes management. Despite promising results in experimental studies, rigorous investigations with well-designed cellular and clinical investigations will need to validate SGLT2 inhibitors' anti-aging effects.

A Fenton-like cation can improve arsenic trioxide treatment of sclerodermatous chronic Graft-versus-Host Disease in mice.

Graft-versus Host Disease (GvHD) is a major complication of hematopoietic stem cell transplant. GvHD is characterized by the chronic activation of immune cells leading to the development of systemic inflammation, autoimmunity, fibrosis and eventually death. Arsenic trioxide (ATO) is a therapeutic agent under clinical trial for the treatment of patients with systemic lupus erythematosus (SLE) and chronic GvHD (cGvHD). This therapy is admittedly rather safe although adverse effects can occur and may necessitate short interruptions of the treatment. The aim of this study was to combine ATO with a divalent cation, to generate a Fenton or Fenton-like reaction in order to potentiate the deletion of activated immune cells through the reactive oxygen species (ROS)-mediated effects of ATO in a mouse model, and thereby enabling the use of lower and safer ATO concentrations to treat patients with cGvHD. In vitro, among the various combinations of divalent cations tested, we observed that the combination of ATO and CuCl2 (copper chloride) induced a high level of oxidative stress in HL-60 and A20 cells. In addition, this co-treatment also decreased the proliferation of CD4+ T lymphocytes during a mixed lymphocyte reaction (MLR). In vivo, in a cGvHD mouse model, daily injections of ATO 2.5 µg/g + CuCl2 0.5 µg/g induce a decrease in lymphocyte activation and fibrosis that was equivalent to that induced by ATO 5 µg/g. Our results show that the addition of CuCl2 improved the effects of ATO and significantly limited the development of the disease. This co-treatment could be a real benefit in human patients to substantially decrease the known ATO side effects and optimize ATO treatment in pathologies characterized by activated cells sensitive to an increase in oxidative stress.

Periodontitis and Gestational Diabetes Mellitus: A Potential Inflammatory Vicious Cycle.

Periodontitis is a chronic inflammatory immune disease associated with a dysbiotic state, influenced by keystone bacterial species responsible for disrupting the periodontal tissue homeostasis. Furthermore, the severity of periodontitis is determined by the interaction between the immune cell response in front of periodontitis-associated species, which leads to the destruction of supporting periodontal tissues and tooth loss in a susceptible host. The persistent bacterial challenge induces modifications in the permeability and ulceration of the sulcular epithelium, which facilitates the systemic translocation of periodontitis-associated bacteria into distant tissues and organs. This stimulates the secretion of pro-inflammatory molecules and a chronic activation of immune cells, contributing to a systemic pro-inflammatory status that has been linked with a higher risk of several systemic diseases, such as type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM). Although periodontitis and GDM share the common feature of systemic inflammation, the molecular mechanistic link of this association has not been completely clarified. This review aims to examine the potential biological mechanisms involved in the association between periodontitis and GDM, highlighting the contribution of both diseases to systemic inflammation and the role of new molecular participants, such as extracellular vesicles and non-coding RNAs, which could act as novel molecular intercellular linkers between periodontal and placental tissues.

Immune cells in repair of the infarcted myocardium.

The immune system plays a critical role in both repair and remodeling of the infarcted myocardium. Danger signals released by dying cardiomyocytes mobilize, recruit, and activate immune cells, triggering an inflammatory reaction. CXC chemokines containing the ELR motif attract neutrophils, while CC chemokines mediate recruitment of mononuclear cell subpopulations, contributing to clearance of the infarct from dead cells and matrix debris. Immune cell subsets also participate in suppression and containment of the postinfarction inflammatory response by secreting anti-inflammatory mediators, such as IL-10 and TGF-β. As proinflammatory signaling is suppressed, macrophage subpopulations, mast cells and lymphocytes, activate fibrogenic and angiogenic responses, contributing to scar formation. In the viable remodeling myocardium, chronic activation of immune cells may promote fibrosis and hypertrophy. This review discusses the role of immune cells in repair and remodeling of the infarcted myocardium. Understanding the role of immune cells in myocardial infarction is critical for the development of therapeutic strategies aimed at protecting the infarcted heart from adverse remodeling. Moreover, modulation of immune cell phenotype may be required in order to achieve the visionary goal of myocardial regeneration.

Ageing and obesity similarly impair antibody responses

Ageing is characterized by increased low-grade chronic inflammation, which is a significant risk factor for morbidity and mortality of elderly individuals. Similar to ageing, obesity is considered to be an inflammatory predisposition associated with chronic activation of immune cells and consequent local and systemic inflammation. Both ageing and obesity are characterized by reduced innate and adaptive immune responses. This review focuses on B cells, how they may contribute, at least locally, to low-grade chronic inflammation in ageing and obesity and on the mechanisms involved.

Cancer, cognition and cardiac disease: The many complications of HIV

Nurse PrescribingVol. 13, No. 11 NewsCancer, cognition and cardiac disease: The many complications of HIVAysha MendesAysha MendesSearch for more papers by this authorAysha MendesPublished Online:14 Nov 2015https://doi.org/10.12968/npre.2015.13.11.526AboutSectionsView articleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareShare onFacebookTwitterLinked InEmail View article References American Diabetes Association (2013) HIV/AIDS and Diabetes. www.diabetes.org/living-with-diabetes/complications/related-conditions/hivaids-and-diabetes.html (accessed 14 October 2015) Google ScholarAVERT (2014) HIV Treatment in the UK. www.avert.org/hiv-treatment-uk.htm (accessed 14 October 2015) Google ScholarBC Centre for Excellence in HIV/AIDS (2015) Women living with HIV face higher rates of cancer diagnosis: study [press release]. BC-CfE, Vancouver Google ScholarBest C, Struthers H, Laciny E et al. (2015) Sitagliptin reduces inflammation and chronic immune cell activation in HIV+ adults with impaired glucose tolerance. J Clin Endocrinol Metab 100(7): 2621–9. doi: https://doi.org/10.1210/jc.2015-1531 Crossref, Google ScholarHemkens LG, Bucher HC (2014) HIV infection and cardiovascular disease. Eur Heart J 35(21): 1373-81. doi: https://doi.org/10.1093/eurheartj/eht528 Crossref, Google ScholarNAM Aidsmap (2015) Memory problems. www.aidsmap.com/Memory-problems/page/1733071/ (accessed 14 October 2015) Google ScholarNational Institute of Mental Health (2015) HIV-associated neurocognitive disorders. www.nimh.nih.gov/health/topics/hiv-aids/hiv-associated-neurocognitive-disorders.shtml (accessed 14 October 2015) Google ScholarNHS Choices (2015) HIV and AIDS. www.nhs.uk/Conditions/HIV/Pages/Introduction.aspx (accessed 14 October 2015) Google ScholarSalters KA, Cescon A, Zhang W et al. (2015) Cancer incidence among HIV-positive women in British Columbia: Heightened risk of virus-related malignancies. HIV Med doi: https://doi.org/10.1111/hiv.12290 [Epub ahead of print] Google ScholarUS Department of Health and Human Services (2011) Cardiovascular Health. www.aids.gov/hiv-aids-basics/staying-healthy-with-hiv-aids/potential-related-health-problems/cardiovascular-health/ (accessed 14 October 2015) Google Scholar FiguresReferencesRelatedDetailsCited byContending with the chronicity of HIV and associated comorbidities9 November 2015 | British Journal of Community Nursing, Vol. 20, No. 11 2 November 2015Volume 13Issue 11ISSN (print): 1479-9189ISSN (online): 2052-2924 Metrics History Published online 14 November 2015 Published in print 2 November 2015 Information© MA Healthcare LimitedPDF download

Contending with the chronicity of HIV and associated comorbidities

British Journal of Community NursingVol. 20, No. 11 Long-Term ConditionsContending with the chronicity of HIV and associated comorbiditiesAysha MendesAysha MendesSearch for more papers by this authorAysha MendesPublished Online:9 Nov 2015https://doi.org/10.12968/bjcn.2015.20.11.568AboutSectionsView articleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareShare onFacebookTwitterLinked InEmail View article References American Diabetes Association (2015) HIV/AIDS and Diabetes. http://bit.ly/1GDsIPG (accessed 26 October 2015) Google ScholarAVERT (2014) HIV Treatment in the UK. http://tinyurl.com/qfkjutu (accessed 26 October 2015) Google ScholarBest C, Struthers H, Laciny E, Royal M, Reeds DN, Yarasheski KE (2015) Sitagliptin reduces inflammation and chronic immune cell activation in HIV+ adults with impaired glucose tolerance. J Clin Endocrinol Metab 100(7): 2621–9. doi:https://doi.org/10.1210/jc.2015-1531 Crossref, Medline, Google ScholarLewis R (2011) Stamping out stigma in HIV. Nurs Times 107(11): 16–7 Medline, Google ScholarMendes A (2015) Cancer, cognition and cardiac disease: The many complications of HIV. Nurse Prescribing 13(11) (in press) Link, Google ScholarNational Institute of Mental Health (2015) HIV associated neurocognitive disorders. http://tinyurl.com/noq7wp5 (accessed 26 October 2015) Google ScholarSalters KA, Cescon A, Zhang W et al. (2015) Cancer incidence among HIV-positive women in British Columbia, Canada: heightened risk of virus-related malignancies. HIV Med. doi: https://doi.org/10.1111/hiv.12290 Medline, Google ScholarUS Department of Health & Human Services (2011) Cardiovascular Health. http://tinyurl.com/pg7khb9 (accessed 26 October 2015) Google Scholar FiguresReferencesRelatedDetails 2 November 2015Volume 20Issue 11ISSN (print): 1462-4753ISSN (online): 2052-2215 Metrics History Published online 9 November 2015 Published in print 2 November 2015 Information© MA Healthcare LimitedPDF download

T Lymphocyte Prestimulation Impairs in a Time-Dependent Manner the Capacity of Adipose Mesenchymal Stem Cells to Inhibit Proliferation: Role of Interferon γ, Poly I:C, and Tryptophan Metabolism in Restoring Adipose Mesenchymal Stem Cell Inhibitory Effect.

The immunomodulatory properties of mesenchymal stem/stromal cells (MSCs) make them an attractive therapeutic tool to treat chronic inflammatory diseases, such as rheumatoid arthritis or Crohn's disease. These indications are characterized by a chronic activation of immune cells that perpetuates the disease. In vitro, when adipose mesenchymal stem cells (ASCs) are cultured with T lymphocytes at the time of stimulation, their proliferation is inhibited. However, these experimental settings do not necessarily fit with what ASCs will face in inflammatory conditions in vivo, where ASCs will likely encounter and interact with already activated immune cells which might affect their immunomodulatory capacity. In most in vitro studies, MSCs have been cultured with peripheral blood mononuclear cells at the time of lymphocyte stimulation and information about the interaction between MSCs and prestimulated lymphocytes in vitro is scarce. Therefore, a better understanding of the capacity of MSCs to modulate the responses of preactivated immune cells is needed. In this study we focused on the effects of ASCs on prestimulated lymphocytes and systematically investigated the potential mechanisms involved. We report that prestimulation of T lymphocytes 48 h before the coculture with ASCs impairs the capacity of ASCs to inhibit proliferation. Preactivation of ASCs with interferon γ or the toll-like receptor ligand Poly I:C, but not other stimuli tested, enhanced the ability to inhibit the proliferation of 48 h-stimulated T lymphocytes. The inhibitory effect of ASCs was shown to be time dependent and mediated through the actual magnitude of tryptophan degradation by indoleamine 2,3-dioxygenase.

Sitagliptin Reduces Inflammation and Chronic Immune Cell Activation in HIV+ Adults With Impaired Glucose Tolerance.

HIV infection is associated with a greater risk for fasting hyperinsulinemia, impaired glucose tolerance, and higher incidence rates for vascular disease, myocardial infarction, or stroke despite effective combination antiretroviral therapy (cART). The underlying mechanism(s) may involve chronic low-grade systemic inflammation and immune cell activation. Dipeptidyl peptidase-4 inhibitors (sitagliptin) improve glucose tolerance and may possess immunomodulatory effects because leukocyte CD26 cell surface receptors express dipeptidyl peptidase-4 activity. Sitagliptin will reduce inflammatory and immune cell activation markers known to be elevated in cART-treated HIV-infected (HIV+) adults with impaired glucose tolerance. This was designed as a prospective, randomized, placebo-controlled, double-blind trial of sitagliptin in HIV+ adults. The setting was an academic medical center. Patients were cART-treated HIV+ men and women (n = 36) with stable HIV disease and impaired glucose tolerance. Interventions included sitagliptin 100 mg/d or placebo for 8 weeks. At baseline and week 8, plasma high-sensitivity C-reactive protein and C-X-C motif chemokine 10 concentrations (ELISA), oral glucose tolerance, and abdominal sc adipose mRNA expression for M1 macrophage markers (monocyte chemotactic protein-1, EGF-like module-containing, mucin-like hormone receptor 1). Sitagliptin reduced glucose area under the curve (P = .002) and improved oral glucose insulin sensitivity index (P = .04) more than placebo. Sitagliptin reduced plasma high-sensitivity C-reactive protein and C-X-C motif chemokine 10 levels more than placebo (P < .009). Adipose tissue monocyte chemotactic protein-1 mRNA abundance declined significantly more (P = .01), and adipose EGF-like module-containing, mucin-like hormone receptor 1 mRNA expression tended to decline more (P = .19) in sitagliptin than placebo. Sitagliptin had beneficial systemic and adipose anti-inflammatory effects in cART-treated HIV+ adults with impaired glucose tolerance. Large-scale, long-term studies should determine whether sitagliptin reduces cardiovascular risk and events in HIV+ adults.

Induced keratinocyte hyper-proliferation in α2β1 integrin transgenic mice results in systemic immune cell activation

α2β1 integrins are normally confined to the proliferating basal layers of the epidermis. However, during wound healing and in psoriasis, these integrins are expressed on keratinocytes in suprabasal layers correlating with a less differentiated phenotype. Transgenic mice expressing α2β1 integrins under the involucrine promoter have previously been demonstrated, to various degrees, spontaneously develop a skin disorder resembling psoriasis. Herein, we show that a mild epidermal wounding induces a uniform acanthosis together with an influx of immune cells. The disease initiates as a normal wound healing process and is completely restored in wildtype mice by day 14. However, in the integrin transgenic mice a chronic inflammation develops, a process that can be compared to the Koebner phenomenon in psoriatic patients. In this study, we have followed the integrin transgenic mice for five weeks, where substantial keratinocyte hyper-proliferation, inflammatory infiltration and high cytokine levels within the skin can still be observed. In addition, draining lymph nodes were dramatically increased in size and contained highly activated T cells, as well as APCs secreting large amounts of pro-inflammatory cytokines. Furthermore, the systemic immune response was affected with increased spleen size, elevated cytokine levels in the serum and altered lymphocyte trafficking patterns, very much resembling what is seen in psoriasis patients. Finally, CD4 + T cell depletion was not able to affect the onset or progression of skin inflammation. This suggests that altered keratinocyte differentiation and proliferation can drive a skin inflammation and cause chronic immune cell activation both at a local and systemic level.

Quality of life and cost-effectiveness of anti-HCV therapy in HIV-infected patients

Quality of life studies in chronic hepatitis C using specific questionnaires have been performed in mono-infected patients; however, these studies have just begun in HIV-HCV co-infected patients. The questionnaires used in mono-infected patients are not well adapted for co-infected patients and need to be redesigned. Typically, co-infected patients have multiple symptoms that may be attributable to HIV, to HCV, to a combination of both diseases or even to side effects related to drug therapy. These patients usually need substitutive therapy to manage side effects related to HCV therapy, particularly anaemia, leukopenia and depression. There are no cost-effectiveness studies published on the current HCV standard therapy with pegylated interferon and ribavirin. However, there is some research on the old standard interferon and ribavirin, which shows that HCV therapy is cost-effective. Cost-effectiveness studies in co-infected patients will have to take into account variables that do not affect mono-infected patients, such as the different levels of CD4, the increase in the fibrosis progression rate and the use of other expensive drugs for the management of side effects. Currently, the literature does not provide adequate information on the effect of HCV infection on the quality of life of HIV-HCV co-infected patients or the most cost-effective HCV therapy.

672. The Effect of Serine Protease Inhibitor 6 (SPI-6) Gene Transfer on a Mouse Model of Sjögren's Syndrome

Top of pageAbstract Sj|[ouml]|gren's syndrome (SS) is an autoimmune disease characterized by a focal and diffuse lymphoid cell infiltration into the salivary and lacrimal glands. This chronic immune cell activation leads to reduced secretory function with symptoms of xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). It has been hypothesized that these sequelae are due to apoptosis of the exocrine epithelial cells. Apoptosis can be induced by cytotoxic T-lymphocytes (CTLs), which contain the enzyme Granzyme B (GrB) in cytoplasmic granules. GrB initiates a caspase-independent apoptosis pathway and is inhibited by serine proteinase inhibitor 6 (SPI-6) in the mouse. In this study, we evaluated the effect of transgenic SPI-6 produced in salivary glands after gene transfer to non-obese diabetic (NOD) mice, which develop exocrine gland infiltrates and are a commonly used disease model for SS. We constructed two serotype 2 rAAV vectors, rAAVSPI-6 and rAAVLacZ (encoding |[beta]|-galactosidase; vector control) using the CMV promoter. rAAVs (1010 particles/gland) were administered directly into both submandibular glands of 8-week old female NOD mice (n=8) via retroductal delivery. Salivary flow rates were determined before vector delivery and at time of sacrifice (16-weeks old). Serum glucose levels and weight were measured weekly and diabetic mice (serum glucose|[ge]|400 mg/dL) were treated with insulin. After sacrifice, submandibular glands were harvested and analyzed for inflammatory infiltrates (focus scores), as well as SPI-6 expression and cytokine profile [mouse interleukins (IL)-2, 4, 6, 12, 18, interferon (IFN)-|[gamma]|, tumor necrosis factor-|[alpha]| and RANTES] in aqueous gland extracts. At 8 weeks, salivary flow rates were not different between mice assigned to the rAAVSPI-6 and rAAVLacZ groups. In contrast, at 16 weeks flow rates were significantly higher in the rAAVSPI-6-treated mice (p=0.018). Submandibular gland IL-10 levels were significantly increased (p=0.009), while IFN-|[gamma]| levels were significantly decreased (p=0.029), in the rAAVSPI-6 mice compared to the rAAVLacZ group. There were no differences in focus scores, serum glucose levels or animal weights between the two treatment groups at 16 weeks. Overall, these results suggest that SPI-6 gene transfer may be beneficial in limiting the autoimmune exocrinopathy of NOD mice.

Mechanisms of alcohol-mediated CD4+ T lymphocyte death: relevance to HIV and HCV pathogenesis

Clinical and experimental studies have demonstrated that excessive alcohol consumption can result in impairment of the immune system, and can impact several immune functions including immune tolerance and host defense against opportunistic infections, and development of certain tumors. Although multiple factors are involved in the effects of ethanol on the immune system, several studies implicate chronic activation of immune cells and impairment of thymus-derived lymphocytes (T lymphocytes). Helper CD4+ T lymphocytes are the central regulators of the immune system and depletion of these lymphocytes is a major contributing factor in ethanol-induced immune dysfunction and exacerbation of HIV and/or HCV pathogenesis. However, the mechanisms involved in the ethanol induced CD4+ T cell depletion have only recently begun to be elucidated. Our work demonstrates that exposure of human CD4+ T cells to physiologically relevant concentrations of ethanol leads to the (i) enhanced activation of TNFalpha-inducible NFkappaB, the transcriptional regulator of the Fas promoter and ii) increased susceptibility to Fas-and activation-induced apoptotic death via augmentation of caspase 3 activity. Work done by us, and others, on the effects of ethanol on CD4+ T cell function and survival strongly suggests that alcohol plays a significant role as a co-factor in HIV and/or HCV pathogenesis.

Mechanisms of alcohol-mediated CD4+ T lymphocyte death: relevance to HIV and HCV pathogenesis.

Clinical and experimental studies have demonstrated that excessive alcohol consumption can result in impairment of the immune system, and can impact several immune functions including immune tolerance and host defense against opportunistic infections, and development of certain tumors. Although multiple factors are involved in the effects of ethanol on the immune system, several studies implicate chronic activation of immune cells and impairment of thymus-derived lymphocytes (T lymphocytes). Helper CD4+ T lymphocytes are the central regulators of the immune system and depletion of these lymphocytes is a major contributing factor in ethanol-induced immune dysfunction and exacerbation of HIV and/or HCV pathogenesis. However, the mechanisms involved in the ethanol induced CD4+ T cell depletion have only recently begun to be elucidated. Our work demonstrates that exposure of human CD4+ T cells to physiologically relevant concentrations of ethanol leads to the (i) enhanced activation of TNFalpha-inducible NFkappaB, the transcriptional regulator of the Fas promoter and ii) increased susceptibility to Fas-and activation-induced apoptotic death via augmentation of caspase 3 activity. Work done by us, and others, on the effects of ethanol on CD4+ T cell function and survival strongly suggests that alcohol plays a significant role as a co-factor in HIV and/or HCV pathogenesis.

Prednisolone for HIV

This one-year pilot study from France tested an intriguing hypothesis: that the chronic immune-cell activation typical of early HIV infection damages the immune system, and that immunosuppressive drugs to reduce this activity might be helpful. The authors treated 44 consecutive adults (24 asymptomatic, …

Increased concentrations of neopterin in carotid atherosclerosis

Activation of T-cells and macrophages may play a role in the pathogenesis of atherosclerosis. Therefore, serum concentrations of the immune activation markers neopterin and soluble interleukin-2 receptor were compared with routine laboratory parameters, candidate risk variables and degree of carotid atherosclerosis. Study subjects were 561 individuals (293 men and 268 women) aged between 50 and 79 years who were enrolled in a cross-sectional community based study (Ischemic Heart Disease and Stroke Prevention Study, Bruneck, Italy). Extent of carotid atherosclerosis was quantitated by an ultrasound B-mode procedure based scoring system. Detailed physical examination and quantification of laboratory and candidate risk variables were performed. By univariate as well as multivariate statistical analyses, serum concentrations of neopterin but not soluble interleukin-2 receptor were significantly higher in subjects with carotid atherosclerosis (men, 8.5 ± 2.7 nmol/1 neopterin; women, 9.6 ± 3.3) than in those without (men, 6.7 ± 2.3, P < 0.0001; women, 7.5 ± 2.3, P < 0.0001). The data show that the macrophage-derived immune activation marker neopterin is closely correlated with the extent of carotid atherosclerosis. Chronic activation of immune cells, preferentially of macrophages, may play a key role in atherogenesis and/or progression of atherosclerosis.