Expression of chemokine receptor CXCR3 on T cells affects the balance between effector and memory CD8 T-cell generation

Generation of a robust immunological memory response is essential for protection on subsequent encounters with the same pathogen. The magnitude and quality of the memory CD8 T-cell population are shaped and influenced by the strength and duration of the initial antigenic stimulus as well as by inflammatory cytokines. Although chemokine receptors have been established to play a role in recruitment of effector CD8 T cells to sites of inflammation, their contribution to determination of T-cell fate and shaping of the long-lived memory T-cell population is not fully understood. Here, we investigated whether reduced access to antigen and inflammation through alterations in expression of inflammatory and homeostatic chemokine receptors has an impact on generation of effector and memory CD8 T cells. We found that in mice infected with lymphocytic choriomeningitis virus, colocalization of virus-specific CD8 T cells with antigen in spleen is dependent on expression of the inflammatory chemokine receptor, CXCR3. In addition, absence of CXCR3 expression on CD8 T cells leads to formation of fewer short-lived effector cells and more memory precursor cells. Furthermore, the memory CD8 T-cell population derived from CXCR3-deficient cells has fewer cells of the effector memory phenotype and exhibits a recall response of greater magnitude than that of WT cells. These data demonstrate that CD8 T-cell positioning relative to antigen and inflammatory cytokines in secondary lymphoid organs affects the balance of effector and memory T-cell formation and has both a quantitative and qualitative impact on the long-lived memory CD8 T-cell population.     

Virus activation and immune function during intense training in rugby football players

Epidemiological studies suggest that highly trained athletes are more susceptible to upper respiratory tract infections (URTI) compared with the general population. Upper respiratory symptoms (URS) often appear as either primary invasion of pathogenic organisms and/or reactivation of latent viruses such as Epstein-Barr virus (EBV). The purpose of this study was to examine the relationship between EBV reactivation and the appearance of URS during intensive training in collegiate rugby football players. We evaluated EBV-DNA expression in saliva and examined the relationship between onset of URS and daily changes in EBV-DNA as well as secretory immunoglobulin A (SIgA) levels among 32 male collegiate rugby football players during a 1-month training camp. The EBV-DNA expression tended to be higher in subjects who exhibited sore throat (p=0.07) and cough (p=0.18) than that of those who had no symptoms, although their differences were not significant. The SIgA level was significantly lower 1 day before the EBV-DNA expression (p<0.05). The number of URS increased along with the EBV-DNA expression and decrease of SIgA levels. These results suggest that the appearance of URS is associated with reactivation of EBV and reduction of SIgA during training.     

Ovarian hormones influence corticotropin releasing factor receptor colocalization with delta opioid receptors in CA1 pyramidal cell dendrites

Stress interacts with addictive processes to increase drug use, drug seeking, and relapse. The hippocampal formation (HF) is an important site at which stress circuits and endogenous opioid systems intersect and likely plays a critical role in the interaction between stress and drug addiction. Our prior studies demonstrate that the stress-related neuropeptide corticotropin-releasing factor (CRF) and the delta-opioid receptor (DOR) colocalize in interneuron populations in the hilus of the dentate gyrus and stratum oriens of CA1 and CA3. While independent ultrastructural studies of DORs and CRF receptors suggest that each receptor is found in CA1 pyramidal cell dendrites and dendritic spines, whether DORs and CRF receptors colocalize in CA1 neuronal profiles has not been investigated. Here, hippocampal sections of adult male and proestrus female Sprague–Dawley rats were processed for dual label pre-embedding immunoelectron microscopy using well-characterized antisera directed against the DOR for immunoperoxidase and against the CRF receptor for immunogold. DOR-immunoreactivity (− ir) was found presynaptically in axons and axon terminals as well as postsynaptically in somata, dendrites and dendritic spines in stratum radiatum of CA1. In contrast, CRF receptor-ir was predominantly found postsynaptically in CA1 somata, dendrites, and dendritic spines. CRF receptor-ir frequently was observed in DOR-labeled dendritic profiles and primarily was found in the cytoplasm rather than at or near the plasma membrane. Quantitative analysis of CRF receptor-ir colocalization with DOR-ir in pyramidal cell dendrites revealed that proestrus females and males show comparable levels of CRF receptor-ir per dendrite and similar cytoplasmic density of CRF receptor-ir. In contrast, proestrus females display an increased number of dual-labeled dendritic profiles and an increased membrane density of CRF receptor-ir in comparison to males. We further examined the functional consequences of CRF receptor-ir colocalization with DOR-ir in the same neuron using the hormone responsive neuronal cell line NG108-15, which endogenously expresses DORs, and assayed intracellular cAMP production in response to CRF receptor and DOR agonists. Results demonstrated that short-term application of DOR agonist SNC80 inhibited CRF-induced cAMP accumulation in NG108-15 cells transfected with the CRF receptor. These studies provide new insights on opioid-stress system interaction in the hippocampus of both males and females and establish potential mechanisms through which DOR activation may influence CRF receptor activity.     

Effect of free-living daily physical activity on salivary secretory IgA in elderly

PURPOSE: The aim of this work was to assess the relationship in elderly subjects between free-living daily physical activity and mucosal immunity, especially salivary secretory immunoglobulin A (SIgA). METHODS: Elderly volunteers (114 men and 170 women) aged 71.3 +/- 0.3 yr (range: 65-86 yr) participated in this study. Resting saliva samples were collected in the morning. Saliva samples stimulated by chewing a sterile cotton ball at a frequency of 60/60 s were collected. The SIgA concentration was measured using enzyme-linked immunosorbent assay (ELISA), and the SIgA secretion rate was calculated. Free-living step count (steps per day), energy expenditure (kJ x kg(-1) x d(-1)), and activity durations (min x d(-1)) at specific intensity levels (inactive, light, moderate, and vigorous) were evaluated using an electric pedometer. The data obtained were stratified by pedometer-determined steps per day using quartiles (Q1-Q4) for distribution. RESULTS: Elderly in quartiles showed step counts of 2962 +/- 94, 5118 +/- 62, 6832 +/- 59, and 9951 +/- 264 steps per day. Significant differences were found in the mean step count (P<0.0001), energy expenditure (P<0.0001), and activity duration (P<0.0001) with increasing pedometer-determined activity quartiles. Both SIgA concentration and SIgA-secretion rate were significantly higher for Q3 than for Q1 (P<0.05). Meanwhile, saliva flow rates showed no significant differences across quartiles. CONCLUSION: These results suggest that a free-living daily physical activity level of approximately 7000 steps per day might be regarded as a moderate daily physical activity target for elderly people to improve mucosal immune function.     

Circulating platelet and neutrophil activation correlates with the clinical course of unstable angina

Recent studies have suggested important roles of inflammation in the pathophysiology of unstable angina (UA). We investigated whether activation of the circulating platelets and neutrophils were implicated in inflammatory reactions associated with unstable angina Expressions of platelet P-selectin and neutrophil CD11b, and neutrophil–platelet aggregates were evaluated by flow cytometry in anticoagulated peripheral venous blood from 71 patients with UA and 22 patients with stable angina (SA). Expressions of platelet P-selectin and neutrophil CD11b, and neutrophil–platelet aggregates on the admission day were all significantly higher in 71 patients with UA than 22 with SA (median, mean fluorescence intensity [MFI]: 7.00 vs 4.51, P < 0.01, 64.68 vs 47.75, P = 0.0007; and % of 10 000 neutrophils: 7.84 vs 3.40, P = 0.0001, respectively). These three parameters in 43 patients with UA were significantly decreased (MFI: 4.23, P = 0.003, 50.82, P = 0.0003; and % of 10 000 neutrophils: 5.04, P = 0.0001, respectively) 7 days after the first measurement. These results indicate that circulating activated platelets and neutrophils are more strongly implicated in the acute phase of UA. These findings also suggest that thrombus formation after rupture of atherosclerotic plaques as well as plaque formation involves inflammatory reactions.     

Increases in circulating T lymphocytes expressing HLA-DR and CD40 ligand in patients with dilated cardiomyophthy

Inflammatory and immunological mechanisms are implicated in the development of idiopathic dilated cardiomyopathy (DCM). Since activated T lymphocytes express surface HLA-DR antigens, an increased level of these cells in the circulation could indicated an ongoing immune response. While the role of activated T lymphocytes in experimental myocarditis has been elucidated, the contribution of T lymphocyte activation in clinical DCM remains unclear. We therefore examined the role of T-cell activation in peripheral blood samples obtained from 10 patients with DCM (mean age, 49 ± 12 years) and from 10 age-matched healthy controls. Citrated whole blood was mixed with fluorescein isothiocyanate- or phycoerythrin-conjugated specific monoclonal antibodies and analyzed using a fluorescence-activated cell sorter (FACS). The ratio (%) of histocompatibility leukocyte antigen (HLA)-DR positive cells in the FACS gated lymphocyte population was significantly higher in DCM patients than in controls (7.9% ± 5.3% vs 2.0% ± 0.9%; P < 0.01). The expression of CD40L on T cells determined as mean fluorescence intensity (MFI) was also significantly higher in DCM patients than in controls (3.6 ± 2.1 vs 1.8 ± 0.4 MFI; P < 0.05). Furthermore, the ratios of T cells expressing HLA-DR and serum brain natriuretic peptide (BNP) levels closely correlated (P = 0.0008). We showed that HLA-DR on peripheral T cells significantly correlated with serum BNP levels and that high CD40L expression on T cells was concomitant with increased BNP levels (P < 0.05). Therefore the magnitude of T-cell expression, such as increased expression of HLA-DR and CD40L, contributes to myocardial dysfunction in DCM.     

Estrogen effects on the brain: actions beyond the hypothalamus via novel mechanisms

From its origins in how the brain controls the endocrine system via the hypothalamus and pituitary gland, neuroendocrinology has evolved into a science that now includes hormone action on many aspects of brain function. These actions involve the whole central nervous system and not just the hypothalamus. Advances in our understanding of cellular and molecular actions of steroid hormones have gone beyond the important cell nuclear actions of steroid hormone receptors to include signaling pathways that intersect with other mediators such as neurotransmitters and neuromodulators. This has, in turn, broadened the search for and identification of steroid receptors to include nonnuclear sites in synapses, dendrites, mitochondria, and glial cells, as well as cell nuclei. The study of estrogen receptors and estrogen actions on processes related to cognition, mood, autonomic regulation, pain, and neuroprotection, among other functions, has led the way in this new view of hormone actions on the brain. In this review, we summarize past and current work in our laboratory on this topic. This exciting and growing field involving many laboratories continues to reshape our ideas and approaches to neuroendocrinology both at the bench and the bedside.     

Current status of leprosy: epidemiology, basic science and clinical perspectives

Leprosy has affected humans for millennia and remains an important health problem worldwide, as evidenced by nearly 250 000 new cases detected every year. It is a chronic infectious disorder, caused by Mycobacterium leprae, that primarily affects the skin and peripheral nerves. Recent advances in basic science have improved our knowledge of the disease. Variation in the cellular immune response is the basis of a range of clinical manifestations. The introduction of multidrug therapy has significantly contributed to a decrease in the prevalence of the disease. However, leprosy control activities, including monitoring and prevention programs, must be maintained.