Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell–mediated deletion

Antiviral T cell responses in hepatotropic viral infections such as hepatitis B virus (HBV) are profoundly diminished and prone to apoptotic deletion. In this study, we investigate whether the large population of activated NK cells in the human liver contributes to this process. We show that in vitro removal of NK cells augments circulating CD8⁺ T cell responses directed against HBV, but not against well-controlled viruses, in patients with chronic hepatitis B (CHB). We find that NK cells can rapidly eliminate HBV-specific T cells in a contact-dependent manner. CD8⁺ T cells in the liver microcirculation are visualized making intimate contact with NK cells, which are the main intrahepatic lymphocytes expressing TNF-related apoptosis-inducing ligand (TRAIL) in CHB. High-level expression of the TRAIL death receptor TRAIL-R2 is found to be a hallmark of T cells exposed to the milieu of the HBV-infected liver in patients with active disease. Up-regulation of TRAIL-R2 renders T cells susceptible to caspase-8–mediated apoptosis, from which they can be partially rescued by blockade of this death receptor pathway. Our findings demonstrate that NK cells can negatively regulate antiviral immunity in chronic HBV infection and illustrate a novel mechanism of T cell tolerance in the human liver.T cell responses are tightly regulated to maintain immune homeostasis and limit damage to vital organs. T cells in the liver, in particular, are subjected to potent tolerizing mechanisms. Although these mechanisms prevent overzealous responses causing tissue injury, they may be exploited by hepatotropic pathogens to subvert antiviral immunity (Protzer et al., 2012). There have been major recent advances in our understanding of the multiple co-inhibitory pathways driving T cell exhaustion in the liver and perpetuating persistent viral infections (Protzer et al., 2012). However, the potential for NK cells to regulate T cell immunity has not been defined in human viral infections.NK cells can contribute to the containment of many infections by intracellular pathogens (Orange et al., 2002; Khakoo et al., 2004; Lodoen and Lanier, 2006; Alter et al., 2011), acting though cytolytic or noncytolytic effects on target cells or by promoting adaptive immunity (Vivier et al., 2008). Accumulating data highlight the capacity of NK cells to also exert a negative regulatory effect on T cells (Su et al., 2001) through inhibition of antigen presentation (Andrews et al., 2010), production of IL-10 (Lee et al., 2009), or direct killing of T cells. Several receptor–ligand interactions between NK cells and T cells have been found to be capable of leading to autologous lysis of activated T cells (Rabinovich et al., 2003; Cerboni et al., 2007; Lu et al., 2007; Soderquest et al., 2011). More recently, NK cells have been shown to limit T cell immunity in a mouse model of chronic viral infection (Waggoner et al., 2010; Lang et al., 2012; Waggoner et al., 2012).In this study, we sought to investigate the impact of NK cells on antiviral T cell responses in the setting of persistent infection with a human hepatotropic virus. Activated NK cells are markedly enriched in the liver microcirculation, where we hypothesized they would come into prolonged, close contact with infiltrating T cells. Although NK cells in patients with chronic hepatitis B (CHB) infection have impaired noncytolytic antiviral function, we have previously shown that they maintain their cytotoxic potential and up-regulate the death ligand TRAIL, particularly in the intrahepatic compartment (Dunn et al., 2007; Peppa et al., 2010). HBV-specific CD8⁺ T cells, which are essential for viral control, are profoundly depleted in these patients (Maini et al., 2000; Boni et al., 2007). Here, we demonstrate that hepatitis B virus–specific T cells up-regulate a death receptor for TRAIL and become susceptible to NK cell–mediated killing, thereby contributing to the failure of antiviral immunity in CHB.     

High risk studies and developmental antecedents of anxiety disorders

The past two decades have witnessed significant growth in our understanding of the developmental antecedents of anxiety disorders. In this article, we review studies of offspring at risk for anxiety disorders, longitudinal studies of the course of anxiety disorders in clinical, epidemiologic, and at-risk samples, studies of hypothesized temperamental risk factors for anxiety, and give a brief overview of the literature on environmental risk factors. Clear developmental antecedents to anxiety disorders identified include (1) childhood anxiety disorders [in particular, separation anxiety and overanxious disorder/general anxiety disorder (GAD)], (2) behavioral inhibition which predicts later social phobia, (3) anxiety sensitivity which predicts later panic disorder, and (4) negative affectivity, which predicts a spectrum of psychopathology including anxiety disorders. Further prospective studies are needed to examine the roles of environmental factors such as parenting practices, peer influences, stressful life events, and perinatal stressors. Future studies could benefit from (1) beginning earlier in development and following individuals into adulthood, (2) assessing the overlap between multiple temperamental constructs, (3) greater use of observational measures of temperament and of parent-child and peer interactions, (4) greater attention to parental psychopathology which may confound associations noted, (5) exploration of other features of anxiety disorders (neurofunctional correlates, cognitive features, other aspects of emotional regulation) as potential precursors, and (6) intervention studies exploring whether modifying developmental antecedents can alter the course of anxiety disorders.     

Isoleucyl-tRNA synthetase levels modulate the penetrance of a homoplasmic m.4277T>C mitochondrial tRNA(Ile) mutation causing hypertrophic cardiomyopathy

The genetic and epigenetic factors underlying the variable penetrance of homoplasmic mitochondrial DNA mutations are poorly understood. We investigated a 16-year-old patient with hypertrophic cardiomyopathy harboring a homoplasmic m.4277T>C mutation in the mt-tRNA(Ile) (MTTI) gene. Skeletal muscle showed multiple respiratory chain enzyme abnormalities and a decreased steady-state level of the mutated mt-tRNA(Ile). Transmitochondrial cybrids grown on galactose medium demonstrated a functional effect of this mutation on cell viability, confirming pathogenicity. These findings were reproduced in transmitochondrial cybrids, harboring a previously described homoplasmic m.4300A>G MTTI mutation. The pathogenic role of the m.4277T>C mutation may be ascribed to misfolding of the mt-tRNA molecule, as demonstrated by the altered electrophoretic migration of the mutated mt-tRNA. Indeed, structure and sequence analyses suggest that thymidine at position 4277 of mt-tRNA(Ile) is involved in a conserved tertiary interaction with thymidine at position 4306. Interestingly, the mutation showed variable penetrance within family members, with skeletal muscle from the patient's clinically unaffected mother demonstrating normal muscle respiratory chain activities and steady-state levels of mt-tRNA(Ile), while homoplasmic for the m.4277T>C mutation. Analysis of mitochondrial isoleucyl-tRNA synthetase revealed significantly higher expression levels in skeletal muscle and fibroblasts of the unaffected mother when compared with the proband, while the transient over-expression of the IARS2 gene in patient transmitochondrial cybrids improved cell viability. This is the first observation that constitutively high levels of aminoacyl-tRNA synthetases (aaRSs) in human tissues prevent the phenotypic expression of a homoplasmic mt-tRNA point mutation. These findings extend previous observations on aaRSs therapeutic effects in yeast and human.     

Predictors of adherence to a behavioral therapy sleep intervention during breast cancer chemotherapy

Background  

This study’s purpose was twofold: (1) to establish adherence rates to a behavioral therapy (BT) sleep intervention and (2) to identify psychological and physical symptom predictors of adherence to the intervention in women undergoing breast cancer chemotherapy.     

Following the money: factors associated with the cost of treating high-cost Medicare beneficiaries

Objective. To identify factors associated with the cost of treating high‐cost Medicare beneficiaries. Data Sources. A national sample of 1.6 million elderly, Medicare beneficiaries linked to 2004–2005 Community Tracking Study Physician Survey respondents and local market data from secondary sources. Study Design. Using 12 months of claims data from 2005 to 2006, the sample was divided into predicted high‐cost (top quartile) and lower cost beneficiaries using a risk‐adjustment model. For each group, total annual standardized costs of care were regressed on beneficiary, usual source of care physician, practice, and market characteristics. Principal Findings. Among high‐cost beneficiaries, health was the predominant predictor of costs, with most physician and practice and many market factors (including provider supply) insignificant or weakly related to cost. Beneficiaries whose usual physician was a medical specialist or reported inadequate office visit time, medical specialist supply, provider for‐profit status, care fragmentation, and Medicare fees were associated with higher costs. Conclusions. Health reform policies currently envisioned to improve care and lower costs may have small effects on high‐cost patients who consume most resources. Instead, developing interventions tailored to improve care and lowering cost for specific types of complex and costly patients may hold greater potential for “bending the cost curve.”     

Comparison of [¹¹¹In]pentetreotide-SPECT and [¹⁸F]FDOPA-PET in the localization of extra-adrenal paragangliomas: the case for a patient-tailored use of nuclear imaging modalities

Aims and methods The aim of this prospective study was to compare the diagnostic value of [¹⁸F]FDOPA‐PET and [¹¹¹In]pentetreotide‐SPECT somatostatin receptor scintigraphy (SRS) in patients with nonmetastatic extra‐adrenal paragangliomas (PGLs). Twenty‐five consecutive unrelated patients who were known or suspected of having nonmetastatic extra‐adrenal PGLs were prospectively evaluated with SRS and [¹⁸F]FDOPA‐PET. ¹³¹I‐MIBG and [¹⁸F]FDG‐PET were added to the work‐up in patients with a personal or familial history of PGL, predisposing mutations, abdominal PGLs, metanephrine hypersecretion and abdominal foci on SRS and/or [¹⁸F]FDOPA‐PET. Results SRS correctly detected 23/45 lesions of which 20 were head or neck lesions (H&N) and 3 were abdominal lesions. [¹⁸F]FDOPA‐PET detected significantly more lesions than SRS (39/45, P < 0·001). Both SRS and ¹⁸F‐DOPA‐PET detected significantly more H&N than abdominal lesions (66·7%vs 20%, P = 0·003 and 96·7%vs 67%, P = 0·012, respectively). In two patients with the succinate dehydrogenase D (SDHD) mutation, [¹⁸F]FDOPA‐PET missed five abdominal PGLs which were detected by the combination of SRS, [¹³¹I]MIBG and [¹⁸F]FDG‐PET. A lesion‐based analysis using a forward stepwise logistic regression model demonstrates that size ≤ 10 mm (P = 0·002) and abdominal lesions (P = 0·031) were independently associated with “[¹⁸F]FDOPA‐PET diagnosis only”. In turn, a previous history of surgery and/or the presence of germline mutation was associated with lower lesion size (P = 0·001). Conclusions The sensitivity of SRS for localizing parasympathetic PGLs is lower than originally reported, and [¹⁸F]FDOPA‐PET is better than SRS for localizing small lesions. SRS should be replaced by [¹⁸F]FDOPA‐PET as the first‐line imaging procedure in H&N PGL, especially in patients at risk of multifocal disease (predisposing mutations and or previous history of surgery).     

Cerebellar stimulation in the rat: complex stimulation-bound oral behaviors and self-stimulation

An extensive stimulation mapping study of the rat cerebellum was carried out in 82 animals. It was found that complex oral behaviors (eating, grooming, and gnawing) as well as self-stimulation could be obtained from a region including the rostro-ventral anterior lobe vermis, fastigial nucleus, and superior cerebellar peduncle. The behaviors, differing in several respects from hypothalamic-elicited behaviors, appeared only in the presence of the appropriate goal object, thus ruling out simple motor automatisms. The present results suggest that the traditional view of the cerebellar role of improving the coordination of individual muscle movements and posture may need to be expanded. Indeed, the cerebellum may act to facilitate and coordinate complex chains of species-specific behavior patterns.