The role of the vascular endothelium in arenavirus haemorrhagic fevers.

Viral haemorrhagic fevers (VHF) caused by arenaviruses are among the most devastating emerging human diseases. The most important pathogen among the arenaviruses is Lassa virus (LASV), the causative agent of Lassa fever that is endemic to West Africa. On the South American continent, the New World arenavirus Junin virus (JUNV), Machupo (MACV), Guanarito (GTOV), and Sabia virus (SABV) have emerged as causative agents of severe VHFs. Clinical and experimental studies on arenavirus VHF have revealed a crucial role of the endothelium in their pathogenesis. However, in contrast to other VHFs, haemorrhages are not a salient feature of Lassa fever and fatal cases do not show overt destruction of vascular tissue. The functional alteration of the vascular endothelium that precede shock and death in fatal Lassa fever may be due to more subtle direct or indirect effects of the virus on endothelial cells. Haemorrhagic disease manifestations and vascular involvement are more pronounced in the VHF caused by the South American haemorrhagic fever viruses. Recent studies on JUNV revealed perturbation of specific endothelial cell function, including expression of cell adhesion molecules, coagulation factors, and vasoactive mediators as a consequence of productive viral infection. These studies provided first possible links to some of the vascular abnormalities observed in patients, however, their relevance in vivo remains to be investigated.

Principal components of functional connectivity: A new approach to study dynamic brain connectivity during rest.

Functional connectivity (FC) as measured by correlation between fMRI BOLD time courses of distinct brain regions has revealed meaningful organization of spontaneous fluctuations in the resting brain. However, an increasing amount of evidence points to non-stationarity of FC; i.e., FC dynamically changes over time reflecting additional and rich information about brain organization, but representing new challenges for analysis and interpretation. Here, we propose a data-driven approach based on principal component analysis (PCA) to reveal hidden patterns of coherent FC dynamics across multiple subjects. We demonstrate the feasibility and relevance of this new approach by examining the differences in dynamic FC between 13 healthy control subjects and 15 minimally disabled relapse-remitting multiple sclerosis patients. We estimated whole-brain dynamic FC of regionally-averaged BOLD activity using sliding time windows. We then used PCA to identify FC patterns, termed "eigenconnectivities", that reflect meaningful patterns in FC fluctuations. We then assessed the contributions of these patterns to the dynamic FC at any given time point and identified a network of connections centered on the default-mode network with altered contribution in patients. Our results complement traditional stationary analyses, and reveal novel insights into brain connectivity dynamics and their modulation in a neurodegenerative disease.

Agonistes de neurotrofines com a teràpia neuroprotectora per la Esclerosi Múltiple

Les neurotrofines son factors tròfics que poden induir la supervivencia, la diferenciació i el creixement de les neurones i aquesta és la principal raó per la qual les estudiem en el context de les malalties neurológiques. Les propietats nombrades son crucials per a la cerca d’efectes funcionals pel que fa a tractaments de malalties neurológiques. Avui en dia. donada la seva activitat neuroprotectora, s’ha intentat l’administració extena de neurotrofines com una terapia per diverses enfermetats cerebrals, pero fins ara han tingut poc o cap resultat donada la inhabilitat d’aquestes molècules per creuar la barrera hematoencefàlica i pels seus efectes secondaris, com ara el dolor neuroilogic. Per això, l’aplicació de petites molècules similars a les neurotrofines es considerada com unapossible sol•lució com un possible tractament neuroprotector amb el cervell com a diana. L’objectiu principal d’aquest projecte és testar l’eficacia d’un compost replicant de la neurotrofina pel tractament de algunes enfermetats neurològiques i per a estudiar el mecanisme d’acció d’aquesta molècula. Els resultats obtinguts fins al moment mostren que hem desenvolupat e identificat un compost replicant de la neurotrofina (G79) que manté la seva capacitat com a factor de creixement nerviós (NGF) en un assaig funcional d’NGF (diferenciació i tests de supervivència). A més a més, hem obtingut una proba de concepte per a la eficacia d’aquest compost com un agent terapèutic en diversos models in vivo e in vitro d’Esclerosi Múltiple, glaucoma, enfermetat de Parkinson y Esclerosi Lateral Amiotrófica. En conclusió, els resultats obtinguts durant aquests dos anys suggereixen que la molècula replicant d’NGF G79 és un bon candidat per a ser desenvolutat com a part d’una estratégica terapeutica la diferenciació neuronal, promou la supervivència, activa la fosforilització de TrkA i TrkB, vies de senyalització específiques de la neurotrofina. Aquesta molècula ademés pot creuar la barrera hematoencefàlica per vies de transport actiu, millora el score clínic en animals infectats per Encefalomielitis Autoinmune Experimental, protegeix les cèlules gangliars retinals en el model in vivo de Glaucoma, promou la supervivència de les cèlules en els models in vitro de l’enfermetat de Parkinson i en ELA. En resum, els nostres resultats sugereixen que les molècules replicants de neurotrofina poden desenvoluparse com part d’una estratègia terapéutica neuroprotectora.

A TARBP2-dependent miRNA expression profile underlies cancer stem cell properties and provides candidate therapeutic reagents in Ewing sarcoma.

We have recently demonstrated that human pediatric mesenchymal stem cells can be reprogrammed toward a Ewing sarcoma family tumor (ESFT) cancer stem cell (CSC) phenotype by mechanisms that implicate microRNAs (miRNAs). Here, we show that the miRNA profile of ESFT CSCs is shared by embryonic stem cells and CSCs from divergent tumor types. We also provide evidence that the miRNA profile of ESFT CSCs is the result of reversible disruption of TARBP2-dependent miRNA maturation. Restoration of TARBP2 activity and systemic delivery of synthetic forms of either of two of its targets, miRNA-143 or miRNA-145, inhibited ESFT CSC clonogenicity and tumor growth in vivo. Our observations suggest that CSC self-renewal and tumor maintenance may depend on deregulation of TARBP2-dependent miRNA expression.

Monitoring of human CD4 T cell responses in metastatic melanoma and arthritic patients

SUMMARY : Detailed knowledge of the different components of the immune system is required for the development of new immunotherapeutic strategies. CD4 T lymphocytes represent a highly heterogeneous group of cells characterized by various profiles of cytokine production and effector vs. regulatory functions. They are central players in orchestrating adaptive immune responses: unbalances between the different subtypes can lead either to aggressive autoimmune disorders or can favour the uncontrolled growth of malignancies. In this study we focused on the characterization of human CD4 T cells in advanced stage melanoma patients as well as in patients affected by various forms of autoimmune inflammatory spondyloarthropathies. In melanoma patients we report that a population of FOXP3 CD4 T cells, known as regulatory T cells, is overrepresented in peripheral blood, and even more in tumor-infitrated lymph nodes as well as at tumor sites, as compared to healthy donors. In tumor-infiltrated lymph nodes, but not in normal lymph nodes or in peripheral blood, FOXP3 CD4 T cells feature a highly differentiated phenotype (CD45RA-CCR7+/-), which suggests for a recent encounter with their cognate antigen. FOXP3 CD4 T cells have been described to be an important component of the several known immune escape mechanisms. We demonstrated that FOXP3 CD4 T cells isolated from melanoma patients exert an in vitro suppressive action on autologous CD4 T cells, thus possibly inhibiting an efficient anti-tumor response. Next, we aimed to analyse CD4 T cells at antigen-specific level. In advanced stage melanoma patients, we identified for the first time, using pMHCII multimers, circulating CD4 T cells specific for the melanoma antigen Melan-A, presented by HLA-DQB1 *0602. Interestingly, in a cohort of melanoma patients enrolled in an immunotherapy trails consisting of injection of a Melan-A derived peptide, we did not observe signif cant variations in the ex vivo frequencies of Melan-A specific CD4 T cells, but important differences in the quality of the specific CD4 T cells. In fact, up to 50% of the ex vivo Melan-A/DQ6 specific CD4 T cells displayed a regulatory phenotype and were hypoproliferative before vaccination, while more effector, cytokine-secreting Melan-A/DQ6 specific CD4 T cells were observed after immunization. These observations suggest that peptide vaccination may favourably modify the balance between regulatory and effector tumor-specific CD4 T cells. Finally, we identified another subset of CD4 T cells as possible mediator of pathology in a group of human autoimmune spondyloarthropathies, namely Th17 cells. These cells were recently described to play a critical role in the pathogenesis of some marine models of autommunity. We document an elevated presence of circulating Th17 cells in two members of seronegative spondyloarthropathies, e.g. psoriatic arthritis and ankylosing spondylitis, while we do not observe increased frequencies of Th17 cells in peripheral blood of rheumatoid arthritic patients. In addition, Th17 cells with a more advanced differentiation state (CD45RA-CCR7-CD27-) and polyfunctionality (concomitant secretion of IL-17, IL-2 and TNFα) were observed exclusively in patients with seronegative spondylarthropathies. Together, our observations emphasize the importance of CD4 T cells in various diseases and suggest that immunotherapeutic approaches considering CD4 T cells as targets should be evaluated in the future.

Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer.

The tumor microenvironment mediates induction of the immunosuppressive programmed cell death-1 (PD-1) pathway, and targeted interventions against this pathway can help restore antitumor immunity. To gain insight into these responses, we studied the interaction between PD-1 expressed on T cells and its ligands (PD-1:PD-L1, PD-1:PD-L2, and PD-L1:B7.1), expressed on other cells in the tumor microenvironment, using a syngeneic orthotopic mouse model of epithelial ovarian cancer (ID8). Exhaustion of tumor-infiltrating lymphocytes (TIL) correlated with expression of PD-1 ligands by tumor cells and tumor-derived myeloid cells, including tumor-associated macrophages (TAM), dendritic cells, and myeloid-derived suppressor cells (MDSC). When combined with GVAX or FVAX vaccination (consisting of irradiated ID8 cells expressing granulocyte macrophage colony-stimulating factor or FLT3 ligand) and costimulation by agonistic α-4-1BB or TLR 9 ligand, antibody-mediated blockade of PD-1 or PD-L1 triggered rejection of ID8 tumors in 75% of tumor-bearing mice. This therapeutic effect was associated with increased proliferation and function of tumor antigen-specific effector CD8(+) T cells, inhibition of suppressive regulatory T cells (Treg) and MDSC, upregulation of effector T-cell signaling molecules, and generation of T memory precursor cells. Overall, PD-1/PD-L1 blockade enhanced the amplitude of tumor immunity by reprogramming suppressive and stimulatory signals that yielded more powerful cancer control.

Intrathecal immune responses to EBV in early MS.

EBV has been consistently associated with MS, but its signature in the CNS has rarely been examined. In this study, we assessed EBV-specific humoral and cellular immune responses in the cerebrospinal fluid (CSF) of patients with early MS, other inflammatory neurological diseases (OIND) and non-inflammatory neurological diseases (NIND). The neurotropic herpesvirus CMV served as a control. Virus-specific humoral immune responses were assessed in 123 consecutive patients and the intrathecal recruitment of virus-specific antibodies was expressed as antibody indexes. Cellular immune responses tested in the blood of 55/123 patients were positive in 46/55. The CD8(+) CTL responses of these 46 patients were assessed in the blood and CSF using a CFSE-based CTL assay. We found that viral capsid antigen and EBV-encoded nuclear antigen-1, but not CMV IgG antibody indexes, were increased in early MS as compared with OIND and NIND patients. There was also intrathecal enrichment in EBV-, but not CMV-specific, CD8(+) CTL in early MS patients. By contrast, OIND and NIND patients did not recruit EBV- nor CMV-specific CD8(+) CTL in the CSF. Our data, showing a high EBV-, but not CMV-specific intrathecal immune response, strengthen the association between EBV and MS, in particular at the onset of the disease.

A novel and divergent role of granzyme a and B in resistance to helminth infection.

Granzyme (gzm) A and B, proteases of NK cells and T killer cells, mediate cell death, but also cleave extracellular matrices, inactivate intracellular pathogens, and induce cytokines. Moreover, macrophages, Th2 cells, regulatory T cells, mast cells, and B cells can express gzms. We recently reported gzm induction in human filarial infection. In this study, we show that in rodent filarial infection with Litomosoides sigmodontis, worm loads were significantly reduced in gzmA×B and gzmB knockout mice during the whole course of infection, but enhanced only early in gzmA knockout compared with wild-type mice. GzmA/B deficiency was associated with a defense-promoting Th2 cytokine and Ab shift, enhanced early inflammatory gene expression, and a trend of reduced alternatively activated macrophage induction, whereas gzmA deficiency was linked with reduced inflammation and a trend toward increased alternatively activated macrophages. This suggests a novel and divergent role for gzms in helminth infection, with gzmA contributing to resistance and gzmB promoting susceptibility.

Modulation of the airway allergic response : characterization of the cellular and molecular mechanisms

ABSTRACT Allergic asthma is a major complication of atopy. Its severity correlates with the presence of activated T lymphocytes and eosinophils in the bronchoalveolar lavage fluid (BALF). Mechanisms that protect against asthma are poorly understood. Based on oral models of mucosal tolerance induction, models using the nasal route showed that uptake of important amounts of antigen can induce tolerance and reverse the allergic phenotype. 1L-10 producing regulatory T cells were proposed as key players in tolerance induction, but other players, e.g. dendritic cells (DC), B cells and epithelial cells may have to be taken into consideration. The objective of the present study is to characterize the effects of a therapeutic intranasal treatment (INT) in a murine model of asthma and to determine, in this model, the cellular and molecular mechanisms leading to protection against asthma. First, we established an asthma model by sensitizing the BALB/c mouse to ovalbumin (OVA) by two intraperitoneal injections of alum-adsorbed OVA and three inhalations of aerosolized OVA. Then OVA was applied to the nasal mucosa of OVA- sensitized mice. Mice were later re-exposed to OVA aerosols to assess the protection induced by OVA INT. OVA sensitization induced strong eosinophil recruitment, OVA-specific T cell proliferation and IgE production. Three intranasal treatments at 24-hour intervals with 1.5 mg OVA drastically reduced inflammatory cell recruitment into the BALF and inhibited OVA-specific IgE production upon allergen re-exposure. T cell proliferation in ex vivo bronchial lymph node (BLN) cells was inhibited, as well as TH2 cytokine production. Protection against OVA-induced bronchial inflammation was effective for an extended period of time and treated mice resisted a second re-exposure. Transfer of CD4+ cells from BLN and lungs of OVA-treated mice protected asthmatic recipient mice from subsequent aerosol challenge indicating an involvement of CD4+ T regulatory cells in this protection. RESUME L'asthme allergique est une manifestation clinique majeure de l'atopie. La sévérité de l'asthme est liée à la présence de lymphocytes T activés ainsi que d'éosinophiles dans le lavage broncho-alvéolaire (LBA). Les mécanismes permettant de se prémunir contre l'asthme sont mal connus. Basés sur des modèles muqueux d'induction de tolérance par la voie orale, des modèles utilisant la voie nasale ont montré que d'importantes quantités d'antigène peuvent induire une tolérance et ainsi reverser le phénotype allergique. Des cellules régulatrices produisant de l'IL-10 pourraient jouer un rôle clé dans l'induction de la tolérance mais d'autres acteurs tels que les cellules dendritiques, les cellules B et les cellules épithéliales doivent aussi être prises en compte. L'objectif de la présente étude est de caractériser les effets d'un traitement intranasal thérapeutique dans un modèle murin d'asthme et de déterminer dans ce modèle les mécanismes cellulaires et moléculaires conférant une protection contre l'asthme. En premier lieu, un modèle d'asthme allergique a été établi en sensibilisant des souris BALB/c à l'ovalbumine (OVA) par deux injections intraperitonéales d'OVA adsorbé sur de l'alum et trois séances d'OVA en aérosol. Dans un second temps, de l'OVA a été administrée sur la muqueuse nasale des souris sensibilisées à l'OVA. Les souris furent ensuite challengées par des aérosols d'OVA afin d'évaluer la protection conférée par le traitement intranasal à l'OVA. La sensibilisation à l'OVA a induit un fort recrutement d'éosinophiles, une réponse proliférative des cellules T à l'OVA ainsi qu'une production d'lgE spécifiques. Trois traitements intranasaux à 24 heures d'intervalle avec 1.5 mg d'OVA ont permis de réduire drastiquement le recrutement des cellules inflammatoires dans le LBA ainsi que d'inhiber la production d'lgE spécifiques à l'OVA produits lors d'une ré-exposition à l'OVA. La prolifération en réponse à l'OVA de cellules extraites ex vivo de ganglions bronchiques a, elle aussi, été inhibée de même que la production de cytokines TH2. La protection contre l'inflammation provoquée par l'aérosol est efficace pour une longue période et les souris traitées résistent à une seconde ré- exposition. Le transfert de cellules CD4+ issues de ganglions bronchiques et de poumons de souris traitées à l'OVA protège les souris asthmatiques receveuses contre les effets inflammatoires d'un aérosol, indiquant que des cellules T CD4+ régulatrices pourraient être impliquées dans cette protection. RESUME DESTINE A UN LARGE PUBLIC L'asthme est une affection des voies respiratoires qui se caractérise par une contraction de la musculature des voies aériennes, une production de mucus et d'anticorps de l'allergie (IgE). On parle d'asthme allergique lorsque les facteurs déclenchant l'asthme sont des allergènes inhalés tels que acariens, pollens ou poils d'animaux. Le système immunitaire des patients asthmatiques a un défaut de programmation qui le rend réactif à des substances qui sont normalement inoffensives. Le traitement actuel de l'asthme repose sur le soulagement des symptômes grâce à des produits à base de stéroïdes. Les techniques permettant de reprogrammer le système immunitaire (immunothérapie) ne sont pas efficaces pour tous les antigènes et prennent beaucoup de temps. En conséquence, il est nécessaire de mieux comprendre les mécanismes sous-tendant une telle reprogrammation afin d'en améliorer le rendement et l'efficacité. Dans ce but, des modèles d'immunothérapie ont été mis au point chez la souris. Ils permettent une plus grande liberté d'investigation. Dans cette étude, un modèle d'asthme allergique dans la souris a été établi par une sensibilisation à un antigène particulier : l'ovalbumine (OVA). Ce modèle présente les caractéristiques principales de l'asthme humain : recrutement de cellules inflammatoires dans les poumons, augmentation de la production d'anticorps et de la résistance des bronches aux flux respiratoires. Cette souris asthmatique a ensuite été traitée par application nasale d'OVA. Comparées aux souris non traitées, les souris traitées à l'OVA ont moins de cellules inflammatoires dans leurs poumons et produisent moins d'anticorps IgE. D'autres marqueurs inflammatoires sont aussi fortement diminués. Des cellules de poumons ou de ganglions bronchiques prélevées sur des souris traitées injectées dans des souris asthmatiques améliorent les symptômes de l'asthme. Ces cellules pourraient donc avoir un rôle régulateur dans l'asthme. Les caractériser et les étudier afin d'être capable de les générer est crucial pour les futures thérapies de l'asthme.

Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients.

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and attacks of muscle atonia triggered by strong emotions (cataplexy). Narcolepsy is caused by hypocretin (orexin) deficiency, paralleled by a dramatic loss in hypothalamic hypocretin-producing neurons. It is believed that narcolepsy is an autoimmune disorder, although definitive proof of this, such as the presence of autoantibodies, is still lacking. We engineered a transgenic mouse model to identify peptides enriched within hypocretin-producing neurons that could serve as potential autoimmune targets. Initial analysis indicated that the transcript encoding Tribbles homolog 2 (Trib2), previously identified as an autoantigen in autoimmune uveitis, was enriched in hypocretin neurons in these mice. ELISA analysis showed that sera from narcolepsy patients with cataplexy had higher Trib2-specific antibody titers compared with either normal controls or patients with idiopathic hypersomnia, multiple sclerosis, or other inflammatory neurological disorders. Trib2-specific antibody titers were highest early after narcolepsy onset, sharply decreased within 2-3 years, and then stabilized at levels substantially higher than that of controls for up to 30 years. High Trib2-specific antibody titers correlated with the severity of cataplexy. Serum of a patient showed specific immunoreactivity with over 86% of hypocretin neurons in the mouse hypothalamus. Thus, we have identified reactive autoantibodies in human narcolepsy, providing evidence that narcolepsy is an autoimmune disorder.

The cdc7 protein kinase is a dosage dependent regulator of septum formation in fission yeast.

Mutation of the Schizosaccharomyces pombe cdc7 gene prevents formation of the division septum and cytokinesis. We have cloned the cdc7 gene and show that it encodes a protein kinase which is essential for cell division. In the absence of cdc7 function, spore germination, DNA synthesis and mitosis are unaffected, but cells are unable to initiate formation of the division septum. Overexpression of p120cdc7 causes cell cycle arrest; cells complete mitosis and then undergo multiple rounds of septum formation without cell cleavage. This phenotype, which is similar to that resulting from inactivation of cdc16 protein, requires the kinase activity of p120cdc7. Mutations inactivating the early septation gene, cdc11, suppress the formation of multiple septa and allow cells to proliferate normally. If formation of the division septum is prevented by inactivation of either cdc14 or cdc15, p120cdc7 overproduction does not interfere with other events in the mitotic cell cycle. Septation is not induced by overexpression of p120cdc7 in G2 arrested cells, indicating that it does not bypass the normal dependency of septation upon initiation of mitosis. These findings indicate that the p120cdc7 protein kinase plays a key role in initiation of septum formation and cytokinesis in fission yeast and suggest that p120cdc7 interacts with the cdc11 protein in the control of septation.

Revue de la littérature 2011 : neuropathies dysimmunitaires [2011: What's new in dysimmune neuropathies].

There are strong research activities in the field of dysimmune neuropathies. In Guillain-Barré syndrome, new pathophysiological mechanisms have been demonstrated with the potential development of new therapies, a clinical prediction model is applicable early in the course of disease, and under investigation are new treatment strategies with adapted intravenous Ig dosages. In chronic inflammatory demyelinating polyneuropathies, current diagnostic tests are discussed but biomarkers are needed, such as histological changes or differential gene expression in nerve or skin biopsies. The exploration of novel therapeutic approaches including monoclonal antibodies and oral immunosuppressants, known from multiple sclerosis studies, suggests new approaches to treatment. Changes of the peripheral nerves on MR imaging are better known and the usefulness of serum antibodies is reviewed.

Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy.

Objectives In this study, we have investigated the effects of cannabidiol (CBD) on myocardial dysfunction, inflammation, oxidative/nitrative stress, cell death, and interrelated signaling pathways, using a mouse model of type I diabetic cardiomyopathy and primary human cardiomyocytes exposed to high glucose. Background Cannabidiol, the most abundant nonpsychoactive constituent of Cannabis sativa (marijuana) plant, exerts anti-inflammatory effects in various disease models and alleviates pain and spasticity associated with multiple sclerosis in humans. Methods Left ventricular function was measured by the pressure-volume system. Oxidative stress, cell death, and fibrosis markers were evaluated by molecular biology/biochemical techniques, electron spin resonance spectroscopy, and flow cytometry. Results Diabetic cardiomyopathy was characterized by declined diastolic and systolic myocardial performance associated with increased oxidative-nitrative stress, nuclear factor-kappa B and mitogen-activated protein kinase (c-Jun N-terminal kinase, p-38, p38 alpha) activation, enhanced expression of adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1), tumor necrosis factor-alpha, markers of fibrosis (transforming growth factor-beta, connective tissue growth factor, fibronectin, collagen-1, matrix metalloproteinase-2 and -9), enhanced cell death (caspase 3/7 and poly[adenosine diphosphate-ribose] polymerase activity, chromatin fragmentation, and terminal deoxynucleotidyl transferase dUTP nick end labeling), and diminished Akt phosphorylation. Remarkably, CBD attenuated myocardial dysfunction, cardiac fibrosis, oxidative/nitrative stress, inflammation, cell death, and interrelated signaling pathways. Furthermore, CBD also attenuated the high glucose-induced increased reactive oxygen species generation, nuclear factor-kappa B activation, and cell death in primary human cardiomyocytes. Conclusions Collectively, these results coupled with the excellent safety and tolerability profile of CBD in humans, strongly suggest that it may have great therapeutic potential in the treatment of diabetic complications, and perhaps other cardiovascular disorders, by attenuating oxidative/nitrative stress, inflammation, cell death and fibrosis. (J Am Coll Cardiol 2010;56:2115-25) (C) 2010 by the American College of Cardiology Foundation.

Neurologie [Therapeutic advances in neurology].

This article summarizes the main therapeutic advances of 2010 in the field of neurology. It focuses on aspects that are likely to change the care of patients in clinical practice. Among these, we discuss the new oral treatments that have proved to be effective in multiple sclerosis, the results of two large studies comparing endarterectomy and stenting in carotid stenosis, novel therapeutic approaches for the treatment of non-motor symptoms in Parkinson's disease as well as the results of several pharmacological studies in the field of epilepsy.

Differential reactivity of TCR Vbeta10 alleles to a mouse mammary tumor virus superantigen.

Mouse mammary tumor virus (MMTV) expresses a superantigen (SAg) which plays a critical role in the viral life cycle. We have recently described the new infectious MMTV (SIM) encoding a Vbeta4-specific SAg in mice with a TCR-Vbeta(b) haplotype. We have now compared the SAg activity of this virus in BALB/c mice harboring the TCR-Vbeta(a), TCR-Vbeta(b) or TCR-Vbeta(c) haplotypes which differ by a central deletion in the TCR-Vbeta(a) and TCR-Vbeta(c) locus and by mutations in some of the remaining Vbeta elements. Injection of MMTV (SIM) led to a strong stimulation of Vbeta4+ CD4+ T cells in TCR-Vbeta(b) mice, but only to a weak stimulation of these cells in TCR-Vbeta(a) or TCR-Vbeta(c) mice. A large increase in the percentage of Vbeta10+ cells was observed among CD4+ T cells in mice with the Vbeta(a) or Vbeta(c), but not the Vbeta(b) TCR-Vbeta haplotype. Vbeta10+ cells dominated the response when Vbeta10(a/c) and Vbeta4 subsets were present together. This is the first report of a viral SAg interacting with murine Vbeta10+ cells. Six amino acid differences between Vbeta10(a/c) and Vbeta10(b) could account for the gain of reactivity of Vbeta10(a/c) to the MMTV(SIM) SAg. No mutations were found in the hypervariable region 4 (HV4) of the TCR. Mutations at positions 22 and 28 introduce into Vbeta10(a/c) the same amino acids which are found at these positions in the MMTV(SIM)-reactive Vbeta4. Tridimensional models indicated that these amino acids lie close to HV4 and are likely to be important for the interaction of the SAg with the TCR.