Autoimmune mechanisms in myasthenia gravis

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Análise econômico-financeira da Lojas Renner S.A.

Este trabalho realiza uma avaliação econômico-financeira das Lojas Renner S.A. A Lojas Renner é uma das maiores empresas do setor de moda varejista, foi fundada em 1965 e foi a primeira empresa brasileira a ter 100% das suas ações negociadas na bolsa de valores. A avaliação da empresa é feita através do método do Fluxo de Caixa Descontado, um dos principais métodos utilizados atualmente. O objetivo do trabalho foi encontrar o valor justo para a ação da Companhia, a partir do estabelecimento de premissas para realização de projeções e comparar com o preço da ação negociado no mercado

Etiology of myasthenia gravis: Innate immunity signature in pathological thymus

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Landslides and predisposing factors of the Southern Apennines, Italy

The FiumarelladiCorletodrainagebasinisanemblematicsectorofthesouthernApennine thrust beltintheBasilicataregion(SouthernItaly),whichisstronglyaffected bylandslides. Landslides bothaffect theurbanareaandthefacilitiesrelatedtohydrocarbonexploitation, such asthepipelinesandoilwellsconnectedwiththeoilcentrelocatedjustoutsidethe eastern borderofthestudyarea.Basedonadetailed field survey,supportedby stereoscopic analysis,alandslideinventorymaphasbeenrealized,whichalsoreportsthe associated processesandlandforms.Therelationshipsbetweenthedifferent typesof landslides andthevariouspredisposingfactorslikeoutcroppinglithologies,slopes steepness, slopeexpositionandlandusehavebeenalsoinvestigated.Theacquireddata relate toageologicallycomplexareaofthesouthernApenninessubjecttorecentupliftand represent afundamentalcontributionusefulforthecorrectmanagementoftheterritory

Targeting autoimmune mechanisms by precision medicine in Myasthenia Gravis

Myasthenia Gravis (MG) is a chronic disabling autoimmune disease caused by autoantibodies to the neuromuscular junction (NMJ), characterized clinically by fluctuating weakness and early fatigability of ocular, skeletal and bulbar muscles. Despite being commonly considered a prototypic autoimmune disorder, MG is a complex and heterogeneous condition, presenting with variable clinical phenotypes, likely due to distinct pathophysiological settings related with different immunoreactivities, symptoms’ distribution, disease severity, age at onset, thymic histopathology and response to therapies. Current treatment of MG based on international consensus guidelines allows to effectively control symptoms, but most patients do not reach complete stable remission and require life-long immunosuppressive (IS) therapies. Moreover, a proportion of them is refractory to conventional IS treatment, highlighting the need for more specific and tailored strategies. Precision medicine is a new frontier of medicine that promises to greatly increase therapeutic success in several diseases, including autoimmune conditions. In MG, B cell activation, antibody recycling and NMJ damage by the complement system are crucial mechanisms, and their targeting by innovative biological drugs has been proven to be effective and safe in clinical trials. The switch from conventional IS to novel precision medicine approaches based on these drugs could prospectively and significantly improve MG care. In this review, we provide an overview of key immunopathogenetic processes underlying MG, and discuss on emerging biological drugs targeting them. We also discuss on future direction of research to address the need for patients’ stratification in endotypes according with genetic and molecular biomarkers for successful clinical decision making within precision medicine workflow

"THE THYMUS IN MYASTHENIA GRAVIS: SITE OF ""INNATE AUTOIMMUNITY""?"

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Epstein-Barr Virus in Myasthenia Gravis: Key Contributing Factor Linking Innate Immunity with B-Cell-Mediated Autoimmunity

Epstein-Barr virus (EBV), a common human herpes virus latently infecting most of the world’s population with periodic reactivations, is the main environmental factor suspected to trigger and/or sustain autoimmunity by its ability to disrupt B-cell tolerance checkpoints. Myasthenia gravis (MG) is a prototypic autoimmune disorder, mostly caused by autoantibodies to acetylcholine receptor (AChR) of the neuromuscular junction, which cause muscle weakness and fatigability. Most patients display hyperplastic thymus, characterized by ectopic germinal center formation, chronic inflammation, exacerbated Toll-like receptor activation, and abnormal B-cell activation. After an overview on MG clinical features and intra-thymic pathogenesis, in the present chapter, we describe our main findings on EBV presence in MG thymuses, including hyperplastic and thymoma thymuses, in relationship with innate immunity activation and data from other autoimmune conditions. Our overall data strongly indicate a critical contribution of EBV to innate immune dysregulation and sustained B-cell-mediated autoimmune response in the pathological thymus of MG patients

Innate immunity in myasthenia gravis thymus: Pathogenic effects of Toll-like receptor 4 signaling on autoimmunity

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Inflammation and Epstein-Barr Virus Infection Are Common Features of Myasthenia Gravis Thymus: Possible Roles in Pathogenesis

The thymus plays a major role in myasthenia gravis (MG). Our recent finding of a persistent Epstein-Barr (EBV) virus infection in some MG thymuses, combined with data showing that the thymus is in a proinflammatory state in most patients, supports a viral contribution to the pathogenesis of MG. Aim of this study was to gain further evidence for intrathymic chronic inflammation and EBV infection in MG patients. Transcriptional profiling by low density array and real-time PCR showed overexpression of genes involved in inflammatory and immune response in MG thymuses. Real-time PCR for EBV genome, latent (EBER1, EBNA1, LMP1) and lytic (BZLF1) transcripts, and immunohistochemistry for LMP1 and BZLF1 proteins confirmed an active intrathymic EBV infection, further supporting the hypothesis that EBV might contribute to onset or perpetuation of the autoimmune response in MG. Altogether, our results support a role of inflammation and EBV infection as pathogenic features of MG thymus