Articolo del 14 aprile preso da www.healthdesk.it
Nelle persone con sclerosi multipla le cellule immunitarie che combattono il virus di Epstein-Barr (i cosiddetti linfociti T citotossici) aumentano durante le ricadute della malattia, raggiungendo livelli più alti rispetto alle persone sane, e diminuiscono nelle fasi di remissione.
È alla riattivazione del virus e alla risposta del sistema immunitario che, in sostanza, potrebbe essere dovuto il decorso della malattia fatto periodi di tranquillità alternati a ricadute.
L’ipotesi arriva da uno studio condotto dall’Unità di Neuroimmunologia della Fondazione Santa Lucia e dal Dipartimento di Biologia Cellulare e Neuroscienze dell’Istituto Superiore di Sanità, in collaborazione con i Centri per la Sclerosi Multipla dell’Università di Tor Vergata, dell’ospedale San Camillo-Forlanini e dell’ospedale S. Andrea di Roma, pubblicato sulla rivista americana PLoS Pathogens.
«Si tratta di un risultato molto importante», ha spiegato Luca Battistini, coordinatore del gruppo di neuroimmunologia della Fondazione Santa Lucia di Roma che ha effettuato lo studio sui pazienti. «Per la prima volta si osserva che la risposta immunitaria contro il virus di Epstein-Barr, ma non quella contro un altro virus della stessa famiglia, è più forte in concomitanza degli episodi di infiammazione acuta a livello cerebrale rilevati con la risonanza magnetica, suggerendo quindi un ruolo diretto della risposta antivirale nel processo patologico».
«I risultati ottenuti nei pazienti si spiegherebbero con il tentativo di eliminare il virus dal sistema nervoso centrale», ha aggiunto prosegue Francesca Aloisi, coordinatrice del gruppo di ricerca dell’Istituto Superiore di Sanità che ha effettuato gli studi su campioni di tessuto cerebrale donati da persone con sclerosi multipla. «A sostegno di ciò, abbiamo dimostrato che nelle lesioni cerebrali è presente la stessa proteina virale verso la quale il sistema immunitario risponde vigorosamente durante le riacutizzazioni della malattia. Il virus sarebbe trasportato nel sistema nervoso centrale dai linfociti B, le cellule responsabili della produzione di anticorpi, costituendo un focolaio nascosto, ma sempre attivo, di infezione».
La ricerca, che è stata finanziata dal Sesto Programma Quadro dell’Unione Europea, dal Ministero della Salute e dalla Fondazione Italiana Sclerosi Multipla, avvalora una tesi sostenuta da tempo. Il virus di Epstein-Barr è la causa della mononucleosi infettiva e di alcuni tumori. Quasi tutta la popolazione è esposta al virus che permane nell’organismo sotto lo stretto controllo del sistema immunitario, generalmente senza creare problemi.
Tuttavia solo una minoranza sviluppa la sclerosi multipla. Questo significa che, a causa di una complessa interazione tra geni e ambiente, in alcuni individui predisposti l’equilibrio tra virus e sistema immunitario si altera causando problemi neurologici. La dimostrazione che il virus di Epstein-Barr accende il sistema immunitario durante le riacutizzazioni della sclerosi multipla apre nuove prospettive per la terapia e la prevenzione di questa malattia.
Abstract
It has long been known that multiple sclerosis (MS) is associated with an increased Epstein-Barr virus (EBV) seroprevalence and high immune reactivity to EBV and that infectious mononucleosis increases MS risk. This evidence led to postulate that EBV infection plays a role in MS etiopathogenesis, although the mechanisms are debated. This study was designed to assess the prevalence and magnitude of CD8+ T-cell responses to EBV latent (EBNA-3A, LMP-2A) and lytic (BZLF-1, BMLF-1) antigens in relapsing-remitting MS patients (n = 113) and healthy donors (HD) (n = 43) and to investigate whether the EBV-specific CD8+ T cell response correlates with disease activity, as defined by clinical evaluation and gadolinium-enhanced magnetic resonance imaging. Using HLA class I pentamers, lytic antigen-specific CD8+ T cell responses were detected in fewer untreated inactive MS patients than in active MS patients and HD while the frequency of CD8+ T cells specific for EBV lytic and latent antigens was higher in active and inactive MS patients, respectively. In contrast, the CD8+ T cell response to cytomegalovirus did not differ between HD and MS patients, irrespective of the disease phase. Marked differences in the prevalence of EBV-specific CD8+ T cell responses were observed in patients treated with interferon-β and natalizumab, two licensed drugs for relapsing-remitting MS. Longitudinal studies revealed expansion of CD8+ T cells specific for EBV lytic antigens during active disease in untreated MS patients but not in relapse-free, natalizumab-treated patients. Analysis of post-mortem MS brain samples showed expression of the EBV lytic protein BZLF-1 and interactions between cytotoxic CD8+ T cells and EBV lytically infected plasma cells in inflammatory white matter lesions and meninges. We therefore propose that inability to control EBV infection during inactive MS could set the stage for intracerebral viral reactivation and disease relapse.
Author Summary
There is general consensus that multiple sclerosis (MS) is associated with Epstein-Barr virus (EBV) infection but the mechanistic links are still debated. EBV is a B-lymphotropic herpesvirus widespread in the human population and normally contained as a persistent, asymptomatic infection by immune surveillance. However, EBV can cause infectious mononucleosis, is associated with numerous human malignancies, and is implicated in some common autoimmune diseases. While EBV infection alone cannot explain MS development, it has been postulated that in susceptible individuals alterations in the mechanisms regulating the immune response to the virus may contribute to MS pathogenesis. Here, we show that MS patients with inactive disease exhibit a lower CD8+ T-cell response to EBV when compared to healthy donors and active MS patients while the latter have a higher frequency of CD8+ T cells specific for EBV lytic antigens. Therapy with interferon-β and natalizumab, two treatments for relapsing-remitting MS, was associated with marked changes in the EBV specific CD8+ T cell response. We also demonstrate that one of the EBV lytic antigens recognized by CD8+ T cells expanding in the blood during active MS is expressed in the inflamed MS brain. Our results support a model of MS pathogenesis in which EBV infection and reactivation in the CNS stimulates an immunopathological response and suggest that antiviral or immunomodulatory therapies aimed at restoring the host-EBV balance could be beneficial to MS patients.
Citation: Angelini DF, Serafini B, Piras E, Severa M, Coccia EM, et al. (2013) Increased CD8+ T Cell Response to Epstein-Barr Virus Lytic Antigens in the Active Phase of Multiple Sclerosis. PLoS Pathog 9(4): e1003220. doi:10.1371/journal.ppat.1003220
Editor: Brian D. Evavold, Emory University, United States of America
Received: July 31, 2012; Accepted: January 15, 2013; Published: April 11, 2013
Copyright: © 2013 Angelini et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The study was supported by Italian Multiple Sclerosis Foundation (to DC, MS, EMC, FA, LB), European FP6 NeuroproMiSe Integrated project (Contract: LSHM-CT-2005-01863) (to FA, LB), Italian Ministry of Health, Ricerca Finalizzata 2007 - Strategic Project on Multiple Sclerosis (Contract: 107 to EMC, MS, FA, LB), and Ricerca Finalizzata 2010-Giovani Ricercatori (to DC), the French Society for Research in Multiple Sclerosis (ARSEP) (to MS, LB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: Marco Salvetti, MD, received lecture fees from Biogen-Dompé and research support from Bayer-Schering, Biogen-Dompé, Merck-Serono, Sanofi-Aventis. Claudio Gasperini, MD, has served as a consultant for Merck Serono and Biogen Idec, and has received speaker honoraria from Teva, Merck Serono, Bayer Shering and Biogec Idec. Diego Centonze, MD, is an Advisory Board member of Merck-Serono, Teva and Bayer Shering and received funding for travelling and speaker honoraria or consultation fees from Merck Serono, Teva, Novartis, Bayer Shering, Sanofi-Aventis and Biogen Idec. He is also an external expert consultant of the European Medicine Agency (EMA) and the principal investigator in clinical trials for Novartis, Merck Serono, Teva, Bayer Shering, Sanofi Aventis and Biogen Idec. The other authors have no competing interests to report. This does not alter our adherence to all PLoS Pathogens policies on sharing data and materials.
Nelle persone con sclerosi multipla le cellule immunitarie che combattono il virus di Epstein-Barr (i cosiddetti linfociti T citotossici) aumentano durante le ricadute della malattia, raggiungendo livelli più alti rispetto alle persone sane, e diminuiscono nelle fasi di remissione.
È alla riattivazione del virus e alla risposta del sistema immunitario che, in sostanza, potrebbe essere dovuto il decorso della malattia fatto periodi di tranquillità alternati a ricadute.
L’ipotesi arriva da uno studio condotto dall’Unità di Neuroimmunologia della Fondazione Santa Lucia e dal Dipartimento di Biologia Cellulare e Neuroscienze dell’Istituto Superiore di Sanità, in collaborazione con i Centri per la Sclerosi Multipla dell’Università di Tor Vergata, dell’ospedale San Camillo-Forlanini e dell’ospedale S. Andrea di Roma, pubblicato sulla rivista americana PLoS Pathogens.
«Si tratta di un risultato molto importante», ha spiegato Luca Battistini, coordinatore del gruppo di neuroimmunologia della Fondazione Santa Lucia di Roma che ha effettuato lo studio sui pazienti. «Per la prima volta si osserva che la risposta immunitaria contro il virus di Epstein-Barr, ma non quella contro un altro virus della stessa famiglia, è più forte in concomitanza degli episodi di infiammazione acuta a livello cerebrale rilevati con la risonanza magnetica, suggerendo quindi un ruolo diretto della risposta antivirale nel processo patologico».
«I risultati ottenuti nei pazienti si spiegherebbero con il tentativo di eliminare il virus dal sistema nervoso centrale», ha aggiunto prosegue Francesca Aloisi, coordinatrice del gruppo di ricerca dell’Istituto Superiore di Sanità che ha effettuato gli studi su campioni di tessuto cerebrale donati da persone con sclerosi multipla. «A sostegno di ciò, abbiamo dimostrato che nelle lesioni cerebrali è presente la stessa proteina virale verso la quale il sistema immunitario risponde vigorosamente durante le riacutizzazioni della malattia. Il virus sarebbe trasportato nel sistema nervoso centrale dai linfociti B, le cellule responsabili della produzione di anticorpi, costituendo un focolaio nascosto, ma sempre attivo, di infezione».
La ricerca, che è stata finanziata dal Sesto Programma Quadro dell’Unione Europea, dal Ministero della Salute e dalla Fondazione Italiana Sclerosi Multipla, avvalora una tesi sostenuta da tempo. Il virus di Epstein-Barr è la causa della mononucleosi infettiva e di alcuni tumori. Quasi tutta la popolazione è esposta al virus che permane nell’organismo sotto lo stretto controllo del sistema immunitario, generalmente senza creare problemi.
Tuttavia solo una minoranza sviluppa la sclerosi multipla. Questo significa che, a causa di una complessa interazione tra geni e ambiente, in alcuni individui predisposti l’equilibrio tra virus e sistema immunitario si altera causando problemi neurologici. La dimostrazione che il virus di Epstein-Barr accende il sistema immunitario durante le riacutizzazioni della sclerosi multipla apre nuove prospettive per la terapia e la prevenzione di questa malattia.
Abstract
It has long been known that multiple sclerosis (MS) is associated with an increased Epstein-Barr virus (EBV) seroprevalence and high immune reactivity to EBV and that infectious mononucleosis increases MS risk. This evidence led to postulate that EBV infection plays a role in MS etiopathogenesis, although the mechanisms are debated. This study was designed to assess the prevalence and magnitude of CD8+ T-cell responses to EBV latent (EBNA-3A, LMP-2A) and lytic (BZLF-1, BMLF-1) antigens in relapsing-remitting MS patients (n = 113) and healthy donors (HD) (n = 43) and to investigate whether the EBV-specific CD8+ T cell response correlates with disease activity, as defined by clinical evaluation and gadolinium-enhanced magnetic resonance imaging. Using HLA class I pentamers, lytic antigen-specific CD8+ T cell responses were detected in fewer untreated inactive MS patients than in active MS patients and HD while the frequency of CD8+ T cells specific for EBV lytic and latent antigens was higher in active and inactive MS patients, respectively. In contrast, the CD8+ T cell response to cytomegalovirus did not differ between HD and MS patients, irrespective of the disease phase. Marked differences in the prevalence of EBV-specific CD8+ T cell responses were observed in patients treated with interferon-β and natalizumab, two licensed drugs for relapsing-remitting MS. Longitudinal studies revealed expansion of CD8+ T cells specific for EBV lytic antigens during active disease in untreated MS patients but not in relapse-free, natalizumab-treated patients. Analysis of post-mortem MS brain samples showed expression of the EBV lytic protein BZLF-1 and interactions between cytotoxic CD8+ T cells and EBV lytically infected plasma cells in inflammatory white matter lesions and meninges. We therefore propose that inability to control EBV infection during inactive MS could set the stage for intracerebral viral reactivation and disease relapse.
Author Summary
There is general consensus that multiple sclerosis (MS) is associated with Epstein-Barr virus (EBV) infection but the mechanistic links are still debated. EBV is a B-lymphotropic herpesvirus widespread in the human population and normally contained as a persistent, asymptomatic infection by immune surveillance. However, EBV can cause infectious mononucleosis, is associated with numerous human malignancies, and is implicated in some common autoimmune diseases. While EBV infection alone cannot explain MS development, it has been postulated that in susceptible individuals alterations in the mechanisms regulating the immune response to the virus may contribute to MS pathogenesis. Here, we show that MS patients with inactive disease exhibit a lower CD8+ T-cell response to EBV when compared to healthy donors and active MS patients while the latter have a higher frequency of CD8+ T cells specific for EBV lytic antigens. Therapy with interferon-β and natalizumab, two treatments for relapsing-remitting MS, was associated with marked changes in the EBV specific CD8+ T cell response. We also demonstrate that one of the EBV lytic antigens recognized by CD8+ T cells expanding in the blood during active MS is expressed in the inflamed MS brain. Our results support a model of MS pathogenesis in which EBV infection and reactivation in the CNS stimulates an immunopathological response and suggest that antiviral or immunomodulatory therapies aimed at restoring the host-EBV balance could be beneficial to MS patients.
Citation: Angelini DF, Serafini B, Piras E, Severa M, Coccia EM, et al. (2013) Increased CD8+ T Cell Response to Epstein-Barr Virus Lytic Antigens in the Active Phase of Multiple Sclerosis. PLoS Pathog 9(4): e1003220. doi:10.1371/journal.ppat.1003220
Editor: Brian D. Evavold, Emory University, United States of America
Received: July 31, 2012; Accepted: January 15, 2013; Published: April 11, 2013
Copyright: © 2013 Angelini et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The study was supported by Italian Multiple Sclerosis Foundation (to DC, MS, EMC, FA, LB), European FP6 NeuroproMiSe Integrated project (Contract: LSHM-CT-2005-01863) (to FA, LB), Italian Ministry of Health, Ricerca Finalizzata 2007 - Strategic Project on Multiple Sclerosis (Contract: 107 to EMC, MS, FA, LB), and Ricerca Finalizzata 2010-Giovani Ricercatori (to DC), the French Society for Research in Multiple Sclerosis (ARSEP) (to MS, LB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: Marco Salvetti, MD, received lecture fees from Biogen-Dompé and research support from Bayer-Schering, Biogen-Dompé, Merck-Serono, Sanofi-Aventis. Claudio Gasperini, MD, has served as a consultant for Merck Serono and Biogen Idec, and has received speaker honoraria from Teva, Merck Serono, Bayer Shering and Biogec Idec. Diego Centonze, MD, is an Advisory Board member of Merck-Serono, Teva and Bayer Shering and received funding for travelling and speaker honoraria or consultation fees from Merck Serono, Teva, Novartis, Bayer Shering, Sanofi-Aventis and Biogen Idec. He is also an external expert consultant of the European Medicine Agency (EMA) and the principal investigator in clinical trials for Novartis, Merck Serono, Teva, Bayer Shering, Sanofi Aventis and Biogen Idec. The other authors have no competing interests to report. This does not alter our adherence to all PLoS Pathogens policies on sharing data and materials.
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