[Show abstract][Hide abstract] ABSTRACT:
Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS). Neither the antigenic target(s) nor the cell population(s) responsible for CNS tissue destruction in MS have been fully defined. The objective of this study was to simultaneously determine the antigen (Ag)-specificity and phenotype of un-manipulated intrathecal CD4+ and CD8+ T cells of patients with relapsing-remitting and progressive MS compared to subjects with other inflammatory neurological diseases. We applied a novel Ag-recognition assay based on co-cultures of freshly obtained cerebrospinal fluid T cells and autologous dendritic cells pre-loaded with complex candidate Ag's. We observed comparably low T cell responses to complex auto-Ag's including human myelin, brain homogenate, and cell lysates of apoptotically modified oligodendroglial and neuronal cells in all cohorts and both compartments. Conversely, we detected a strong intrathecal enrichment of Epstein-Barr virus- and human herpes virus 6-specific (but not cytomegalovirus-specific) reactivities of the Th1-phenotype throughout all patients. Qualitatively, the intrathecal enrichment of herpes virus reactivities was more pronounced in MS patients. This enrichment was completely reversed by long-term treatment with the IL-2 modulating antibody daclizumab, which strongly inhibits MS disease activity. Finally, we observed a striking discrepancy between diminished intrathecal T cell proliferation and enhanced cytokine production of herpes virus-specific T cells among progressive MS patients, consistent with the phenotype of terminally differentiated cells. The data suggest that intrathecal administration of novel therapeutic agents targeting immune cells outside of the proliferation cycle may be necessary to effectively eliminate intrathecal inflammation in progressive MS.
PLoS ONE 08/2014; 9(8):e105434. DOI:10.1371/journal.pone.0105434 · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT:
Multiple sclerosis (MS) is a common chronic inflammatory demyelinating disease of the central nervous system (CNS) causing progressive disability. Many observations implicate Epstein-Barr virus (EBV) in the pathogenesis of MS, namely universal EBV seropositivity, high anti-EBV antibody levels, alterations in EBV-specific CD8(+) T-cell immunity, increased spontaneous EBV-induced transformation of peripheral blood B cells, increased shedding of EBV from saliva and accumulation of EBV-infected B cells and plasma cells in the brain. Several mechanisms have been postulated to explain the role of EBV in the development of MS including cross-reactivity between EBV and CNS antigens, bystander damage to the CNS by EBV-specific CD8(+) T cells, activation of innate immunity by EBV-encoded small RNA molecules in the CNS, expression of αB-crystallin in EBV-infected B cells leading to a CD4(+) T-cell response against oligodendrocyte-derived αB-crystallin and EBV infection of autoreactive B cells, which produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells in the CNS. The rapidly accumulating evidence for a pathogenic role of EBV in MS provides ground for optimism that it might be possible to prevent and cure MS by effectively controlling EBV infection through vaccination, antiviral drugs or treatment with EBV-specific cytotoxic CD8(+) T cells. Adoptive immunotherapy with in vitro-expanded autologous EBV-specific CD8(+) T cells directed against viral latent proteins was recently used to treat a patient with secondary progressive MS. Following the therapy, there was clinical improvement, decreased disease activity on magnetic resonance imaging and reduced intrathecal immunoglobulin production.
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