Molecular signature of Epstein-Barr virus infection in MS brain lesions.

OBJECTIVE: We sought to confirm the presence and frequency of B cells and Epstein-Barr virus (EBV) (latent and lytic phase) antigens in archived MS and non-MS brain tissue by immunohistochemistry. METHODS: We quantified the type and location of B-cell subsets within active and chronic MS brain lesions in relation to viral antigen expression. The presence of EBV-infected cells was further confirmed by in situ hybridization to detect the EBV RNA transcript, EBV-encoded RNA-1 (EBER-1). RESULTS: We report the presence of EBV latent membrane protein 1 (LMP-1) in 93% of MS and 78% of control brains, with a greater percentage of MS brains containing CD138+ plasma cells and LMP-1-rich populations. Notably, 78% of chronic MS lesions and 33.3% of non-MS brains contained parenchymal CD138+ plasma cells. EBV early lytic protein, EBV immediate-early lytic gene (BZLF1), was also observed in 46% of MS, primarily in association with chronic lesions and 44% of non-MS brain tissue. Furthermore, 85% of MS brains revealed frequent EBER-positive cells, whereas non-MS brains seldom contained EBER-positive cells. EBV infection was detectable, by immunohistochemistry and by in situ hybridization, in both MS and non-MS brains, although latent virus was more prevalent in MS brains, while lytic virus was restricted to chronic MS lesions. CONCLUSIONS: Together, our observations suggest an uncharacterized link between the EBV virus life cycle and MS pathogenesis.

Effects of sphingosine-1-phosphate receptor 1 phosphorylation in response to FTY720 during neuroinflammation.

Fingolimod (FTY720, Gilenya), a sphingosine-1-phosphate receptor (S1PR) modulator, is one of the first-line immunomodulatory therapies for treatment of relapsing-remitting multiple sclerosis (MS). Human S1PR1 variants have been reported to have functional heterogeneity in vitro, suggesting that S1PR1 function may influence FTY720 efficacy. In this study, we examined the influence of S1PR1 phosphorylation on response to FTY720 in neuroinflammation. We found that mice carrying a phosphorylation-defective S1pr1 gene [S1PR1(S5A) mice] were refractory to FTY720 treatment in MOG35-55-immunized and Th17-mediated experimental autoimmune encephalomyelitis (EAE) models. Long-term treatment with FTY720 induced significant lymphopenia and suppressed Th17 response in the peripheral immune system via downregulating STAT3 phosphorylation in both WT and S1PR1(S5A) mice. However, FTY720 did not effectively prevent neuroinflammation in the S1PR1(S5A) EAE mice as a result of encephalitogenic cells expressing C-C chemokine receptor 6 (CCR6). Combined treatment with FTY720 and anti-CCR6 delayed disease progression in S1PR1(S5A) EAE mice, suggesting that CCR6-mediated cell trafficking can overcome the effects of FTY720. This work may have translational relevance regarding FTY720 efficacy in MS patients and suggests that cell type-specific therapies may enhance therapeutic efficacy in MS.

Therapeutic depletion of monocyte-derived cells protects from long-term axonal loss in experimental autoimmune encephalomyelitis.

Studies in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) suggest that peripheral monocyte-derived cells (MDCs) are instrumental for disease initiation. MDCs, however, are plastic, and may exert various functions once in the central nervous system (CNS) for prolonged periods. Furthermore, the long-term effect of MDC depletion on continuing axon loss is not known. We show that long-lasting depletion of MDCs, after onset of EAE clinical deficits, is accompanied by decreased CNS infiltration by pathogenic T lymphocytes. Although this treatment does not reverse clinical disease, it prevents worsening of neurological deficits and long-term axonal loss.