Abstract
BackgroundIt is debated whether multiple sclerosis (MS) might result from an immunopathological response toward an active Epstein-Barr virus (EBV) infection brought into the central nervous system (CNS) by immigrating B cells. Based on this model, a relationship should exist between the local immune milieu and EBV infection status in the MS brain. To test this hypothesis, we analyzed expression of viral and cellular genes in brain-infiltrating immune cells.MethodsTwenty-three postmortem snap-frozen brain tissue blocks from 11 patients with progressive MS were selected based on good RNA quality and prominent immune cell infiltration. White matter perivascular and intrameningeal immune infiltrates, including B cell follicle-like structures, were isolated from brain sections using laser capture microdissection. Enhanced PCR-based methods were used to investigate expression of 75 immune-related genes and 6 EBV genes associated with latent and lytic infection. Data were analyzed using univariate and multivariate statistical methods.ResultsGenes related to T cell activation, cytotoxic cell-mediated (or type 1) immunity, B cell growth and differentiation, pathogen recognition, myeloid cell function, type I interferon pathway activation, and leukocyte recruitment were found expressed at different levels in most or all MS brain immune infiltrates. EBV genes were detected in brain samples from 9 of 11 MS patients with expression patterns suggestive of in situ activation of latent infection and, less frequently, entry into the lytic cycle. Comparison of data obtained in meningeal and white matter infiltrates revealed higher expression of genes related to interferonγ production, B cell differentiation, cell proliferation, lipid antigen presentation, and T cell and myeloid cell recruitment, as well as more widespread EBV infection in the meningeal samples. Multivariate analysis grouped genes expressed in meningeal and white matter immune infiltrates into artificial factors that were characterized primarily by genes involved in type 1 immunity effector mechanisms and type I interferon pathway activation.ConclusionThese results confirm profound in situ EBV deregulation and suggest orchestration of local antiviral function in the MS brain, lending support to a model of MS pathogenesis that involves EBV as possible antigenic stimulus of the persistent immune response in the central nervous system.
Highlights
It is debated whether multiple sclerosis (MS) might result from an immunopathological response toward an active Epstein-Barr virus (EBV) infection brought into the central nervous system (CNS) by immigrating B cells
These cases were selected because some of the brain tissue blocks analyzed in previous studies were highly inflamed and comprised B cell follicle-like structures in the brain meninges and active white matter (WM) lesions, which are rarely found in chronic MS stages ([6, 7, 46, 52, 53]; our unpublished observations)
Tissue blocks with RNA integrity number (RIN) values ≥ 6 and prominent immune infiltration in the WM and/or the meninges were selected for laser capture microdissection (LCM) and subsequent RNA analysis (Additional file 1)
Summary
Twenty-three postmortem snap-frozen brain tissue blocks from 11 patients with progressive MS were selected based on good RNA quality and prominent immune cell infiltration. White matter perivascular and intrameningeal immune infiltrates, including B cell follicle-like structures, were isolated from brain sections using laser capture microdissection. Tissues and sample selection Postmortem frozen tissue blocks (4 cm each) from the cerebral hemispheres of MS patients were obtained from the UK Multiple Sclerosis Tissue Bank at Imperial College London. Twenty-two cases who died in the progressive phase of MS, mainly during secondary progressive MS, and with postmortem delay ≤ 26 h were selected (Additional file 1). Brain samples that showed RIN values ≥ 6 were used for neuropathological analysis; among these, only samples containing prominent immune infiltrates in the WM and/or meninges were used for the subsequent LCM procedure (Additional file 1)
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