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Abstract
Objective: To determine whether the activation of innate immune responses, which can be elicited by pathogenic and endogenous triggers, is associated with the presence of Epstein-Barr virus (EBV) infection in the multiple sclerosis (MS) brain.
Methods: White matter postmortem MS (n = 10) and control tissue (n = 11) was analyzed for the expression of the proinflammatory cytokine interferon α (IFNα) by immunohistochemistry and for EBV by using the highly sensitive method of EBV-encoded RNA (EBER) in situ hybridization.
Results: We detected overexpression of IFNα in active areas of white matter MS lesions but not in inactive MS lesions, normal-appearing white matter, or normal brains. The presence of IFNα in macrophages and microglia (expressing human leukocyte antigen class II) is suggestive of local production as part of an acute inflammatory process. Interestingly, EBERs were also specifically detected in areas where IFNα was overexpressed in these preselected active MS lesions. EBER+ cells were also found in CNS lymphoma and stroke cases, but were absent in other control brains. We next addressed a potential mechanism, e.g., the role of EBERs in eliciting IFNα production, and transfected EBERs into human embryonic kidney (HEK) cells. We used HEK cells that stably expressed Toll-like receptor-3, which recognizes double-stranded RNAs, associated with many viral infections. EBERs elicited IFNα production in vitro.
Conclusion: These findings suggest that latent EBV infection may contribute to the inflammatory milieu in active MS lesions by activating innate immune responses, e.g., IFNα production. Unraveling the underlying mechanisms may help in uncovering causal pathways and developing better treatment strategies for MS and other neuroinflammatory diseases.
GLOSSARY
- ds=
- double-stranded;
- EBER=
- EBV-encoded RNA;
- EBNA-1=
- EBV nuclear antigen 1;
- EBV=
- Epstein-Barr virus;
- FCS=
- fetal calf serum;
- H&E=
- hematoxylin & eosin;
- HEK=
- human embryonic kidney;
- HLA=
- human leukocyte antigen;
- HSE=
- herpes simplex encephalitis;
- IFNα=
- interferon α;
- IgG=
- immunoglobulin G;
- ISH=
- in situ hybridization;
- LFB=
- Luxol fast blue;
- mAb=
- monoclonal antibody;
- MS=
- multiple sclerosis;
- OHL=
- oral hairy leukoplakia;
- PBS=
- phosphate-buffered saline;
- pDC=
- plasmacytoid dendritic cell;
- PLP=
- protein lipid protein;
- SLE=
- systemic lupus erythematosus;
- SSPE=
- subacute sclerosing panencephalitis;
- TLR3=
- Toll-like receptor-3
Footnotes
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Study funding: AIMS2CURE (G.G., U.M.), Roan Charitable Trust (U.M., G.G.), MRC grant (G.G.), UAEU FMHS Project Grant (G.K.), Wellcome Trust grant no. WT082609MA (M.C.).
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Editorial, page 11
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Supplemental data at www.neurology.org
- Received December 14, 2010.
- Accepted June 27, 2011.
- Copyright © 2012 by AAN Enterprises, Inc.
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- Epstein-Barr virus may cause disruption of the blood brain barrier, with macrophage invasion of brain parenchyma and development of MS plaques
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