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Regional CNS responses to IFN- determine lesion localization patterns during EAE pathogenesis

¹ Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201
² Departments of Neurology and Pediatrics, ³ Department of Developmental Biology, and ⁴ The Immunology Program, Washington University, St. Louis, MO 63110

CORRESPONDENCE John H. Russell: jrussell{at}wustl.edu

The localization of inflammatory foci within the cerebellum is correlated to severe clinical outcomes in multiple sclerosis (MS). Previous studies of experimental autoimmune encephalomyelitis (EAE), a model of MS, revealed distinct clinical outcomes correlated with the capacity of the animal to produce IFN-. Outcomes were linked to localization of inflammatory cells in either the spinal cord (wild type [WT]) or the cerebellum and brain stem (IFN- deficient). We demonstrate, using an adoptive transfer system, that the ability of the central nervous system (CNS) to sense pathogenic T cell–produced IFN- during EAE initiation determines the sites of CNS pathogenesis. Transfer of WT Th1 cells into IFN- receptor–deficient mice results in pathogenic invasion of the brain stem and cerebellum with attendant clinical symptoms, which are identical to the disease observed after transfer of IFN-–deficient T cells to WT hosts. Inflammation of the spinal cord associated with classical EAE is abrogated in both IFN-–deficient systems. Cotransfer of CNS antigen-specific WT Th1 cells with IFN-–deficient T cells is sufficient to restore spinal cord invasion and block cerebellar and brain stem invasion. These data demonstrate that interaction between IFN- and host CNS cells during the initiation of EAE can selectively promote or suppress neuroinflammation and pathogenesis.

Abbreviations used: BBE, Bickerstaff's brainstem encephalitis; CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; GBS, Guillain Barre syndrome; IFN-R, IFN- receptor; MFS, Miller Fisher syndrome; MOG, myelin/oligodendrocyte glycoprotein; MS, multiple sclerosis.

© 2008 Lees et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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