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The Innate Immune Response Affects the Development of the Autoimmune Response in Theiler’s Virus-Induced Demyelinating Disease¹

Julie K. Olson^2,* and Stephen D. Miller

^* Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, WI 53706; and Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611

Multiple sclerosis (MS) is a human CNS autoimmune demyelinating disease. Epidemiological evidence has suggested a role for virus infection in the initiation and/or exacerbation of MS. Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating disease serves as a relevant mouse model for MS. TMEV-infected mice develop a demyelinating disease with clinical symptoms beginning around 35 days after infection, which is associated with development of myelin-specific, PLP_139–151, CD4⁺ T cell responses. Viruses have been suggested to initiate autoimmune disease through bystander activation of immune cells or through bystander damage to tissue during infection. We examined the effect of the innate immune response on development of autoimmune demyelinating disease by altering the innate immune response through administration of innate immune cytokines, IFN- or IFN-β, or antiserum against the type I IFNs during the innate immune response to TMEV. Administration of IFN-β, but not IFN-, to TMEV- infected mice led to reduced myelin-specific CD4⁺ T cell responses and reduced demyelinating disease, which was associated with decreased immune cell infiltration into the CNS and increased expression of IL-10 in the CNS. Conversely, administration of antiserum to IFN-β led to a more severe demyelinating disease. In addition, administration of poly(I:C), which is an innate immune agonist, to TMEV-infected mice during the innate immune response resulted in decreased myelin-specific CD4⁺ T cell responses and reduced demyelinating disease. These results demonstrate that activating or enhancing the innate immune response can reduce the subsequent initiation and progression of the autoimmune response and demyelinating disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Multiple Sclerosis Society Grants RG3625 and RG3629 and National Institutes of Health Grant NS023349.

² Address correspondence and reprint requests to Dr. Julie K. Olson, Department of Neurological Surgery, University of Wisconsin, 1300 University Avenue, Madison, WI 53706. E-mail address: j.olson{at}neurosurg.wisc.edu

³ Abbreviations used in this paper: MS, multiple sclerosis; PLP, proteolipid protein; TMEV, Theiler’s murine encephalomyelitis virus; PAMP, pathogen-associated molecular pattern; IRF, IFN regulatory factor; DAMP, damage-associated molecular pattern; MMP, matrix metalloproteinase.

⁴ The online version of this article contains supplemental material.

This article has been cited by other articles:

				J. L. Bowen and J. K. Olson Innate Immune CD11b+Gr-1+ Cells, Suppressor Cells, Affect the Immune Response during Theiler's Virus-Induced Demyelinating Disease J. Immunol., December 1, 2009; 183(11): 6971 - 6980. [Abstract] [Full Text] [PDF]