The mechanism(s) underlying the initiation and progression of autoimmune diseases are not well understood. Clinical and epidemiologic evidence supports a role for viral infections. Postulated mechanisms include: molecular' mimicry (activation of autoreactive T cells secondarily by viral epitopes shared or cross-reactive with self antigens); epitope spreading (de novo activation of autoreactive T cells by sequestered antigens released secondary to self tissue destruction); and superantigens (non-specific stimulation of autoreactive T cells bearing particular VB receptors). Evidence for a viral etiology is particularly strong for multiple sclerosis (MS), a human CD4+ T cell mediated demyelinating disease associated with anti-myelin responses. The investigators have used the Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease model of MS to examine mechanisms of initiation and progression of virus-induced autoimmunity. TMEV is a natural mouse pathogen which establishes a life-long persistent CNS infection. Demyelination following infection of SJL mice with the wildtype BeAn strain of TMEV is initiated by virus-specific CD4+ Thl cells targeting virus persisting in CNS macrophages/microglia. Autoreactivity to the immunodominant myelin proteolipid protein epitope, PLP139-151, arises via epitope spreading two months post infection and plays a pathologic role in disease progression. To test the ability of molecular mimicry to initiate CNS demyelination, they engineered TMEV expressing PLP139-151 in the viral leader (PLP139-BeAn). SJL mice infected with PLP1 39-BeAn develop a severe, rapid-onset clinical demyelinating disease characterized by early activation of PLP1 39-151-specific T cells. They will test the hypothesis that CNS autoimmunity can be initiated by molecular mimicry induced by infection with a neurotropic virus.
Aim 1 will further characterize PLP139-BeAn-induced disease by determining the pathologic role of PLP139-151-specific T cells (using tolerance and adoptive transfer) and the precursor frequency and temporal appearance of CD4+ and CD8+ TMEV- and myelin epitope-specific responses.
Aim 2 will directly test the molecular mimicry hypothesis by assessing activation of autoreactive T cells1and clinical disease following infection with TMEV encoding molecular mimics of PLP139-151 naturally expressed by mouse hepatitis virus and H. influenzae. Relevant to human MS, Aim 3 will assess activation of autoreactive T cells and clinical disease induced by infection with TMEV encoding molecular mimics of the MS-associated MBP85 99 epitope naturally expressed by HSV, EBV, influenza A virus and Reovirus type 3 in HLA-DR2 transgenic mice. These studies should further our understanding of the potential role of molecular mimicry in MS etiology by defining activation requirements for autoreactive T cells primed by infection with a virus expressing molecular mimics of defined murine and human encephalitogenic myelin peptides and assessing their pathologic capacity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040460-04
Application #
6613316
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Utz, Ursula
Project Start
2000-07-01
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
4
Fiscal Year
2003
Total Cost
$294,000
Indirect Cost
Name
Northwestern University at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Croxford, J Ludovic; Ercolini, Anne M; Degutes, Mathew et al. (2006) Structural requirements for initiation of cross-reactivity and CNS autoimmunity with a PLP139-151 mimic peptide derived from murine hepatitis virus. Eur J Immunol 36:2671-80

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