A virus-induced molecular mimicry model of multiple sclerosis
Julie K. Olson, J. Ludovic Croxford, Miriam. A. Calenoff, Mauro C. Dal Canto, Stephen D. Miller
Julie K. Olson, J. Ludovic Croxford, Miriam. A. Calenoff, Mauro C. Dal Canto, Stephen D. Miller
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A virus-induced molecular mimicry model of multiple sclerosis

Abstract

Molecular mimicry is the process by which virus infection activates T cells that are cross-reactive with self antigens. Infection of SJL/J mice with the neurotropic picornavirus Theiler’s murine encephalomyelitis virus (TMEV) leads to a progressive CD4+ T cell–mediated demyelinating disease similar to multiple sclerosis. To study the potential of virus-induced molecular mimicry to initiate autoimmune demyelination, a nonpathogenic TMEV variant was engineered to encode a 30-mer peptide encompassing the immunodominant encephalitogenic myelin proteolipid protein (PLP139-151) epitope. Infection with the PLP139-151–encoding TMEV led within 10–14 days to a rapid-onset paralytic demyelinating disease characterized by PLP139-151–specific CD4+ Th1 responses; insertion of a non-self ovalbumin sequence led to restoration of the normal late-onset disease. Early-onset disease was also observed in mice infected with a TMEV encoding PLP139-151 with an amino acid substitution at the secondary T cell receptor (TCR) contact residue (H147A), but not in mice infected with TMEV encoding a PLP139-151 substitution at the primary TCR contact (W144A). Most significantly, mice infected with TMEV encoding a Haemophilus influenzae mimic peptide, sharing only 6 of 13 amino acids with PLP139-151, displayed rapid-onset disease and developed cross-reactive PLP139-151–specific CD4+ Th1 responses. To our knowledge, this is the first study showing that a naturally infectious virus encoding a myelin epitope mimic can directly initiate organ-specific T cell–mediated autoimmunity.

Authors

Julie K. Olson, J. Ludovic Croxford, Miriam. A. Calenoff, Mauro C. Dal Canto, Stephen D. Miller

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SJL mice infected with TMEV containing native PLP139-151 sequence or seq...
SJL mice infected with TMEV containing native PLP139-151 sequence or sequence mimics develop early demyelinating disease. Separate groups of SJL mice (n = 10) were injected intracerebrally with 3 × 107 PFU of the indicated recombinant viruses as well as wild-type virus (WT BeAn) or the parental construct (ΔClaI-BeAn). The mean clinical score (a) based on a grading scale of 0–5 and the percentage of mice showing clinical signs of demyelination (b) were determined at varying times after infection. Results are representative of at least three separate experiments. At 14 days PI, mice infected with OVA323-BeAn (c) or PLP139-BeAn (d) were anesthetized and sacrificed by total body perfusion through the left ventricle using chilled 3% glutaraldehyde in PBS, pH 7.3. Spinal cords were cut into 1-μm-thick segments and post-fixed in OsO4, dehydrated, and embedded in Epon. Toluidine blue–stained sections from ten segments per mouse were read and scored blind.