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

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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 PLP 139-151-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.

Original languageEnglish (US)
Pages (from-to)311-318
Number of pages8
JournalJournal of Clinical Investigation
Volume108
Issue number2
DOIs
StatePublished - 2001

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    Olson, J. K., Croxford, J. L., Calenoff, M. A., Dal Canto, M. C., & Miller, S. D. (2001). A virus-induced molecular mimicry model of multiple sclerosis. Journal of Clinical Investigation, 108(2), 311-318. https://doi.org/10.1172/JCI200113032