A virus-induced molecular mimicry model of multiple sclerosis
Julie K. Olson, … , Mauro C. Dal Canto, Stephen D. Miller
Julie K. Olson, … , Mauro C. Dal Canto, Stephen D. Miller
Published July 15, 2001
Citation Information: J Clin Invest. 2001;108(2):311-318. https://doi.org/10.1172/JCI13032.
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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 the H147A, but not the W144A, PLP...
SJL mice infected with TMEV containing the H147A, but not the W144A, PLP139-151 APL develop early cross-reactive T cell responses to native PLP139-151. SJL mice were infected with PLP139-BeAn, H147A PLP139-BeAn, or W144A PLP139-BeAn. (a) At 14 days PI, the mice were ear-challenged with 5 μg PLP139-151 or VP2 70-86 and in vivo DTH responses were determined at 24 hours after challenge. **DTH responses were significantly higher than those in mock-infected controls; P ≤ 0.01. Splenic CD4+ T cell proliferative responses from 2–3 mice per group were determined at 14 days (b), 28 days (c), and 90 days PI (d) to the immunodominant TMEV epitope, VP2 70-86, and to a panel of self myelin epitopes — PLP139-151, PLP56-70, and PLP178-191. T cell proliferation was determined at 96 hours and results expressed as mean cpm ± SEM of triplicate cultures. *Stimulation index (cpm + antigen)/(cpm – antigen) ≥ 3. Results are representative of three separate experiments.