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: J K Olson, J L Croxford, M A Calenoff, M C Dal Canto, S D Miller
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 108 Issue 2 Pg. 311-8 (Jul 2001) ISSN: 0021-9738 [Print] United States
• PMID: 11457884 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cytokines
• Epitopes
• Myelin Proteolipid Protein
• Peptide Fragments
• myelin proteolipid protein (139-151)

Topics

• Amino Acid Sequence
• Animals
• Autoimmunity
• CD4-Positive T-Lymphocytes (immunology)
• Cardiovirus Infections (immunology, virology)
• Cross Reactions
• Cytokines (analysis)
• Demyelinating Autoimmune Diseases, CNS (immunology)
• Disease Models, Animal
• Encephalitis, Viral (immunology, virology)
• Epitopes (chemistry)
• Mice
• Molecular Mimicry
• Molecular Sequence Data
• Multiple Sclerosis (etiology)
• Myelin Proteolipid Protein (biosynthesis, chemistry, genetics)
• Peptide Fragments (biosynthesis, chemistry, genetics)
• Recombination, Genetic
• Th1 Cells (immunology)
• Theilovirus (genetics, metabolism)