TY - JOUR
T1 - A virus-induced molecular mimicry model of multiple sclerosis
AU - Olson, Julie K.
AU - Croxford, J. Ludovic
AU - Calenoff, Miriam A.
AU - Dal Canto, Mauro C.
AU - Miller, Stephen D.
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI200113032
DO - 10.1172/JCI200113032
M3 - Article
C2 - 11457884
AN - SCOPUS:0034947448
SN - 0021-9738
VL - 108
SP - 311
EP - 318
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 2
ER -