A virus-induced molecular mimicry model of multiple sclerosis

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 simil ar 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 p aralytic demyelinating disease characterized by PLP139-151-specific CD4(+) Th1 responses; insertion of a non-self ovalbumin sequence led to restoratio n of the normal late-onset disease. Early-onset disease was also observed i n mice infected with a TMEV encoding PLP139-151 with an amino acid substitu tion at the secondary T cell receptor (TCR) contact residue (H147A), but no t in mice infected with TMEV encoding a PLP139-151 substitution at the prim ary TCR contact (W144A), Most significantly, mice infected with TMEV encodi ng a Haemophilus influenzae mimic peptide, sharing only 6 of 13 amino acids with PLP139-151, displayed rapid-onset disease and developed cross-reactiv e PLP139-151-specific CD4(+) Th1 responses. To our knowledge, this is the f irst study showing char a naturally infectious virus encoding a myelin epit ope mimic can directly initiate organ-specific T cell-mediated autoimmunity .