Multiple pathways to induction of virus-induced autoimmune demyelination: Lessons from Theiler's virus infection

Infection of SJL mice with wild-type BeAn strain of Theiler's murine enceph alomyelitis virus (TMEV) leads to CD4(+) T cell-mediated CNS demyelination characterized by the development of anti-myelin epitope autoimmune response s via epitope spreading during the chronic stage of disease. To examine the feasibility of virus-encoded mimic epitopes to initiate CNS autoimmunity, we recently developed a molecular mimicry model of virus-induced demyelinat ing disease wherein a non-pathogenic variant strain of TMEV was engineered to encode a 30-mer peptide encompassing the immunodominant myelin proteolip id protein, PLP139-151, epitope. SJL,mice infected intracerebrally with TME V encoding either the native PLP139-151 determinant or various peptide mimi cs of the epitope develop an early onset demyelinating disease mediated by activated PLP139-151-specific Thl cells. The autoimmune nature of this earl y-onset demyelinating disease is shown by the fact that induction of tolera nce to the PLP139-151 peptide prevents clinical disease and associated PLP1 39-151-specific T cell responses without affecting T cell reactivity to vir us epitopes. Most significantly, TMEV encoding a molecular mimic peptide de rived from the Haemophilus influenzae bacteria, homologous at only six out of thirteen of the core amino acids, led to CNS disease. These studies prov ide conclusive evidence that virus-induced myelin-specific autoreactive T c ells can be induced by molecular mimicry and provide a useful model to stud y the disease inducing ability of viruses encoding human-disease-related mi micry peptides. (C) 2001 Academic Press.