Molecular mimicry. The initial expansion of naive autoreactive T cells requires activation of the TCR by MHC-bound peptides or CD1-bound lipids/glycolipids. The molecular mimicry hypothesis proposes that microbial peptides with sufficient sequence similarity to selfpeptides can activate such T cells (2). Such sequence similarities were initially identified by homology searches (2), and more recently with search algorithms that consider the structural requirements for T cell receptor (TCR) recognition of MHC-bound peptides (3). The concept of molecular mimicry was first tested in an experimental animal model with a hepatitis B virus polymerase peptide in which six amino acids were identical to the encephalitogenic region of rabbit myelin basic protein (MBP). T cell reactivity to MBP was observed following immunization of rabbits with this peptide, and four of eleven animals showed histological signs of experimental autoimmune encephalomyelitis (EAE)(2). This finding raised the important question of whether infection with viral or bacterial pathogens, rather than immunization with synthetic peptides, can also induce autoimmunity. This issue has now been addressed in a murine model of herpes simplex keratitis (HSK), a T cell–mediated inflammatory disease of the cornea that is induced by local application of herpes simplex virus (HSV). In humans, HSV-1–induced destruction of corneal tissue represents a leading cause of blindness. In the mouse model, keratogenic T cell clones induce disease following corneal application of the virus. These T cell clones crossreact with a peptide from the HSV-1 UL6 protein, and a virus with a mutated UL6 gene is greatly impaired in its ability to induce HSK (4). Together with more recent experiments employing a virus with a single amino acid mutation in the UL6 T cell epitope (5), these findings demonstrate that a viral infection can trigger T cell–mediated autoimmunity by molecular mimicry. Another example of molecular mimicry comes from a murine myocarditis model in which disease is induced with peptides from Chlamydia. In BALB/c mice, immunization with a 30–amino acid peptide from the cardiac myosin heavy chain induces a severe inflammatory heart disease. Peptides from the 60-kDa cysteine-rich outer membrane protein of Chlamydia trachomatis and other Chlamydia species have sequence similarity with this myosin peptide and induce inflammatory heart disease at a similar frequency as the myosin peptide, although with a significantly lower severity. T cells from mice immunized with the Chlamydia peptide show a strong proliferative response to the myosin peptide, and such Chlamydia-reactive T cell lines induce moderately severe myocarditis. Bachmeier et al.(6) have observed that Chlamydia infection in mice results in the production of antibodies that crossreact with myosin, but the authors did not report whether such an infection induces myocarditis.

A new animal model of molecular mimicry was recently reported in which recombinant Theiler’s viruses were generated by insertion of short segments that encoded for 30–amino acid peptides. This model was first tested with a virus that expressed a self-peptide from proteolipid protein (PLP, residues 139–151).