Viral Infection of Transgenic Mice Expressing a Viral Protein in Oligodendrocytes Leads to Chronic Central Nervous System Autoimmune Disease

Evans, Claire F.; Horwitz, Marc S.; Hobbs, Monte V.; Oldstone, Michael B.A.

The enhanced pathology seen after a second infection with a virus not encoding LCMV gene products is likely due to activation of LCMV-specific memory CTL (Table 2 ). This could be due to a general nonspecific stimulation of memory cells (bystander activation) after the upregulation of cytokine expression in response to the second viral infection (49) . Preliminary experiments have shown that treatment of LCMV-immune MBP-NP mice with the interferon-inducer poly I/C (50, 51) did not result in enhanced CNS pathology. Alternatively, reactivation may be a result of cross-reactivities of LCMV-specific CTL with heterologous viral peptides presented by MHC class I molecules (33, 52) . Experiments to distinguish between these possibilities are in progress. After poliovirus immunization of human adults previously vaccinated for polio in childhood, immune responses to unrelated antigens (reovirus and tetanus toxoid) were observed, indicating that secondary activation of immune responses also occurs in humans (53) . The cross-activation of memory T cells specific for an oligodendrocyte protein by subsequent viral infections may explain why patients with an autoimmune disease such as MS often exhibit disease exacerbations after infections by different viruses (54) (55) (56) . It may also serve to explain both the long lag period before disease symptoms and the risk factor association of disease to the first 15 yr of life (57) . A cross-reactive immune response to oligodendrocyte-specific antigens through a process of molecular mimicry early in life could lead to the generation of memory T cells specific for a myelin antigen. These self-reactive T cells could then be reactivated after subsequent pathogen exposures, eventually leading to clinically observable disease exacerbations. Exploitation of the model described here will be useful for evaluating the potential of unrelated viruses to contribute to the exacerbation of CNS autoimmune disease, and for developing therapies to modify such disease.