Immune mechanisms of Theiler's virus-induced demyelination.

Abstract

Multiple sclerosis (MS) is an immune-mediated neurological disease reflecting demyelination in the white matter of the brain and spinal cord (Adams and Victor, 1977). The clinical symptoms range from a mild nervous system disability to a severe degenerative paralyzing disorder. Generally, MS is considered to involve autoimmunity to myelin components and is one of the most common neurological disorders of young adults. It is estimated that approximately 300,000 patients are affected in the USA alone. Because of the chronic nature of the disease, social and economic loss by this disease is enormous. Although the cause of MS is unknown, one or multiple infectious agents may be involved in the initial infliction of tissue damage leading to autoimmunity. A possible viral association is suggested by epidemiological studies (Johnson, 1975; McFarlin and McFarland, 1982) as well as the detection of viral antigens and virus-specific antibodies in the majority of MS patients (Soldan et al., 1997). Several virus-induced and autoimmune models have been used to study the underlying mechanisms of this disease (Daniels et al., 1952; Alford, 1984; Dal Canto et al., 1996; Miller et al., 1997). These models include demyelinating diseases induced by infection with mouse Hepatitis virus (Lane and Buchmeier, 1997), Sindbis virus (Griffin et al., 1992), Semliki Forest virus (Smyth et al., 1990), Herpes virus (Kastrukoff et al., 1992), or Theiler’s murine encephalomyelitis virus (TMEV) as well as immunization with central nervous system autoantigens. Among these experimental model systems, TMEVinduced demyelination (Dal Canto et al., 1996; Miller et al., 1997) provides an excellent infectious model for the following reasons. The viral structure of TMEV is relatively simple and only few proteins are involved in induction of immune responses. In addition, virus infection has neurotrophism and does not induce any other detec diseases except demyelination. An intracerebral inoculation of TMEV into susceptible strains of mice results in a chronic immune-mediated demyelinating disease that shares many of the features of human MS. For example, chronic pathological involvement is limited to the white matter of the CNS and myelin breakdown is directly related to the clinical symptoms. In addition, demyelination is primarily associated with cell-mediated immune responses and strong autoimmunity to myelin antigens is induced following the initial demyelination by virus-specific T cells (Miller et al., 1997). TMEV is a common enteric pathogen in mice and belongs to the picornaviridae (Theiler and Gard, 1940; Lipton and Friedmann, 1980). Like other picornaviruses, TMEV has four structural capsid proteins (VP1, VP2, VP3 and VP4) assembled in an icosahedral structure and thus the major immune responses to the virus are against the capsid proteins (Theiler and Gard, 1940; Lipton and Friedmann, 1980). Two major subgroups of TMEV have been identified: The first subgroup includes GDVII and FA viruses causing rapid and fatal encephalitis and the second subgroup includes the BeAn and DA strains. The second subgroup causes a biphasic neurological disease upon intracerebral inoculation of the virus into susceptible mice (Dal Canto et al., 1996). The early, acute phase displays flaccid limb paralysis and degeneration of neurons. The late phase represents chronic, inflammatory demyelination.