Theiler's virus infection: Pathophysiology of demyelination and neurodegeneration

Multiple sclerosis (MS) has been suggested to be an autoimmune demyelinating disease of the central nervous system (CNS), whose primary target is either myelin itself, or myelin-forming cells, the oligodendrocytes. Although axonal damage occurs in MS, it is regarded as a secondary event to the myelin damage. Here, the lesion develops from the myelin (outside) to the axons (inside) "Outside-In model". The Outside-In model has been supported by an autoimmune model for MS, experimental autoimmune (allergic) encephalomyelitis (EAE). However, recently, (1) EAE-like disease has also been shown to be induced by immune responses against axons, and (2) immune responses against axons and neurons as well as neurodegeneration independent of inflammatory demyelination have been reported in MS, which can not be explained by the Outside-In model. Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD) is a viral model for MS. In TMEV infection, axonal injury precedes demyelination, where the lesion develops from the axons (inside) to the myelin (outside) "Inside-Out model". The initial axonal damage could result in the release of neuroantigens, inducing autoimmune responses against myelin antigens, which potentially attack the myelin from outside the nerve fiber. Thus, the Inside-Out and Outside-In models can make a "vicious" immunological cycle or initiate an immune cascade.