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The primary target in multiple sclerosis (MS) is believed to be either myelin itself (myelinopathy) or the myelin-forming cell, the oligodendrocyte (oligodendrogliopathy). Although axonal injury occurs in MS, it is regarded as a secondary event to the myelin damage. Here, the lesion develops from myelin (outside) to the axon (inside) (Outside-In model). Recently, gray matter lesions and axonal injury in normal-appearing white matter have also been reported in MS. This raises two questions. 1) Is axonal injury exclusively secondary to myelin damage or from a direct insult to the axon or neurons (axonopathy)? (2) Is the injured axon regarded as only an end result of pathology or disease, or can axonal injury contribute to the spread of secondary damage, including demyelination? The former is raised from the fact that axonal damage has been reported in several virus infections, including human immunodeficiency virus, human T-lymphotropic virus 1, herpes simplex virus and coronavirus, which also cause demyelination. The latter possibility where axonal injury leads to other changes is raised from the rather unexpected similarity between spinal cord injury (SCI) and MS where axonal injury, oligodendrocyte apoptosis and demyelination are all present. In SCI, transection of axons leads to delayed oligodendrocyte apoptosis with secondary demyelination. Neurofilament immunostaining of spinal cord sections demonstrates that axonal injury with oligodendrocyte apoptosis also precedes demyelination in an animal model for MS, Theiler's murine encephalomyelitis virus infection. This implies that axonal injury could trigger demyelination. In this instance, lesions develop from the axon (inside) to the myelin (outside) (Inside-Out model).

Multiple sclerosis (MS) can be divided into 4 clinical forms: relapsing‐remitting (RR), primary progressive (PP), secondary progressive (SP), and progressive relapsing (PR). Since PP‐MS is notably different from the other forms of MS, both clinically and pathologically, the question arises whether PP‐MS is immunologically similar to the other forms. The pathogenesis of the PP‐MS remains unclear, partly due to a lack of highly relevant animal models. Using an encephalitogenic peptide from myelin oligodendrocyte glycoprotein (MOG)92–106, we have established animal models that mimic different forms of MS in 2 strains of H‐2s mice, SJL/J and A.SW. We induced experimental allergic encephalomyelitis (EAE) using MOG92‐106 in the presence or absence of supplemental Bordetella pertussis (BP). Although, SJL/J mice developed RR‐EAE whether BP was given or not, A.SW mice developed PP‐EAE without BP and SP‐EAE with BP. Histologically, SJL/J mice developed mild demyelinating disease with T cell infiltration, while A.SW mice developed large areas of plaque‐like demyelination with immunoglobulin deposition and neutrophil infiltration, but with minimal T cell infiltration. In A.SW mice without BP, high titer serum anti‐MOG antibody was detected and the anti‐MOG IgG2a/IgG1 ratio correlated with survival times of mice. We hypothesized that, in A.SW mice, a Th2 response favors production of myelinotoxic antibodies, leading to progressive forms with early death. Our new models indicate that a single encephalitogen could induce either RR‐, PP‐, or SP‐ forms of demyelinating disease in hosts with immunologically different humoral immune responses.

Apoptosis has been observed in neural development and in various neurological diseases, including viral infection and multiple sclerosis. Theiler's murine encephalomyelitis virus is divided into two subgroups based on neurovirulence: the highly neurovirulent GDVII strain produces an acute fatal polioencephalomyelitis in mice, whereas the attenuated DA strain produces demyelination with virus persistence preceded by an acute infection. TUNEL combined with immunocytochemistry was used to detect apoptosis in the central nervous system and to characterize which cell types were involved during the acute stage in both GDVII and DA virus infection and during the chronic stage in DA virus infection. We found that during the acute stage, apoptosis was induced in neurons in both virus infections. However, the number of apoptotic neurons was much greater in GDVII virus-infected mice than in DA virus-infected mice (P < 0.01). During the chronic stage of DA virus infection, apoptotic cells were detected only in the spinal cord white matter. Some of these cells were dual labeled for fragmented DNA and carbonic anhydrase II, an oligodendrocyte marker. Our results indicate that apoptosis of neurons could be responsible for the fatal outcome in GDVII virus infection. In contrast, apoptosis of oligodendrocytes can contribute to the chronic demyelinating DA virus infection.