Fig. 1

Early lesion development theories of multiple sclerosis (MS) and its viral model. When axonal injury (arrow) occurs in Neuron A, it causes degeneration of the distal part of transected axons [Wallerian degeneration (WD)]. This leads to activation of microglia [microglial nodules (MGNs)] and oligodendrocyte apoptosis along the degenerated axon of Neuron A’, which is followed by demyelination of the nerve fiber of Neuron A”. Here, the lesion develops from the inside axon to the outside myelin (Inside-Out model). Later, the changes in the microenvironment of Neuron A” recruit encephalitogenic T cells from the systemic circulation to the site of WD, where extravasated T cells from the blood vessels attack myelin sheaths of neighboring Neurons B and C, resulting in demyelination. Apoptotic oligodendrocytes that make myelin sheaths of Neuron A” also result in demyelination of Neurons C and D. In this active MS plaque, demyelination of Neurons B, C, and D can occur without the damage of axons (primary demyelination, Outside-In model). In a viral model of MS, Theiler’s murine encephalomyelitis virus (TMEV) infection, axonal degeneration, MGNs, and oligodendrocyte apoptosis are visualized by non-phosphorylated neurofilament staining, lectin cytochemistry [Ricinus communis agglutinin (RCA) I], and the terminal deoxynucleotidyl-transferase-mediated dUTP-biotin nick-end labeling (TUNEL) method, respectively, during the early stage of TMEV infection, 1–2 weeks post infection (p.i.), in the normal appearing white matter, preceding demyelination. Full-blown demyelination and T cell infiltration are visualized by Luxol fast blue staining and anti-CD3 immunohistochemistry during the chronic stage of TMEV infection more than 1 month p.i, which is called TMEV-induced demyelinating disease (TMEV-IDD)