Microglial nodules and newly forming lesions may be a Janus face of early MS lesions; implications from virus-induced demyelination, the Inside-Out model

Background: Although the precise mechanism of initial lesion development in multiple sclerosis ( MS) remains unclear, two different neuropathological findings have been reported as a potential early pathology of MS: microglial nodules and newly forming lesions, both of which contain neither T cell infiltration nor demyelination. In microglial nodules, damaged axons were associated with a small number of aggregated macrophages/microglia, while oligodendrocyte apoptosis was a characteristic in newly forming lesions. However, is the presence of microglial nodules and oligodendrogliopathy mutually exclusive? Might these two different observations be the same neuropathology (as proposed by the concept, preactive lesions), but interpreted differently based on the different theories of early MS lesion development, using different staining methods? Discussion: Since two studies are looking at two distinct aspects of early MS pathogenesis (one focused on axons and the other on oligodendrocytes), in a sense, one can say that these two studies are complementary. On the other hand, experimentally, Wallerian degeneration (WD) has been demonstrated to induce both microglial nodules and oligodendrocyte apoptosis in the central nervous system (CNS). Here, when encephalitogenic T cells are present in the periphery in both autoimmune and viral models of MS, induction of WD in the CNS has been shown to result in the recruitment of T cells along the degenerated tract, leading to demyelination (Inside-Out model). These experimental findings are consistent with early MS pathology described by both microglial nodules and newly forming lesions. Conclusions: The differences between the two neuropathological findings may be based on the preference of staining methods, where one group observed axonal and microglial pathology and the other observed oligodendrocyte apoptosis; a Janus face that is looked at from the two different sides.