fig1

Figure 1. Cortical lesions in multiple sclerosis. Coronal brain sections demonstrating cortical demyelination (white) are shown in panels A-C. (A) Leukocortical (type I) and (B) intracortical (type II) lesions form around post-capillary venules (red) in the subcortical white and cortical gray matter, respectively; (C) subpial (type III) lesions extend from the superficial pial surface into the deeper layers of cortex. Type IV lesions involve all cortical layers and are not shown specifically in this schematic; (D) magnified representation of subpial cortical lesion segment demonstrating proposed inflammatory mechanism underlying subpial injury in MS. Meningeal immune cell aggregates are tightly associated with subpial lesions, in which a gradient of demyelination and microglial activation in the subjacent cortex is represented. Meningeal immune cell aggregates are typically B cell-rich and contain proliferating CD20+ B cells, plasmablasts/plasma cells, and CD4+ and CD8+ T cells contained within a network of follicular dendritic cells (see Legend). Mediators released by infiltrating immune cells in the meninges as well as by CNS-resident cells, such as activated microglia and astrocytes, are thought to contribute to ongoing meningeal inflammation and subpial injury in multiple sclerosis. A range of mechanisms have been implicated as underlying subpial cortical injury, including (1) secretion of diffusible toxic factor(s) (e.g., pro-inflammatory cytokines, extracellular vesicles, complement, etc.) released by immune cells in the meninges and/or perivascular spaces; (2) pro-inflammatory and/or toxic substances (e.g., oxygen radicals; nitrogen species; excitotoxic glutamate) released or insufficiently cleared by activated and injured glial cells; (3) mitochondrial dysfunction leading to bioenergetic failure within neurons and oligodendrocytes; and (4) neural-glial uncoupling (including loss of trophic support). CNS: central nervous system; MS: multiple sclerosis