Figure 1.

Pathoetiology of oligodendrocytosis and autoimmunity in MS. There are two principal competing hypotheses of MS pathoetiology. In the “outside-in” hypothesis, an unknown trigger activates peripheral T- and/or B-cells and leads to an infiltration of these cells into the CNS via an apparently dysfunctional blood brain barrier (BBB). T-cells attack myelin in the CNS causing oligodendrocytes to degenerate, resulting in myelin loss and the release of myelin debris. Innate immune cells (e.g., microglia) engulf the myelin debris and act as antigen presenting cells to T-cells that then exacerbate the process of oligodendrocyte damage and demyelination. In contrast, in the “inside-out” hypothesis, oligodendrocyte degeneration is initially triggered by internal metabolic dysfunction in the CNS leading to demyelination and gliosis with subsequent release of inflammatory cytokines and chemokines. This cascade of events compromises the integrity of the BBB resulting in permeability to peripherally circulating T- and B-cells. Within the CNS, T-cells (CD4⁺ and CD8⁺) interact with antigen presenting cells, via major histocompatibility complex, and become activated. These activated T-cells also release inflammatory mediators such as cytokines, nitric oxide, and glutamate, which exacerbate the degenerative process leading to a subsequent immune response which further accelerates oligodendrocytosis and demyelination [adapted from (11)]. Figure was constructed using CorelDraw-version 2018 (www.coreldraw.com, Ottawa, ON, Canada) image processing software.