Abstract:

Multiple sclerosis (MS) is the most common neurological disease of young Caucasian adults. This disease is characterized by inflammatory demyelination of the central nervous system (CNS) and involves activation of key inflammatory cells of both the adaptive and innate immune systems, which target and destroy both myelin and oligodendrocytes (the myelin-forming glial cells in the CNS). Key pathological features of the disease include autoimmune inflammation, demyelination (myelin loss) and axonal degeneration. The key cell type damaged in MS is oligodendrocytes, which produce the insulating myelin sheath surrounding many axons in the CNS. Myelin and oligodendrocytes have critical roles. Myelin is responsible for promoting rapid, saltatory conduction of action potentials throughout much of the CNS. When myelin is lost in diseases such as MS, saltatory conduction is disrupted and conduction block can ensue. Myelin also provides a physical barrier for axons and thus serves to abrogate axonally directed, immune attack. Oligodendrocytes can also provide key nutritive support to axons in the healthy, quiescent state, which is compromised when oligodendrocytes are targeted. There is an emerging consensus that the progressive disability that ultimately ensues for many patients with MS correlates with the degree of accumulative axonal degeneration. It is also apparent that the extent of demyelination, and the degree of oligodendrocyte targeting, are likely to be relevant factors that dictate outcomes. Whilst it is well identified that spontaneous remyelination occurs after a demyelinative insult, the degree of remyelination within MS lesions is variable; generally MS lesions remyelinate relatively efficiently early on in disease; however, at later stages many lesions remain chronically demyelinated. These chronically demyelinated lesions typically contain oligodendrocyte progenitor cells (OPCs) and premyelinating oligodendrocytes that have “stalled” in their differentiation. These findings suggest remyelination is not limited by an absence of oligodendrocyte progenitors or their failure to generate oligodendrocytes, but a failure to differentiate into mature oligodendrocytes and to initiate new myelin formation.