Getting to grips with myelin injury in progressive multiple sclerosis

Abstract

Inflammatory-mediated demyelination of the central nervous system with well-recognized axonal injury has been described for over a hundred years. Yet, many pathologic aspects of multiple sclerosis remain poorly understood (Noseworthy et al ., 2000). Clinically, a high proportion of patients with relapsing–remitting disease advance to the secondary progressive stage of the disease (Lublin and Reingold, 1996). In contrast, ∼15% of patients never experience clinical relapses and demonstrate a steadily progressive phenotype from onset. The ability of available therapies, approved for the relapsing–remitting form of the illness, to modify the disease course in secondary or primary progressive multiple sclerosis is dismal (Compston and Coles, 2008). Paradoxically, success of the immunopathologic ‘line of thinking’ has revealed numerous deficiencies in our understanding of the neurobiology of the disease, including interdependence of the axon and oligodendrocyte (Piaton et al ., 2010). At the heart of this broadening discussion of multiple sclerosis pathology is the question of what triggers disease progression and the mechanisms that lead to increased disability. One area of research germane to this question is the expansion of focal inflammatory demyelinating lesions and the remyelinating capacity of the central nervous system in progressive phenotypes, i.e. secondary and primary progressive multiple sclerosis. Extensive cortical demyelination is a cardinal feature of progressive disease and presumably the cause of many symptoms of late-stage multiple sclerosis. Axonal injury and loss occur in association with activity of the adaptive immune response, thus leading to the question as to why this inflammation is resistant to the anti-inflammatory effects of existing therapies (Kutzelnigg et al ., 2005; Frischer et al ., 2009). The answer may partly lie in the slowly expanding demyelinating ‘front’ and the remyelinating capacity of focal lesions in the central nervous system, although much has yet to be learned about axonal–glial interactions and the state …