The enigma of multiple sclerosis: inflammation and neurodegeneration cause heterogeneous dysfunction and damage

The demyelinating disease multiple sclerosis has an autoimmune inflammatory component, which has dominated the description of multiple sclerosis. A degenerative component to multiple sclerosis was always apparent, but was underappreciated until recently. Recent work has brought axonal pathology and brain atrophy into new focus. The purpose of this review is to highlight the relative roles played by the inflammatory and degenerative processes in multiple sclerosis pathology.

In the past year reports have been published to show that early disability and disease progression correlate with axonal damage, and that brain atrophy resulting from axonal loss is a feature of early multiple sclerosis, and is not restricted to the secondary progressive forms of the disease. Inflammatory mediators (CD8 T cells and antibodies) are implicated in axonal damage, and treatment with steroids or anti-inflammatory therapies reduce brain atrophy, pointing to the involvement of the inflammatory response in the initiation of degeneration. Reduced regenerative capability also contributes to degeneration, and inflammatory responses are shown to inhibit the growth and migration of precursor cells for oligodendrocytes.

Oligodendrocyte precursors are abundant in multiple sclerosis lesions, but fail to remyelinate. Oligodendrocyte growth and regeneration are probably compromised by the action of growth inhibitory signals and lack of growth stimuli. Inflammatory cells and mediators induce axonal loss as well as demyelination. The degenerative response is therefore an integral and early component of multiple sclerosis.