Biochemically altered myelin triggers autoimmune demyelination

Significance Caprariello et al. demonstrate that subtle biochemical pathology to axon-ensheathing myelin, in the absence of overt demyelination, is sufficient to elicit severe secondary demyelinating inflammatory reactions. The resulting lesions bear radiological and histological resemblance to inflammatory demyelinating lesions of multiple sclerosis (MS), raising the possibility that subtle myelin degeneration in the MS brain may be a proximal event in the evolution of inflammation and consequent myelin loss. Consistent with an “inside-out” model of MS pathogenesis, these findings provide a rationale for investigating myelin as a target for early preventive therapy.