Heterogeneity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination

Multiple sclerosis (MS) is a disease with profound heterogeneity in clinica l course, neuroradiological appearance of the lesions, involvement of susce ptibility gene loci, and response to therapy. These features are supported by experimental evidence, which demonstrates that fundamentally different p rocesses, such as autoimmunity or virus infection, may induce MS-like infla mmatory demyelinating plaques and suggest that MS may be a disease with het erogeneous pathogenetic mechanisms. From a large pathology sample of MS, co llected in three international centers, we selected 51 biopsies and 32 auto psies that contained actively demyelinating lesions defined by stringent cr iteria. The pathology of the lesions was analyzed using a broad spectrum of immunological and neurobiological markers. Four fundamentally different pa tterns of demyelination were found, defined on the basis of myelin protein loss, the geography and extension of plaques, the patterns of oligodendrocy te destruction, and the immunopathological evidence of complement activatio n. Two patterns (I and II) showed close similarities to T-cell-mediated or T-cell plus antibody-mediated autoimmune encephalomyelitis, respectively. T he other patterns (III and IV) were highly suggestive of a primary oligoden drocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rat her than autoimmunity. At a given time point of the disease-as reflected in autopsy cases-the patterns of demyelination were heterogeneous between pat ients, but were homogenous within multiple active lesions from the same pat ient. This pathogenetic heterogeneity of plaques from different MS patients may have fundamental implications for the diagnosis and therapy of this di sease.