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

Abstract

Multiple sclerosis (MS) is a disease with profound heterogeneity in clinical course, neuroradiological appearance of the lesions, involvement of susceptibility gene loci, and response to therapy. These features are supported by experimental evidence, which demonstrates that fundamentally different processes, such as autoimmunity or virus infection, may induce MS‐like inflammatory demyelinating plaques and suggest that MS may be a disease with heterogeneous pathogenetic mechanisms. From a large pathology sample of MS, collected in three international centers, we selected 51 biopsies and 32 autopsies that contained actively demyelinating lesions defined by stringent criteria. The pathology of the lesions was analyzed using a broad spectrum of immunological and neurobiological markers. Four fundamentally different patterns of demyelination were found, defined on the basis of myelin protein loss, the geography and extension of plaques, the patterns of oligodendrocyte destruction, and the immunopathological evidence of complement activation. Two patterns (I and II) showed close similarities to T‐cell–mediated or T‐cell plus antibody–mediated autoimmune encephalomyelitis, respectively. The other patterns (III and IV) were highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus‐ or toxin‐induced demyelination rather than autoimmunity. At a given time point of the disease—as reflected in autopsy cases—the patterns of demyelination were heterogeneous between patients, but were homogenous within multiple active lesions from the same patient. This pathogenetic heterogeneity of plaques from different MS patients may have fundamental implications for the diagnosis and therapy of this disease. Ann Neurol 2000;47:707–717

Cause and prevention of demyelination in a model multiple sclerosis lesion

“…The inflammatory reaction is followed by the appearance of a demyelinating lesion in which the demyelination is achieved by the distinctive pattern III mechanism 4, 6, 26. The experimental lesion is achieved by the same mechanisms as implicated in the human MS lesion,27, 28 and notably it does not seem to result from autoimmune mechanisms.…”

Acutely damaged axons are remyelinated in multiple sclerosis and experimental models of demyelination

“…and C.S. according to criteria described elsewhere (Brück et al, 1995, 1994; Kutzelnigg et al, 2005; Lassmann, 2011; Lucchinetti et al, 2000; Schuh et al, 2014). The study was performed in accordance with national and local ethics regulations and approved by the UMG ethics committee.…”

Inflammation and adaptive immune responses to adenoviral vectors injected into the brain: peculiarities, mechanisms, and consequences

“…37 Although the initiation of multiple sclerosis is not well understood, a systemic immune response against myelin antigens results in progressive bouts of brain inflammation, with severe brain toxicity, and behavioral impairments. 38 In the case of paraneoplastic syndromes, the primary tumor can be located in the lung, for example, small cell lung carcinoma, and is sometimes first recognized through neurological symptomatology. In this case, the priming of the immune response occurs in the secondary lymphoid organs.…”

“…The mechanisms underlying the initiation and pathological progression of human multiple sclerosis, however, remain to be elucidated. 38 More recently, authors have demonstrated that inactivated bacillus Calmette-Guerin (BCG) injected into the brain will remain in the CNS, in the absence of a systemic immune response. In the presence of systemic immunization a chronic inflammatory response occurs that can cause pathological brain lesion, even if antigen cannot be eliminated from the brain.…”