Axon‐Myelin Unit Blistering as Early Event in MS Normal Appearing White Matter

Abstract

Objective Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease of unknown etiology. Although the prevalent view regards a CD4+‐lymphocyte autoimmune reaction against myelin at the root of the disease, recent studies propose autoimmunity as a secondary reaction to idiopathic brain damage. To gain knowledge about this possibility we investigated the presence of axonal and myelinic morphological alterations, which could implicate imbalance of axon‐myelin units as primary event in MS pathogenesis. Methods Using high resolution imaging histological brain specimens from patients with MS and non‐neurological/non‐MS controls, we explored molecular changes underpinning imbalanced interaction between axon and myelin in normal appearing white matter (NAWM), a region characterized by normal myelination and absent inflammatory activity. Results In MS brains, we detected blister‐like swellings formed by myelin detachment from axons, which were substantially less frequently retrieved in non‐neurological/non‐MS controls. Swellings in MS NAWM presented altered glutamate receptor expression, myelin associated glycoprotein (MAG) distribution, and lipid biochemical composition of myelin sheaths. Changes in tethering protein expression, widening of nodes of Ranvier and altered distribution of sodium channels in nodal regions of otherwise normally myelinated axons were also present in MS NAWM. Finally, we demonstrate a significant increase, compared with controls, in citrullinated proteins in myelin of MS cases, pointing toward biochemical modifications that may amplify the immunogenicity of MS myelin. Interpretation Collectively, the impaired interaction of myelin and axons potentially leads to myelin disintegration. Conceptually, the ensuing release of (post‐translationally modified) myelin antigens may elicit a subsequent immune attack in MS. ANN NEUROL 2021;89:711–725

Citicoline: A Candidate for Adjunct Treatment of Multiple Sclerosis

“…According to a long-standing concept, currently described as the "outside-in" hypothesis, disease is initiated by infiltration of the brain and spinal cord with autoreactive lymphocytes and monocytes directed toward myelin sheaths of axons in white and grey matter. The results of some recent studies are, however, consistent with the alternative "inside-out" hypothesis according to which MS autoimmunity occurs subsequently to the primary CNS cytodegeneration affecting myelin sheaths [12]. Some data suggest that the pathological mechanisms responsible for brain tissues destruction differ quantitatively in RR-MS and SP-MS. On the other hand, in a pivotal paper by Bramow et al [13] evidence was presented that, in progressive forms of MS, slowly expanding demyelination irreversibly destroys normal and repaired myelin.…”

Editorial: “Inside-Out” vs “Outside-In” Paradigms in Multiple Sclerosis Etiopathogenesis

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Mechanistic underpinning of an inside–out concept for autoimmunity in multiple sclerosis

“…This Opinion discusses recently reported histological abnormalities in the normally appearing white matter (NAWM) of MS brains that are substantially less prevalent in cerebral NAWM of healthy controls, or in patients with encephalitis or neurodegenerative disease. 7 Evidence suggests that these primary lesions release post‐translationally modified myelin constituents against which the immune system reacts. Moreover, studies in a non‐human primate MS model will be discussed that reveal naturally occurring hyper‐reactive T cells against the core‐pathogenic myelin constituent myelin oligodendrocyte glycoprotein (MOG), modified by citrullination.…”