Revisiting the Pathoetiology of Multiple Sclerosis: Has the Tail Been Wagging the Mouse?

Abstract

Multiple Sclerosis (MS) is traditionally considered an autoimmune-mediated demyelinating disease, the pathoetiology of which is unknown. However, the key question remains whether autoimmunity is the initiator of the disease (outside-in) or the consequence of a slow and as yet uncharacterized cytodegeneration (oligodendrocytosis), which leads to a subsequent immune response (inside-out). Experimental autoimmune encephalomyelitis has been used to model the later stages of MS during which the autoimmune involvement predominates. In contrast, the cuprizone (CPZ) model is used to model early stages of the disease during which oligodendrocytosis and demyelination predominate and are hypothesized to precede subsequent immune involvement in MS. Recent studies combining a boost, or protection, to the immune system with disruption of the blood brain barrier have shown CPZ-induced oligodendrocytosis with a subsequent immune response. In this Perspective, we review these recent advances and discuss the likelihood of an inside-out vs. an outside-in pathoetiology of MS.

Oligodendrocyte-Specific Mechanisms of Myelin Thinning: Implications for Neurodegenerative Diseases

“…Interestingly, Caprariello et al ( 2018 ) and Almuslehi et al ( 2020 ) showed that oligodendrocyte degeneration and microglial activation recruit adaptive immune cells (pan CD3 T-cells and CD8 T-cells) and trigger subsequent demyelination in cuprizone-fed mice once the blood-brain barrier is compromised (using pertussis toxin injection). Whether oligodendrocytes apoptosis and microglial activation (as shown in this study; Wu et al, 2020 ) attract adaptive immune cells (e.g., T-cells) into the CNS to facilitate subsequent adaptive immune cell-mediated oligodendrocyte degeneration (Stys et al, 2012 ; Sen et al, 2020b ; as in 'inside-out' theory of MS) remains unexplored.…”

The Impact of SARS-CoV-2 Infection on the Development of Neurodegeneration in Multiple Sclerosis

“…Alternatively, MS can be considered as a primary degenerative condition that initiates the myelinating unit (oligodendroglia, their processes, and myelin) and results in neuroinflammation (the “inside-out” hypothesis) [ 81 ]. Researchers conducting a study on the cuprizone-induced demyelination in an animal model—enabling the study of oligodendrocytosis in the absence (immuno-suppression) and presence (immuno-protection) of the peripheral immune system—postulate that MS primarily originates from a slow, progressive oligodendrocyte degeneration caused by metabolic dysfunction that leads to subsequent reactive gliosis in the absence of adaptive immune cell response [ 82 ].…”

Proteomics of Multiple Sclerosis: Inherent Issues in Defining the Pathoetiology and Identifying (Early) Biomarkers

“…Although no animal models faithfully mimic the complete complexity of MS, the appropriate use of models depends upon the specific research question being posed [ 12 ]. Despite the differences in disease induction in EAE (peripheral injection of myelin protein) and CPZ (feeding of toxic compound), both experimental models show oligodendrocyte degeneration, demyelination, and glial activation in the CNS [ 14 , 224 ].…”

“…Moreover, in MS and EAE, proteins related to the adaptive immune responses (e.g., immunoglobulin and complement) were more common, whereas proteins of the innate immune response were identified in CPZ (e.g., glial fibrillary acidic protein, GFAP; Supplementary Figure S1c,d ). Due to these immunological similarities between EAE and MS, EAE has been widely considered as ‘the’ model of MS [ 12 , 225 ]. However, samples from MS patients were collected after clinical diagnosis or post-mortem [ 58 , 76 ].…”

“…In the CNS, these immune cells contribute to a complex chronic neuro-inflammatory state, oligodendrocyte degeneration or death (i.e., oligodendrocytopathy or oligodendrocytosis), demyelination and neuronal loss [ 6 , 7 , 8 ]. However, other biochemical changes in the CNS may well precede the involvement of the peripheral immune system [ 9 , 10 , 11 , 12 , 13 ]. Based on the clinical diagnostic criteria, MS is categorized into four broad phenotypes: primary progressive MS (PPMS), secondary progressive MS (SPMS), relapsing-remitting MS (RRMS), and progressive relapsing MS (PRMS; [ 7 , 14 , 15 ]).…”