Will the real multiple sclerosis please stand up?
Open accessAbstract
Multiple sclerosis (MS) is generally considered to be an autoimmune, inflammatory disease. In this provocative Perspective, Stys and colleagues propose that non-inflammatory, primary progressive MS is the 'real' MS, and that inflammatory forms of the disorder reflect an aberrant immune reaction to ongoing cytodegeneration. Multiple sclerosis (MS) is considered to be an autoimmune, inflammatory disease of the CNS. In most patients, the disease follows a relapsing–remitting course and is characterized by dynamic inflammatory demyelinating lesions in the CNS. Although on the surface MS may appear consistent with a primary autoimmune disease, questions have been raised as to whether inflammation and/or autoimmunity are really at the root of the disease, and it has been proposed that MS might in fact be a degenerative disorder. We argue that MS may be an 'immunological convolution' between an underlying primary degenerative disorder and the host's aberrant immune response. To better understand this disease, we might need to consider non-inflammatory primary progressive MS as the 'real' MS, with inflammatory forms reflecting secondary, albeit very important, reactions.
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The cuprizone model is particularly suitable for studying subtypes of MS which show primary oligodendrocyte dystrophy.
“This actually makes the cuprizone model particularly suitable for studying subtypes of MS which show primary oligodendrocyte dystrophy, reminiscent of toxin- or virus-, rather than autoimmunity, induced demyelination [31, 32].”
From Strain differences in cuprizone induced demyelination (2017) · cites this paper as [32]
The Conclusions and future directions section says models of primary damage to oligodendrocytes, myelin and axons may be more relevant and informative for MS, and identifies cuprizone as one such model. The Potential mechanisms section reports oligodendroglial damage and demyelination with little inflammation. The paper presents this relevance as a possibility, however; it does not establish specific MS subtypes with primary oligodendrocyte dystrophy or make the sentence’s virus-induced comparison. (LLM, conf=0.82)
Experimental — accuracy not yet measuredDiphtheria Toxin A induced oligodendrocyte ablation models allow for oligodendrocyte-selective cell death, making it possible to study de- and remyelination.
“These models allow for oligodendrocyte-selective cell death, hereby making it possible to study de- and remyelination.”
From Insights and challenges on animal models for progressive multiple sclerosis (2026) · cites this paper as [220]
The ‘Secondary inflammation’ section describes an animal study in which induced primary oligodendrocyte death caused robust demyelination. Our copy does not identify diphtheria toxin A as the means of ablation or say that the model permits study of remyelination; the remyelination mentioned in ‘Clinical observations and inconsistencies’ concerns MS lesions, not this model. No page numbers are available in our copy. (LLM, conf=0.83)
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“A less explored model system, that has potential of modelling the inside-out paradigm of MS or the CNS-compartmentalized inflammation linked to PMS, is Diphtheria Toxin A induced oligodendrocyte ablation models [220, 221].”
- Authors
- Stys, P. K., Zamponi, G. W., van Minnen, J., & Geurts, J. J. G.
- Affiliations
- University of Calgary (CA)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Corresponding author
- Stys, Peter K.
- Venue
- Nature Reviews Neuroscience
- Published
- 2012-06-20
- Volume
- 13
- Issue
- 7
- Pages
- 507-514
- ISSN
- 1471-003X (ISSN-L)
- 1471-0048
- OpenAlex
- W1972752407
- Cited by
- 475
- References
- 6
- Citations by year
- 2026: 8 · 2025: 18 · 2024: 23 · 2023: 21 · 2022: 27 · 2021: 50 · 2020: 24 · 2019: 33 · 2018: 53 · 2017: 50 · 2016: 35 · 2015: 54 · 2014: 38 · 2013: 33 · 2012: 5
- FWCI
- 6.13
- Type
- journal article
- Language
- en
- Update notices
- erratum (2012-07-04)
- Open access
- green
- hdl.handle.net
- Locations
- Nature reviews. Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- VU Research Portal (publishedVersion)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- Libraries and Cultural Resources (University of Calgary) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Multiple Sclerosis Society of Canada
- Canada Research Chairs
- Alberta Innovates
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Peripheral Neuropathies and Disorders
- Keywords
- multiple sclerosis, primary progressive multiple sclerosis, relapsing-remitting multiple sclerosis, autoimmunity, neuroinflammation, demyelination, degenerative diseases, aberrant immune response, central nervous system
- MeSH terms
- Humans, Inflammation, Multiple Sclerosis, Disease Progression, Neurodegenerative Diseases
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