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  • Review Article
  • Published:

Progressive multiple sclerosis: pathology and pathogenesis

Abstract

Major progress has been made during the past three decades in understanding the inflammatory process and pathogenetic mechanisms in multiple sclerosis (MS). Consequently, effective anti-inflammatory and immunomodulatory treatments are now available for patients in the relapsing–remitting stage of the disease. This Review summarizes studies on the pathology of progressive MS and discusses new data on the mechanisms underlying its pathogenesis. In progressive MS, as in relapsing–remitting MS, active tissue injury is associated with inflammation, but the inflammatory response in the progressive phase occurs at least partly behind the blood–brain barrier, which makes it more difficult to treat. The other mechanisms that drive disease in patients with primary or secondary progressive MS are currently unresolved, although oxidative stress resulting in mitochondrial injury might participate in the induction of demyelination and neurodegeneration in both the relapsing–remitting and progressive stages of MS. Oxidative stress seems to be mainly driven by inflammation and oxidative burst in microglia; however, its effects might be amplified in patients with progressive MS by age-dependent iron accumulation in the brain and by mitochondrial gene deletions, triggered by the chronic inflammatory process.

Key Points

  • In all stages of multiple sclerosis (MS), active demyelination and neurodegeneration are associated with inflammation mediated by T cells, B cells, macrophages and activated microglia

  • The basic pathological alterations in the brain are similar between early relapsing and progressive stages of MS, but are increased in their extent in progressive disease

  • Multiple mechanisms contribute to neurodegeneration in progressive MS, including exhaustion of functional compensation, lack of trophic support, chronic microglial activation and altered expression of ion channels in demyelinated axons

  • Mitochondrial injury induced by oxidative stress might underlie the pathological features of MS lesions, such as oligodendrocyte apoptosis, demyelination, destruction of thin-calibre axons, and lack of remyelination

  • Age-related iron accumulation in the human brain and release of iron in lesioned tissue might amplify oxidative damage, particularly in progressive MS

  • Treatment of progressive MS is hindered by the presence of inflammation 'trapped' behind the blood–brain barrier, and might require a combination of anti-inflammatory and neuroprotective strategies

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Figure 1: Characteristic brain pathology in secondary progressive multiple sclerosis.
Figure 2: Schematic highlighting the evolution of structural pathology and disease mechanisms during the course of MS.
Figure 3: The different consequences of mitochondrial injury for axons and oligodendrocytes in patients with MS.
Figure 4: Schematic representing tissue damage induced by oxidative burst in multiple sclerosis and experimental autoimmune encephalitis.121

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Acknowledgements

The authors' research work, which is described in this Review, is funded by Austrian Science Fund grants P 19854 and P 24245 (H. Lassmann), Dutch MS Research Foundation grants 09-686 MS and 09-358d (J. van Horssen) and the Wellcome Trust, grant WT078415MA (D. Mahad).

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H. Lassmann, J. van Horssen and D. Mahad contributed equally to researching data for the article, discussion of the content, and writing and editing of the manuscript before submission.

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Correspondence to Hans Lassmann.

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J. van Horssen receives research funding from Biogen Idec. The other authors declare no competing interests.

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Lassmann, H., van Horssen, J. & Mahad, D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol 8, 647–656 (2012). https://doi.org/10.1038/nrneurol.2012.168

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