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Exploring the origins of grey matter damage in multiple sclerosis

Key Points

  • Although multiple sclerosis has been characterized previously as a white matter disease, it is becoming increasingly apparent that extensive cortical and deep grey matter pathology can be present.

  • Several imaging studies have documented convincing correlations between white matter lesions and grey matter atrophy, suggesting that neurodegeneration can be a consequence of white matter demyelination via retrograde degeneration.

  • Another equally important theory suggests that white matter and grey matter demyelination are two, at least partly, independent phenomena and that neuronal loss is not caused by white matter abnormalities per se.

  • Several inflammatory cells types, including CD4+ and CD8+ T cells, are implicated in grey matter damage.

  • A role for B cells and meningeal inflammatory infiltrates in multiple sclerosis has been recently proposed.

  • It is becoming more widely accepted that microglial activation is necessary and crucial for host defence and neuronal survival, whereas microglial over-activation may be deleterious to neurons and oligodendrocytes.

  • The neuronal energy deficit is crucial for inducing axonal swelling and subsequent neuronal death, especially when it occurs as a consequence of inflammation. Several lines of evidence have led to the hypothesis that mitochondrial injury, and therefore the energy deficit, is a primary phenomenon in multiple sclerosis.

  • A recent theory — the inside-out model — notes the inconsistencies in the inflammatory model described above and suggests a degenerative model as the primary cause of the disease.

Abstract

Multiple sclerosis is characterized at the gross pathological level by the presence of widespread focal demyelinating lesions of the myelin-rich white matter. However, it is becoming clear that grey matter is not spared, even during the earliest phases of the disease. Furthermore, grey matter damage may have an important role both in physical and cognitive disability. Grey matter pathology involves both inflammatory and neurodegenerative mechanisms, but the relationship between the two is unclear. Histological, immunological and neuroimaging studies have provided new insight in this rapidly expanding field, and form the basis of the most recent hypotheses on the pathogenesis of grey matter damage.

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Figure 1: Cortical lesion subtypes in multiple sclerosis.
Figure 2: Inflammatory and non-inflammatory grey matter neurodegeneration mechanisms.
Figure 3: Is grey matter atrophy a primary or secondary pathological process?
Figure 4: Immune-mediated mechanisms of subpial cortical demyelination in progressive multiple sclerosis.

References

  1. Noseworthy, J. H., Lucchinetti, C., Rodriguez, M. & Weinshenker, B. G. Multiple sclerosis. N. Engl. J. Med. 343, 938–952 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Sospedra, M. & Martin, R. Immunology of multiple sclerosis. Annu. Rev. Immunol 23, 683–747 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Lill, C. M. et al. CXCR5, SOX8, RPS6KB1 and ZBTB46 are genetic risk loci for multiple sclerosis. Brain 136, 1778–1782 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ascherio, A. Environmental factors in multiple sclerosis. Expert Rev. Neurother. 13 (Suppl. 12), 3–9 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Dutta, R. & Trapp, B. D. Pathology and definition of multiple sclerosis. Rev. Prat. 56, 1293–1298 (2006).

    PubMed  Google Scholar 

  6. Lassmann, H., Brück, W. & Lucchinetti, C. F. The immunopathology of multiple sclerosis: an overview. Brain Pathol. 17, 210–218 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Dawson, J. D. The histology of disseminated sclerosis. Trans. R. Soc. Edin. 50, 517–740 (1916).

    Article  Google Scholar 

  8. Brownell, B. & Hughes, J. T. The distribution of plaques in the cerebrum in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 25, 315–320 (1962).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chard, D. & Miller, D. Grey matter pathology in clinically early multiple sclerosis: evidence from magnetic resonance imaging. J. Neurol. Sci. 282, 5–11 (2009).

    Article  PubMed  Google Scholar 

  10. Calabrese, M., Filippi, M. & Gallo, P. Cortical lesions in multiple sclerosis. Nature Rev. Neurol. 6, 438–444 (2010).

    Article  Google Scholar 

  11. Kidd, D. et al. Cortical lesions in multiple sclerosis. Brain 122, 17–26 (1999).

    Article  PubMed  Google Scholar 

  12. Peterson, J. W., Bö, L., Mörk, S., Chang, A. & Trapp, B. D. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann. Neurol. 50, 389–400 (2001). The seminal paper on cortical lesions in multiple sclerosis.

    Article  CAS  PubMed  Google Scholar 

  13. Bø, L., Vedeler, C. A., Nyland, H. I., Trapp, B. D. & Mörk, S. J. Subpial demyelination in the cerebral cortex of multiple sclerosis patients. J. Neuropathol. Exp. Neurol. 62, 723–732 (2003).

    Article  PubMed  Google Scholar 

  14. Brink, B. P. et al. The pathology of multiple sclerosis is location-dependent: no significant complement activation is detected in purely cortical lesions. J. Neuropathol. Exp. Neurol. 64, 147–155 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. van Horssen, J., Brink, B. P., de Vries, H. E., van der Valk, P. & Bø, L. The blood–brain barrier in cortical multiple sclerosis lesions. J. Neuropathol. Exp. Neurol. 66, 321–328 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Wegner, C., Esiri, M. M., Chance, S. A., Palace, J. & Matthews, P. M. Neocortical neuronal, synaptic, and glial loss in multiple sclerosis. Neurology 67, 960–967 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Magliozzi, R. et al. A gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann. Neurol. 68, 477 (2010). A very interesting study demonstrating a direct relationship between meningeal inflammation, subpial demyelination and neuronal loss in multiple sclerosis.

    Article  CAS  PubMed  Google Scholar 

  18. Freund, P. et al. Disability, atrophy and cortical reorganization following spinal cord injury. Brain 134, 1610–1622 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Sailer, M. et al. Focal thinning of the cerebral cortex in multiple sclerosis. Brain 126, 1734–1744 (2003).

    Article  PubMed  Google Scholar 

  20. Narayanan, S. et al. Imaging of axonal damage in multiple sclerosis: spatial distribution of magnetic resonance imaging lesions. Ann. Neurol. Mar. 41, 385–391 (1997).

    Article  CAS  Google Scholar 

  21. Varga, A. W. et al. White matter hemodynamic abnormalities precede sub-cortical gray matter changes in multiple sclerosis. J. Neurol. Sci. 282, 28–33 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Dziedzic, T. et al. Wallerian degeneration: a major component of early axonal pathology in multiple sclerosis. Brain Pathol. 20, 976–985 (2010).

    PubMed  PubMed Central  Google Scholar 

  23. Henry, R. G. et al. Connecting white matter injury and thalamic atrophy in clinically isolated syndromes. J. Neurol. Sci. 282, 61–66 (2009).

    Article  PubMed  Google Scholar 

  24. Audoin, B. et al. Localization of grey matter atrophy in early RRMS: A longitudinal study. J. Neurol. 253, 1495–1501 (2006).

    Article  PubMed  Google Scholar 

  25. De Stefano, N. et al. Evidence of early cortical atrophy in MS: relevance to white matter changes and disability. Neurology 60, 1157–1162 (2003). One of the seminal MRI studies on cortical atrophy in multiple sclerosis.

    Article  CAS  PubMed  Google Scholar 

  26. Furby, J. et al. Different white matter lesion characteristics correlate with distinct grey matter abnormalities on magnetic resonance imaging in secondary progressive multiple sclerosis. Mult. Scler. 15, 687–694 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Sanfilipo, M. P., Benedict, R. H., Sharma, J., Weinstock-Guttman, B. & Bakshi, R. The relationship between whole brain volume and disability in multiple sclerosis: a comparison of normalized gray versus white matter with misclassification correction. Neuroimage 26, 1068–1077 (2005).

    Article  PubMed  Google Scholar 

  28. Roosendaal, S. D. et al. Grey matter volume in a large cohort of MS patients: relation to MRI parameters and disability. Mult. Scler. 17, 1098–1106 (2011).

    Article  PubMed  Google Scholar 

  29. Ceccarelli, A. et al. A voxel-based morphometry study of grey matter loss in MS patients with different clinical phenotypes. Neuroimage 42, 315–322 (2008).

    Article  PubMed  Google Scholar 

  30. Battaglini, M. et al. Voxel-wise assessment of progression of regional brain atrophy in relapsing-remitting multiple sclerosis. J. Neurol. Sci. 282, 55–60 (2009).

    Article  PubMed  Google Scholar 

  31. Bendfeldt, K. et al. Association of regional gray matter volume loss and progression of white matter lesions in multiple sclerosis — a longitudinal voxel-based morphometry study. Neuroimage 45, 60–67 (2009).

    Article  PubMed  Google Scholar 

  32. Pagani, E. et al. Regional brain atrophy evolves differently in patients with multiple sclerosis according to clinical phenotype. Am. J. Neuroradiol. 26, 341–346 (2005).

    PubMed  PubMed Central  Google Scholar 

  33. Sepulcre, J. et al. Contribution of white matter lesions to gray matter atrophy in multiple sclerosis: evidence from voxel-based analysis of T1 lesions in the visual pathway. Arch. Neurol. 66, 173–179 (2009).

    Article  PubMed  Google Scholar 

  34. Gilmore, C. P. et al. Regional variations in the extent and pattern of grey matter demyelination in multiple sclerosis: a comparison between the cerebral cortex, cerebellar cortex, deep grey matter nuclei and the spinal cord. J. Neurol. Neurosurg. Psychiatry 80, 182–187 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Kutzelnigg, A. et al. Widespread demyelination in the cerebellar cortex in multiple sclerosis. Brain Pathol. 17, 38–44 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Gilmore, C. P. et al. Spinal cord neuronal pathology in multiple sclerosis. Brain Pathol. 19, 642–649 (2009).

    Article  PubMed  Google Scholar 

  37. Howell, O. et al. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain 134, 2755–2771 (2011).

    Article  PubMed  Google Scholar 

  38. Lucchinetti, C. F. et al. Inflammatory cortical demyelination in early multiple sclerosis. N. Engl. J. Med. 365, 2188–2197 (2011). The first neuropathological characterization of inflammatory cortical lesions in early multiple sclerosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Calabrese, M. et al. Detection of cortical inflammatory lesions by double inversion recovery magnetic resonance imaging in patients with multiple sclerosis. Arch. Neurol. 64, 1416–1422 (2007).

    Article  PubMed  Google Scholar 

  40. Giorgio, A. et al. Cortical lesions in radiologically isolated syndrome. Neurology 77, 1896–1899 (2011).

    Article  CAS  PubMed  Google Scholar 

  41. Calabrese, M. & Gallo, P. Magnetic resonance evidence of cortical onset of multiple sclerosis. Mult. Scler. 15, 933–941 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Seewann, A. et al. Imaging the tip of the iceberg: visualization of cortical lesions in multiple sclerosis. Mult. Scler. 17, 1202–1210 (2011).

    Article  PubMed  Google Scholar 

  43. Chard, D. T. et al. Brain atrophy in clinically early relapsing-remitting multiple sclerosis. Brain 125, 327–337 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Tiberio, M. et al. Gray and white matter volume changes in early RRMS: a 2-year longitudinal study. Neurology 64, 1001–1007 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Sbardella, E. et al. Assessing the correlation between grey and white matter damage with motor and cognitive impairment in multiple sclerosis patients. PLoS ONE 8, e63250 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Steenwijk, M. D. et al. What explains gray matter atrophy in long-standing multiple sclerosis? Radiology 272, 832–842 (2014).

    Article  PubMed  Google Scholar 

  47. Calabrese, M. et al. Imaging distribution and frequency of CLs in patients with multiple sclerosis. Neurology 75, 1234–1240 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. Vercellino, M. et al. Demyelination, inflammation, and neurodegeneration in multiple sclerosis deep gray matter. J. Neuropathol. Exp. Neurol. 68, 489–502 (2009).

    Article  PubMed  Google Scholar 

  49. Geurts, J. J. et al. Extensive hippocampal demyelination in multiple sclerosis. J. Neuropathol. Exp. Neurol. 66, 819–827 (2007).

    Article  PubMed  Google Scholar 

  50. Cohen-Adad, J. et al. In vivo evidence of disseminated subpial T2* signal changes in multiple sclerosis at 7 T: a surface-based analysis. Neuroimage 57, 55–62 (2011).

    Article  CAS  PubMed  Google Scholar 

  51. Audoin, B. et al. Atrophy mainly affects the limbic system and the deep grey matter at the first stage of multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 81, 690–695 (2010).

    Article  PubMed  Google Scholar 

  52. Bendfeldt, K. et al. Spatiotemporal distribution pattern of white matter lesion volumes and their association with regional grey matter volume reductions in relapsing-remitting multiple sclerosis. Hum. Brain Mapp. 31, 1542–1555 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Bettelli, E. et al. Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis. J. Exp. Med. 197, 1073–1081 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Krishnamoorthy, G. et al. Myelin-specific T cells also recognize neuronal autoantigen in a transgenic mouse model of multiple sclerosis. Nature Med. 15, 626–632 (2009).

    Article  CAS  PubMed  Google Scholar 

  55. Serafini, B., Rosicarelli, B., Magliozzi, R., Stigliano, E. & Aloisi, F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol. 14, 164–174 (2004).

    Article  PubMed  Google Scholar 

  56. Ascherio, A. & Munger, K. L. Epstein–Barr virus infection and multiple sclerosis: a review. J. Neuroimmune Pharmacol. 5, 271–277 (2010).

    Article  PubMed  Google Scholar 

  57. Ascherio, A. et al. Epstein–Barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA 286, 3083–3088 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Levin, L. I. et al. Multiple sclerosis and Epstein–Barr virus. JAMA 289, 1533–1536 (2003).

    Article  PubMed  Google Scholar 

  59. Serafini, B. et al. Dysregulated Epstein–Barr virus infection in the multiple sclerosis brain. J. Exp. Med. 204, 2899–2912 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Serafini, B., Muzio, L., Rosicarelli, B. & Aloisi, F. Radioactive in situ hybridization for Epstein–Barr virus-encoded small RNA supports presence of Epstein–Barr virus in the multiple sclerosis brain. Brain 136, e233 (2013).

    Article  PubMed  Google Scholar 

  61. Magliozzi, R. et al. B-cell enrichment and Epstein–Barr virus infection in inflammatory cortical lesions in secondary progressive multiple sclerosis. J. Neuropathol. Exp. Neurol. 72, 29–41 (2013).

    Article  CAS  PubMed  Google Scholar 

  62. Angelini, D. F. et al. Increased CD8+ T cell response to Epstein–Barr virus lytic antigens in the active phase of multiple sclerosis. PLoS Pathog. 9, e1003220 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lossius, A. et al. High-throughput sequencing of TCR repertoires in multiple sclerosis reveals intrathecal enrichment of EBV-reactive CD8+ T cells. Eur. J. Immunol. 44, 3439–3452 (2014).

    Article  CAS  PubMed  Google Scholar 

  64. Sargsyan, S. A. et al. Absence of Epstein–Barr virus in the brain and CSF of patients with multiple sclerosis. Neurology 74, 1127–1135 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Willis, S. N. et al. Epstein–Barr virus infection is not a characteristic feature of multiple sclerosis brain. Brain 132, 3318–3328 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Lassmann, H., Niedobitek, G., Aloisi, F., Middeldorp, J. M. & NeuroproMiSe EBV Working Group. Epstein–Barr virus in the multiple sclerosis brain: a controversial issue — report on a focused workshop held in the Centre for Brain Research of the Medical University of Vienna, Austria. Brain 134, 2772–2786 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Aloisi, F., Serafini, B., Magliozzi, R., Howell, O. W. & Reynolds, R. Detection of Epstein–Barr virus and B-cell follicles in the multiple sclerosis brain: what you find depends on how and where you look. Brain 133, e157 (2010).

    Article  PubMed  Google Scholar 

  68. Maggi, F. et al. Low prevalence of TT virus in the cerebrospinal fluid of viremic patients with central nervous system disorders. J. Med. Virol. 65, 418–422 (2001).

    Article  CAS  PubMed  Google Scholar 

  69. Sospedra, M. et al. Recognition of conserved amino acid motifs of common viruses and its role in autoimmunity. PLoS Pathog. 1, e41 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Lamberto, I., Gunst, K., Müller, H., Zur Hausen, H. & de Villiers, E. M. Mycovirus-like DNA virus sequences from cattle serum and human brain and serum samples from multiple sclerosis patients. Genome Announc. 2, e00848–14 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Borkosky, S. S., Whitley, C., Kopp-Schneider, A., zur Hausen, H. & de Villiers, E. M. Epstein–Barr virus stimulates torque teno virus replication: a possible relationship to multiple sclerosis. PLoS ONE 7, e32160 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Zeis, T., Graumann, U., Reynolds, R. & Schaeren-Wiemers, N. Normal-appearing white matter in multiple sclerosis is in a subtle balance between inflammation and neuroprotection. Brain 131, 288–303 (2008).

    Article  PubMed  Google Scholar 

  73. Baranzini, S. E. et al. Genetic variation influences glutamate concentrations in brains of patients with multiple sclerosis. Brain 133, 2603–2611 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Mastronardi, F. G. & Moscarello, M. A. Molecules affecting myelin stability: a novel hypothesis regarding the pathogenesis of multiple sclerosis. J. Neurosci. Res. 80, 301–308 (2005).

    Article  CAS  PubMed  Google Scholar 

  75. Neumann, H., Cavalié, A., Jenne, D. E. & Wekerle, H. Induction of MHC class I genes in neurons. Science 269, 549–552 (1995).

    Article  CAS  PubMed  Google Scholar 

  76. Jersild, C. et al. Histocompatibility determinants in multiple sclerosis, with special reference to clinical course. Lancet 2, 1221–1225 (1973).

    Article  CAS  PubMed  Google Scholar 

  77. The International Multiple Sclerosis Genetics Consortium (IMSGC) et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219 (2011).

  78. Martin, R. et al. Fine specificity and HLA restriction of myelin basic protein-specific cytotoxic T cell lines from multiple sclerosis patients and healthy individuals. J. Immunol. 145, 540–548 (1990).

    CAS  PubMed  Google Scholar 

  79. Ota, K. et al. T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature 346, 183–187 (1990).

    Article  CAS  PubMed  Google Scholar 

  80. Bielekova, B. et al. Expansion and functional relevance of high-avidity myelin-specific CD4+ T cells in multiple sclerosis. J. Immunol. 172, 3893–3904 (2004).

    Article  CAS  PubMed  Google Scholar 

  81. Yates, R. L., Esiri, M. M., Palace, J., Mittal, A. & DeLuca, G. C. The influence of HLA-DRB1*15 on motor cortical pathology in multiple sclerosis. Neuropathol. Appl. Neurobiol. http://dx.doi.org/10.1111/nan.12165 (2014).

  82. Höftberger, R. et al. Expression of major histocompatibility complex class I molecules on the different cell types in multiple sclerosis lesions. Brain Pathol. 14, 43–50 (2004).

    Article  PubMed  Google Scholar 

  83. Babbe, H. et al. Clonal expansions of CD8+ T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction. J. Exp. Med. 192, 393–404 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Ulvestad, E. et al. HLA class II molecules (HLA-DR, -DP, -DQ) on cells in the human CNS studied in situ and in vitro. Immunology 82, 535–541 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Liblau, R. S., Gonzalez-Dunia, D., Wiendl, H. & Zipp, F. Neurons as targets for T cells in the nervous system. Trends Neurosci. 36, 315–324 (2013).

    Article  CAS  PubMed  Google Scholar 

  86. Meuth, S. G. et al. Cytotoxic CD8+ T cell-neuron interactions: perforin-dependent electrical silencing precedes but is not causally linked to neuronal cell death. J. Neurosci. 29, 15397–15409 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Suidan, H. S. et al. Granzyme A released upon stimulation of cytotoxic T lymphocytes activates the thrombin receptor on neuronal cells and astrocytes. Proc. Natl Acad. Sci. USA 91, 8112–8116 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Medana, I. M. et al. MHC class I-restricted killing of neurons by virus-specific CD8+ T lymphocytes is effected through the Fas/FasL, but not the perforin pathway. Eur. J. Immunol. 30, 3623–3633 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Aktas, O. et al. Neuronal damage in autoimmune neuroinflammation mediated by the death ligand TRAIL. Neuron 46, 421–432 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Mizuno, T. et al. Interferon-gamma directly induces neurotoxicity through a neuron specific, calcium-permeable complex of IFN-γ receptor and AMPA GluR1 receptor. FASEB J. 22, 1797–1806 (2008).

    Article  CAS  PubMed  Google Scholar 

  91. Vergelli, M. et al. Human autoreactive CD4+ T cell clones use perforin- or Fas/Fas ligand-mediated pathways for target cell lysis. J. Immunol. 158, 2756–2761 (1997).

    CAS  PubMed  Google Scholar 

  92. Vergelli, M. et al. A novel population of CD4+CD56+ myelin-reactive T cells lyses target cells expressing CD56/neural cell adhesion molecule. J. Immunol. 157, 679–688 (1996).

    CAS  PubMed  Google Scholar 

  93. Zaguia, F. et al. Cytotoxic NKG2C+ CD4 T cells target oligodendrocytes in multiple sclerosis. J. Immunol. 190, 2510–2518 (2013).

    Article  CAS  PubMed  Google Scholar 

  94. Magliozzi, R. et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 130, 1089–1104 (2007).

    Article  PubMed  Google Scholar 

  95. Magliozzi, R., Columba-Cabezas, S., Serafini, B. & Aloisi, F. Intracerebral expression of CXCL13 and BAFF is accompanied by formation of lymphoid follicle-like structures in the meninges of mice with relapsing experimental autoimmune encephalomyelitis. J. Neuroimmunol. 148, 11–23 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Peters, A. et al. Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity 35, 986–996 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Choi, S. R. et al. Meningeal inflammation plays a role in the pathology of primary progressive multiple sclerosis. Brain 135, 2925–2937 (2012).

    Article  PubMed  Google Scholar 

  98. Kramann, N. et al. Increased meningeal T and plasma cell infiltration is associated with early subpial cortical demyelination in common marmosets with experimental autoimmune encephalomyelitis. Brain Pathol. http://dx.doi.org/10.1111/bpa.12180 (2014).

  99. Gardner, C. et al. Cortical grey matter demyelination can be induced by elevated pro-inflammatory cytokines in the subarachnoid space of MOG-immunized rats. Brain 136, 3596–3608 (2013).

    Article  PubMed  Google Scholar 

  100. Kooi, E. J., Geurts, J. J., van Horssen, J., Bø, L. & van der Valk, P. Meningeal inflammation is not associated with cortical demyelination in chronic multiple sclerosis. J. Neuropathol. Exp. Neurol. 68, 1021–1028 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Guseo, A. & Jellinger, K. The significance of perivascular infiltrations in multiple sclerosis. J. Neurol. 211, 51–60 (1975).

    Article  CAS  PubMed  Google Scholar 

  102. Kutzelnigg, A. et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128, 2705–2712 (2005). This study provides elegant autoptic evidence of white matter and grey matter damage in multiple sclerosis.

    Article  PubMed  Google Scholar 

  103. Reynolds, R. et al. The neuropathological basis of clinical progression in multiple sclerosis. Acta Neuropathol. 122, 155–170 (2011).

    Article  PubMed  Google Scholar 

  104. Fischer, M. T. et al. Disease-specific molecular events in cortical multiple sclerosis lesions. Brain 136, 1799–1815 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Calabrese, M. et al. The changing clinical course of multiple sclerosis: a matter of gray matter. Ann. Neurol. 74, 76–83 (2013). An interesting paper implicating grey matter damage in the progression of clinical disability during the course of multiple sclerosis.

    Article  PubMed  Google Scholar 

  106. Androdias, G. et al. Meningeal T cells associate with diffuse axonal loss in multiple sclerosis spinal cords. Ann. Neurol. 68, 465–476 (2010).

    Article  CAS  PubMed  Google Scholar 

  107. Dutta, R. & Trapp, B. D. Pathogenesis of axonal and neuronal damage in multiple sclerosis. Neurology 68 (Suppl. 3), 22–31 (2007).

    Article  Google Scholar 

  108. Kreutzberg, G. W. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 19, 312–318 (1996).

    Article  CAS  PubMed  Google Scholar 

  109. Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. Aloisi, F. Immune function of microglia. Glia 36, 1 65–179 (2001).

    Article  Google Scholar 

  111. Block, M. L. & Hong, J. S. Chronic microglial activation and progressive dopaminergic neurotoxicity. Biochem. Soc. Trans. 35, 1127–1132 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Polazzi, E. & Contestabile, A. Reciprocal interactions between microglia and neurons: from survival to neuropathology. Rev. Neurosci. 13, 221–242 (2002).

    Article  PubMed  Google Scholar 

  113. Gray, E., Thomas, T. L., Betmouni, S., Scolding, N. & Love, S. Elevated matrix metalloproteinase-9 and degradation of perineuronal nets in cerebrocortical multiple sclerosis plaques. J. Neuropathol. Exp. Neurol. 67, 888–899 (2008).

    Article  PubMed  Google Scholar 

  114. Vercellino, M. et al. Altered glutamate reuptake in relapsing-remitting and secondary progressive multiple sclerosis cortex: correlation with microglia infiltration, demyelination, and neuronal and synaptic damage. J. Neuropathol. Exp. Neurol. 66, 732–739 (2007).

    Article  CAS  PubMed  Google Scholar 

  115. Kooi, E. J., Strijbis, E. M., van der Valk, P. & Geurts, J. J. Heterogeneity of cortical lesions in multiple sclerosis: clinical and pathologic implications. Neurology 79, 1369–1376 (2012).

    Article  CAS  PubMed  Google Scholar 

  116. Stys, P. K., Zamponi, G. W., van Minnen, J. & Geurts, J. J. Will the real multiple sclerosis please stand up? Nature Rev. Neurosci. 13, 507–514 (2012).

    Article  CAS  Google Scholar 

  117. Barnett, M. H. & Prineas, J. W. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann. Neurol. 55, 458–468 (2004).

    Article  PubMed  Google Scholar 

  118. Henderson, A. P., Barnett, M. H., Parratt, J. D. & Prineas, J. W. Multiple sclerosis: distribution of inflammatory cells in newly forming lesions. Ann. Neurol. 66, 739–753 (2009).

    Article  PubMed  Google Scholar 

  119. Lassmann, H., van Horssen, J. & Mahad, D. Progressive multiple sclerosis: pathology and pathogenesis. Nature Rev. Neurol. 8, 647–656 (2012). A comprehensive review on the pathology and pathogenesis of progressive multiple sclerosis.

    Article  CAS  Google Scholar 

  120. Fischer, M. T. et al. NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury. Brain 135, 886–899 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Witte, M. E., Geurts, J. J., de Vries, H. E., van der Valk, P. & van Horssen, J. Mitochondrial dysfunction: a potential link between neuroinflammation and neurodegeneration? Mitochondrion 10, 411–418 (2010).

    Article  CAS  PubMed  Google Scholar 

  122. Campbell, G. R. et al. Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Ann. Neurol. 69, 481–492 (2011).

    Article  CAS  PubMed  Google Scholar 

  123. Nikic, I. et al. A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nature Med. 17, 495–499 (2011).

    Article  CAS  PubMed  Google Scholar 

  124. van Horssen, J., Witte, M. E. & Ciccarelli, O. The role of mitochondria in axonal degeneration and tissue repair in MS. Mult. Scler. 18, 1058–1067 (2012).

    Article  CAS  PubMed  Google Scholar 

  125. Mahad, D., Ziabreva, I., Lassmann, H. & Turnbull, D. Mitochondrial defects in acute multiple sclerosis lesions. Brain 131, 1722–1735 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Marik, C., Felts, P. A., Bauer, J., Lassmann, H. & Smith, K. J. Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity? Brain 130, 2800–2815 (2007).

    Article  PubMed  Google Scholar 

  127. Druzhyna, N. M., Wilson, G. L. & LeDoux, S. P. Mitochondrial DNA repair in aging and disease. Mech. Ageing Dev. 129, 383–390 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Trapp, B. D. Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol. 8, 280–291 (2009).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

M.C. is supported by the Progressive MS Alliance (PA-0124). R.Magliozzi is supported by an Italian Multiple Sclerosis Foundation grant (FISM 2011/R/23) and by an Italian Ministry of Health grant (GR-2010-2313255). R.R. is supported by the UK Multiple Sclerosis Society and the UK Medical Research Council. R. Martin and the Neuroimmunology and Multiple Sclerosis Research Section are supported by the Clinical Research Priority Program MS (CRPPMS) of the University of Zurich, the Swiss National Science Foundation (SNF), a European Research Council (ERC) Advanced Grant, the EU-FP7 framework programme and the Swiss Multiple Sclerosis Society.

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Correspondence to Massimiliano Calabrese.

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Competing interests

M.C. has received speaking and consultancy honoraria from Biogen Idec, Merck Serono, Genzyme (a Sanofi company), and Teva Pharmaceutical companies. J.J.G.G. has received research support from Novartis and Biogen Idec and was a consultant for Novartis, Biogen Idec, Genzyme, Merck Serono, and Teva Pharmaceutical companies.

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Glossary

Complement proteins

A set of plasma proteins that coats pathogens; the coated pathogens are then cleared by phagocytes.

MRI

(Magnetic resonance imaging). A non-invasive method used to obtain images of living tissue. It uses radio-frequency pulses and magnetic field gradients; the principle of nuclear magnetic resonance is used to reconstruct images of tissue characteristics (for example, proton density or water diffusion parameters).

Wallerian degeneration

The degeneration of an axon distal to a site of injury, which begins to occur approximately 1.5 days after the injury.

Clinically isolated syndrome

A syndrome present in a patient experiencing their first clinical episode that is suggestive of an inflammatory demyelinating disease of the CNS.

Relapsing–remitting multiple sclerosis

(RRMS). The early phase of multiple sclerosis characterized by several neurological episodes followed by complete or incomplete recovery.

Radiologically isolated syndrome

A syndrome present in a patient who has radiological evidence of an inflammatory demyelinating disease of the CNS but no clinical signs or symptoms of such disease.

Primary and secondary progressive disease

Phases of multiple sclerosis characterized by a slow progression of disability without a well-defined clinical relapse. These phases usually follow the relapsing–remitting phase (secondary progressive phase) but they can also be in the first phase of the disease (primary progressive multiple sclerosis).

T cell

A lymphocyte that mediates cell-dependent immune responses by providing help (in the form of cytokines, for example) to other immune cells or by cytotoxicity (killing of a virus-infected cell).

B cells

Lymphocytes that express immunoglobulins as surface receptors or, when they are fully mature following antigenic stimulation, release antibodies that are directed against a virus or bacteria.

Natural killer cells

A white blood cell population that does not express antigen-specific recognition receptors such as those expressed by T and B cells, but recognizes cells that express fewer or no HLA class I molecules (such as virus-infected cells). Natural killer cells are important in controlling viral infections and recognition of mutated (tumour) cells.

Experimental autoimmune encephalomyelitis

An animal model of multiple sclerosis that is initiated in animals by injecting myelin proteins or peptides to raise autoreactive T cells or by the transfer of autoreactive T cells into naive recipients.

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Calabrese, M., Magliozzi, R., Ciccarelli, O. et al. Exploring the origins of grey matter damage in multiple sclerosis. Nat Rev Neurosci 16, 147–158 (2015). https://doi.org/10.1038/nrn3900

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