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

2 Frohman, E. M., Racke, M. K. & Raine, C. S. Multiple sclerosis — the plaque and its pathogenesis. N. Engl. J. Med. 354, 942–955 (2006).

3 Geurts, J. J., Stys, P. K., Minagar, A., Amor, S. & Zivadinov, R. Gray matter pathology in (chronic) MS: modern views on an early observation. J. Neurol. Sci. 282, 12–20 (2009).

4 Sawcer, S. et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219 (2011).

5 Herz, J., Zipp, F. & Siffrin, V. Neurodegeneration in autoimmune CNS inflammation. Exp. Neurol. 225, 9–17 (2010).

6 Menge, T. et al. Disease-modifying agents for multiple sclerosis: recent advances and future prospects. Drugs 68, 2445–2468 (2008).

7 Hauser, S. L. & Oksenberg, J. R. The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron 52, 61–76 (2006).

8 Trapp, B. D. & Nave, K. A. Multiple sclerosis: an immune or neurodegenerative disorder? Annu. Rev. Neurosci. 31, 247–269 (2008).

9 Dutta, R. & Trapp, B. D. Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis. Prog. Neurobiol. 93, 1–12 (2011).

10 Rodriguez, M. & Scheithauer, B. Ultrastructure of multiple sclerosis. Ultrastruct. Pathol. 18, 3–13 (1994).

11 Aboul-Enein, F. et al. Preferential loss of myelin-associated glycoprotein reflects hypoxia-like white matter damage in stroke and inflammatory brain diseases. J. Neuropathol. Exp. Neurol. 62, 25–33 (2003).

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

13 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).

14 Bhat, R. & Steinman, L. Innate and adaptive autoimmunity directed to the central nervous system. Neuron 64, 123–132 (2009).

15 Bielekova, B. et al. Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nature Med. 6, 1167–1175 (2000).

16 Podbielska, M. & Hogan, E. L. Molecular and immunogenic features of myelin lipids: incitants or modulators of multiple sclerosis? Mult. Scler. 15, 1011–1029 (2009).

17 Peterson, J. W., Bo, L., Mork, S., Chang, A. & Trapp, B. D. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann. Neurol. 50, 389–400 (2001).

18 Seewann, A. et al. Diffusely abnormal white matter in chronic multiple sclerosis: imaging and histopathologic analysis. Arch. Neurol. 66, 601–609 (2009).

19 Trapp, B. D. et al. Axonal transection in the lesions of multiple sclerosis. N. Engl. J. Med. 338, 278–285 (1998).

20 Frischer, J. M. et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 132, 1175–1189 (2009).

21 Boraschi, D. et al. Ageing and immunity: addressing immune senescence to ensure healthy ageing. Vaccine 28, 3627–3631 (2010).

22 Coles, A. J. et al. Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann. Neurol. 46, 296–304 (1999).

23 Molyneux, P. D. et al. The effect of interferon beta-1b treatment on MRI measures of cerebral atrophy in secondary progressive multiple sclerosis. Brain 123, 2256–2263 (2000).

24 Filippi, M. et al. The effect of cladribine on T1 'black hole' changes in progressive MS. J. Neurol. Sci. 176, 42–44 (2000).

25 Hawker, K. Progressive multiple sclerosis: characteristics and management. Neurol. Clin. 29, 423–434 (2011).

26 Mancardi, G. & Saccardi, R. Autologous haematopoietic stem-cell transplantation in multiple sclerosis. Lancet Neurol. 7, 626–636 (2008).

27 Inglese, M. et al. Brain tissue loss occurs after suppression of enhancement in patients with multiple sclerosis treated with autologous haematopoietic stem cell transplantation. J. Neurol. Neurosurg. Psychiatry 75, 643–644 (2004).

28 Bruck, W. Inflammatory demyelination is not central to the pathogenesis of multiple sclerosis. J. Neurol. 252 (Suppl. 5), 10–15 (2005).

29 Metz, I. et al. Autologous haematopoietic stem cell transplantation fails to stop demyelination and neurodegeneration in multiple sclerosis. Brain 130, 1254–1262 (2007).

30 Lu, J. Q. et al. Neuroinflammation and demyelination in multiple sclerosis after allogeneic hematopoietic stem cell transplantation. Arch. Neurol. 67, 716–722 (2010).

31 Lassmann, H. Pathophysiology of inflammation and tissue injury in multiple sclerosis: what are the targets for therapy. J. Neurol. Sci. 306, 167–169 (2011).

32 Kremenchutzky, M., Rice, G. P., Baskerville, J., Wingerchuk, D. M. & Ebers, G. C. The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease. Brain 129, 584–594 (2006).

33 Confavreux, C. & Vukusic, S. Age at disability milestones in multiple sclerosis. Brain 129, 595–605 (2006).

34 Scalfari, A. et al. The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability. Brain 133, 1914–1929 (2010).

35 Moscarello, M. A., Mastronardi, F. G. & Wood, D. D. The role of citrullinated proteins suggests a novel mechanism in the pathogenesis of multiple sclerosis. Neurochem. Res. 32, 251–256 (2007).

36 Kanter, J. L. et al. Lipid microarrays identify key mediators of autoimmune brain inflammation. Nature Med. 12, 138–143 (2006).

37 Capello, E. & Mancardi, G. L. Marburg type and Balo's concentric sclerosis: rare and acute variants of multiple sclerosis. Neurol. Sci. 25 (Suppl. 4), 361–363 (2004).

38 Lucchinetti, C. F. et al. Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis. Brain 131, 1759–1775 (2008).

39 Zwemmer, J. N., Bot, J. C., Jelles, B., Barkhof, F. & Polman, C. H. At the heart of primary progressive multiple sclerosis: three cases with diffuse MRI abnormalities only. Mult. Scler. 14, 428–430 (2008).

40 Confavreux, C., Vukusic, S., Moreau, T. & Adeleine, P. Relapses and progression of disability in multiple sclerosis. N. Engl. J. Med. 343, 1430–1438 (2000).

41 Kappos, L. et al. Interferon β-1b in secondary progressive MS: a combined analysis of the two trials. Neurology 63, 1779–1787 (2004).

42 Hawker, K. et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann. Neurol. 66, 460–471 (2009).

43 Pachner, A. R. Experimental models of multiple sclerosis. Curr. Opin. Neurol. 24, 291–299 (2011).

44 Sriram, S. & Steiner, I. Experimental allergic encephalomyelitis: a misleading model of multiple sclerosis. Ann. Neurol. 58, 939–945 (2005).

45 Warshawsky, I., Rudick, R. A., Staugaitis, S. M. & Natowicz, M. R. Primary progressive multiple sclerosis as a phenotype of a PLP1 gene mutation. Ann. Neurol. 58, 470–473 (2005).

46 Vanopdenbosch, L., Dubois, B., D'Hooghe, M. B., Meire, F. & Carton, H. Mitochondrial mutations of Leber's hereditary optic neuropathy: a risk factor for multiple sclerosis. J. Neurol. 247, 535–543 (2000).

47 Palace, J. Multiple sclerosis associated with Leber's Hereditary Optic Neuropathy. J. Neurol. Sci. 286, 24–27 (2009).

48 Man, P. Y. et al. The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am. J. Hum. Genet. 72, 333–339 (2003).

49 Koch-Henriksen, N. & Sorensen, P. S. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol. 9, 520–532 (2010).

50 Cooper, G. S. & Stroehla, B. C. The epidemiology of autoimmune diseases. Autoimmun. Rev. 2, 119–125 (2003).

51 Kovacs, G. G. et al. Neuropathology of white matter disease in Leber's hereditary optic neuropathy. Brain 128, 35–41 (2005).

52 Kipp, M., Clarner, T., Dang, J., Copray, S. & Beyer, C. The cuprizone animal model: new insights into an old story. Acta Neuropathol. 118, 723–736 (2009).

53 Prodan, C. I., Holland, N. R., Wisdom, P. J., Burstein, S. A. & Bottomley, S. S. CNS demyelination associated with copper deficiency and hyperzincemia. Neurology 59, 1453–1456 (2002).

54 You, H. et al. Aβ damages neurons by altering copper-dependent prion protein regulation of NMDA receptors. Proc. Natl Acad. Sci. USA 109, 1737–1742 (2012).

55 Stys, P. K., You, H. & Zamponi, G. W. Copper-dependent regulation of NMDA receptors by cellular prion protein: implications for neurodegenerative disorders. J. Physiol. 590, 1357–1368 (2012).

56 Karadottir, R., Cavelier, P., Bergersen, L. H. & Attwell, D. NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature 438, 1162–1166 (2005).

57 Micu, I. et al. NMDA receptors mediate calcium accumulation in central nervous system myelin during chemical ischaemia. Nature 439, 988–992 (2006).

58 Salter, M. G. & Fern, R. NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature 438, 1167–1171 (2005).

59 Tsutsui, S. & Stys, P. K. Metabolic injury to axons and myelin. Exp. Neurol. 1 May 2012 (doi: org/10.1016/j.expneurol.2012.04.016).

60 De Stefano, N. et al. Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes. Neurology 74, 1868–1876 (2010).

61 Fisher, E., Lee, J. C., Nakamura, K. & Rudick, R. A. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann. Neurol. 64, 255–265 (2008).

62 Stys, P. K. The axo-myelinic synapse. Trends Neurosci. 34, 393–400 (2011).

63 Locatelli, G. et al. Primary oligodendrocyte death does not elicit anti-CNS immunity. Nature Neurosci. 543–550 (2012).

64 Wenning, G. K., Stefanova, N., Jellinger, K. A., Poewe, W. & Schlossmacher, M. G. Multiple system atrophy: a primary oligodendrogliopathy. Ann. Neurol. 64, 239–246 (2008).

65 Harauz, G. & Musse, A. A. A tale of two citrullines — structural and functional aspects of myelin basic protein deimination in health and disease. Neurochem. Res. 32, 137–158 (2007).

66 Cao, L., Sun, D. & Whitaker, J. N. Citrullinated myelin basic protein induces experimental autoimmune encephalomyelitis in Lewis rats through a diverse T cell repertoire. J. Neuroimmunol. 88, 21–29 (1998).

67 Wood, D. D., Bilbao, J. M., O'Connors, P. & Moscarello, M. A. Acute multiple sclerosis (Marburg type) is associated with developmentally immature myelin basic protein. Ann. Neurol. 40, 18–24 (1996).

68 Wood, D. D. et al. Myelin localization of peptidylarginine deiminases 2 and 4: comparison of PAD2 and PAD4 activities. Lab. Invest. 88, 354–364 (2008).

69 Ip, C. W. et al. Immune cells contribute to myelin degeneration and axonopathic changes in mice overexpressing proteolipid protein in oligodendrocytes. J. Neurosci. 26, 8206–8216 (2006).

70 Stirling, D. P. & Stys, P. K. Mechanisms of axonal injury: internodal nanocomplexes and calcium deregulation. Trends Mol. Med. 16, 160–170 (2010).

71 Howe, C. L., Adelson, J. D. & Rodriguez, M. Absence of perforin expression confers axonal protection despite demyelination. Neurobiol. Dis. 25, 354–359 (2007).

72 Siffrin, V., Vogt, J., Radbruch, H., Nitsch, R. & Zipp, F. Multiple sclerosis — candidate mechanisms underlying CNS atrophy. Trends Neurosci. 33, 202–210 (2010).

73 Matute, C. Glutamate and ATP signalling in white matter pathology. J. Anat. 219, 53–64 (2011).

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

75 Mahad, D. J. et al. Mitochondrial changes within axons in multiple sclerosis. Brain 132, 1161–1174 (2009).

76 Young, E. A. et al. Imaging correlates of decreased axonal Na+/K+ ATPase in chronic multiple sclerosis lesions. Ann. Neurol. 63, 428–435 (2008).

77 Stys, P. K. Axonal degeneration in MS: is it time for neuroprotective strategies? Ann. Neurol. 55, 601–603 (2004).

78 Court, F. A., Hendriks, W. T., Macgillavry, H. D., Alvarez, J. & van Minnen, J. Schwann cell to axon transfer of ribosomes: toward a novel understanding of the role of glia in the nervous system. J. Neurosci. 28, 11024–11029 (2008).

79 Lublin, F. D. & Reingold, S. C. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 46, 907–911 (1996).

80 Miller, D. H. & Leary, S. M. Primary-progressive multiple sclerosis. Lancet Neurol. 6, 903–912 (2007).

81 Confavreux, C. & Vukusic, S. Accumulation of irreversible disability in multiple sclerosis: from epidemiology to treatment. Clin. Neurol. Neurosurg. 108, 327–332 (2006).

82 Stüve, O. & Oksenberg, J. Multiple sclerosis overview [updated 11 May 2010]. In GeneReviews (eds Pagon R. A. et al.) (University of Washington, Seattle, 1993).

83 Akiyama, H. et al. Inflammation and Alzheimer's disease. Neurobiol. Aging 21, 383–421 (2000).

84 Whitton, P. S. Inflammation as a causative factor in the aetiology of Parkinson's disease. Br. J. Pharmacol. 150, 963–976 (2007).

85 Langston, J. W. et al. Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Ann. Neurol. 46, 598–605 (1999).

86 McGeer, P. L. & McGeer, E. G. Inflammation and neurodegeneration in Parkinson's disease. Parkinsonism Relat. Disord. 10 (Suppl. 1), 3–7 (2004).

87 Pawelec, G., Larbi, A. & Derhovanessian, E. Senescence of the human immune system. J. Comp. Pathol. 142 (Suppl. 1), 39–44 (2010).