Schädigungs- und Reparaturmechanismen in Multiple-Sklerose-Läsionen

Zusammenfassung

Dieser Artikel gibt einen Überblick über die histologischen Charakteristika der Multiplen Sklerose (MS) und die pathogenetischen Konzepte bezüglich der Entstehung der Entzündung, des axonalen Schadens und der Remyelinisierung.

Die MS ist die häufigste entzündlich demyelinisierende Erkrankung des zentralen Nervensystems. Es handelt sich um eine komplexe Erkrankung, deren progrediente Erkrankungsphase medikamentös nicht signifikant beeinflusst werden kann. Histologisch ist diese Erkrankung durch fokal entzündliche, demyelinisierte Läsionen sowie eine diffuse Pathologie in der normal erscheinenden weißen Substanz charakterisiert. Der zum Teil ausgeprägte axonale Schaden und Verlust ist nicht nur in den Läsionen, sondern auch in der normal erscheinenden weißen Substanz nachweisbar. Die Remyelinisierung ist in der Mehrheit der chronischen MS-Läsionen limitiert. Voraussetzung für die Entwicklung Erfolg versprechender neuroprotektiver Therapien ist die Identifizierung der exakten Mechanismen, die zur Demyelinisierung und zum axonalen Verlust in MS-Läsionen führen.

Summary

This article provides an overview about the histopathological hallmarks of multiple sclerosis (MS) and the current pathogenetic concepts regarding inflammation, axonal damage and remyelination.

MS is the most frequent demyelinating disease of the central nervous system. It is a complex disease and no treatment options are available to significantly influence this progressive disease phase. Histopathologically, MS is characterized by focal inflammatory, demyelinating MS lesions and diffuse white matter pathology. Partially extensive axonal damage and loss is detectable in focal lesions and in the normal appearing white matter. Remyelination is limited in the majority of chronic MS lesions. Prerequisite for the development of neuroprotective treatment strategies is the identification of the exact mechanisms leading to demyelination and axonal loss in MS lesions.

Schlüsselwörter

Multiple Sklerose - axonaler Schaden - Remyelinisierung - progrediente MS

Keywords

Multiple sclerosis - axonal damage - remyelination - progressive MS

• Literatur

• 1 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 2003; 62: 25-33.
• 2 Albert M. et al. Extensive cortical remyelination in patients with chronic multiple sclerosis. Brain Pathol 2007; 17: 129-138.
• 3 Arnett HA. et al. TNFa promotes proliferation of oligodendrocyte progenitors and remyelination. Nature Neurosci 2001; 04: 1116-1122.
• 4 Barnett MH, Prineas JW. Relapsing and remitting multiple sclerosis: Pathology of the newly forming lesion. Ann Neurol 2004; 55: 458-468.
• 5 Benedict RH. et al. Neocortical atrophy, third ventricular width, and cognitive dysfunction in multiple sclerosis. Arch Neurol 2006; 63: 1301-1306.
• 6 Bjartmar C. et al. Axonal loss in normal-appearing white matter in a patient with acute MS. Neurology 2001; 57: 1248-1252.
• 7 Bo L. et al. Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration. Mult Scler 2003; 09: 323-331.
• 8 Bo L. et al. Subpial demyelination in the cerebral cortex of multiple sclerosis patients. J Neuropathol Exp Neurol 2003; 62: 723-732.
• 9 Brück W, Lucchinetti C, Lassmann H. The pathology of primary progressive multiple sclerosis. Mult Scler 2002; 08: 93-97.
• 10 Brück W. et al. Monocyte/macrophage differentiation in early multiple sclerosis lesions. Ann Neurol 1995; 38: 788-796.
• 11 Brück W. et al. Oligodendrocytes in the early course of multiple sclerosis. Ann Neurol 1994; 35: 65-73.
• 12 Brück W. et al. Macrophages in multiple sclerosis. Immunobiol 1996; 195: 588-600.
• 13 Buntinx M. et al. Immune-mediated oligodendrocyte injury in multiple sclerosis: molecular mechanisms and therapeutic interventions. Crit Rev Immunol 2002; 22: 391-424.
• 14 Calabrese M. et al. Morphology and evolution of cortical lesions in multiple sclerosis. A longitudinal MRI study. Neuroimage 2008; 42: 1324-1328.
• 15 Carson MJ. et al. Insulin-like growth factor I increases brain growth and central nervous system myelination in transgenic mice. Neuron 1993; 10: 729-740.
• 16 Chang A. et al. Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. New Engl J Med 2002; 346: 165-173.
• 17 Charles P. et al. Negative regulation of central nervous system myelination by polysialylated-neural cell adhesion molecule. Proc Natl Acad Sci U S A 2000; 97: 7585-7590.
• 18 Chen JT. et al. Magnetization transfer ratio evolution with demyelination and remyelination in multiple sclerosis lesions. Ann Neurol 2008; 63: 254-262.
• 19 Dyment D, Ebers G, Sadovnick AD. Genetics of multiple sclerosis. Lancet Neurol 2004; 03: 104-110.
• 20 Ferguson B. et al. Axonal damage in acute multiple sclerosis lesions. Brain 1997; 120: 393-399.
• 21 Fisher E. et al. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol 2008; 64: 255-265.
• 22 Ganter P, Prince C, Esiri MM. Spinal cord axonal loss in multiple sclerosis: a post-mortem study. Neuropathol Appl Neurobiol 1999; 25: 459-467.
• 23 Garbern JY. et al. Patients lacking the major CNS myelin protein, proteolipid protein 1, develop lenght-dependent axonal degeneration in the absence of demyelination and inflammation. Brain 2002; 125: 551-561.
• 24 Goldschmidt T. et al. The remyelination capacity of the MS brain decreases with disease chronicity. Neurology 2009; 72: 1914-1921.
• 25 Griffiths I. et al. Axonal swellings and degeneration in mice lacking the major proteolipidprotein of myelin. Science 1998; 280: 1610-1613.
• 26 Ingle GT. et al. Primary progressive multiple sclerosis: a 5-year clinical and MR study. Brain 2003; 126: 2528-2536.
• 27 Irvine KA, Blakemore WF. Remyelination protects axons from demyelination-associated axon degeneration. Brain 2008; 131: 1464-1477.
• 28 Itoyama Y, Sternberger NH, Webster Hd. Immunocytochemical observations on the distribution of myelin associated glycoprotein and myelin basic protein in multiple sclerosis lesions. Ann Neurol 1980; 07: 167-177.
• 29 Kerschensteiner M, Meinl E, Hohlfeld R. Neuro-immune crosstalk in CNS diseases. Neuroscience 2009; 158: 1122-1132.
• 30 Kotter MR. et al. Macrophage-depletion induced impairment of experimental CNS remyelination is associated with a reduced oligodendrocyte progenitor cell response and altered growth factor expression. Neurobiol Dis 2005; 18: 166-175.
• 31 Kuhlmann T. et al. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 2002; 125: 2202-2212.
• 32 Kuhlmann T. et al. Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis. Brain 2008; 131: 1749-1758.
• 33 Kutzelnigg A. et al. Widespread demyelination in the cerebellar cortex in multiple sclerosis. Brain Pathol 2007; 17: 38-44.
• 34 Kutzelnigg A. et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005; 128: 2705-2712.
• 35 Lappe-Siefke C. et al. Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nat Genet 2003; 33: 366-374.
• 36 Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology 1996; 46: 907-911.
• 37 Lucchinetti C. et al. A quantitative analysis of oligodendrocytes in multiple sclerosis lesions. A study of 113 cases. Brain 1999; 122: 2279-2295.
• 38 Lucchinetti C. et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2000; 47: 707-717.
• 39 McMorris FA, McKinnon RD. Regulation of oligodendrocyte development and CNS myelination by growth factors: prospects for therapy of demyelinating disease. Brain Pathol 1996; 06: 313-329.
• 40 Mews I. et al. Oligodendrocyte and axon pathology in clinically silent multiple sclerosis lesions. Mult Scler 1998; 04: 55-62.
• 41 Mi S. et al. LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOGinduced experimental autoimmune encephalomyelitis. Nat Med 2007; 13: 1228-1233.
• 42 Mi S. et al. LINGO-1 negatively regulates myelination by oligodendrocytes. Nat Neurosci 2005; 08: 745-751.
• 43 Ozawa K. et al. Patterns of oligodendroglia pathology in multiple sclerosis. Brain 1994; 117: 1311-1322.
• 44 Patani R. et al. Remyelination can be extensive in multiple sclerosis despite a long disease course. Neuropathol Appl Neurobiol 2007; 33: 277-287.
• 45 Patrikios P. et al. Remyelination is extensive in a subset of multiple sclerosis patients. Brain 2006; 129: 3165-3172.
• 46 Pelletier D. et al. MRI lesion volume heterogeneity in primary progressive MS in relation with axonal damage and brain atrophy. J Neurol Neurosurg Psychiatry 2003; 74: 950-952.
• 47 Peterson JW. et al. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 2001; 50: 389-400.
• 48 Prineas JW, Connell F. Remyelination in multiple sclerosis. Ann Neurol 1979; 05: 22-31.
• 49 Raine CS, Scheinberg L, Waltz JM. Multiple sclerosis. Oligodendrocyte survival and proliferation in an active established lesion. Lab Invest 1981; 45: 534-546.
• 50 Rocca MA. et al. Occult tissue damage in patients with primary progressive multiple sclerosis is independent of T2-visible lesions A diffusion tensor MR study. J Neurol 2003; 250: 456-460.
• 51 Rodriguez M. et al. Oligodendrocyte injury is an early event in lesions of multiple sclerosis. Mayo Clin Proc 1993; 68: 627-636.
• 52 Rovaris M. et al. Assessment of normal-appearing white and gray matter in patients with primary progressive multiple sclerosis: a diffusion-tensor magnetic resonance imaging study. Arch Neurol 2002; 59: 1406-1412.
• 53 Rovaris M. et al. In vivo assessment of the brain and cervical cord pathology of patients with primary progressive multiple sclerosis. Brain 2001; 124: 2540-2549.
• 54 Setzu A. et al. Inflammation stimulates myelination by transplanted oligodendrocyte precursor cells. Glia 2006; 54: 297-303.
• 55 Stark W, Huppke P, Gartner J. Paediatric multiple sclerosis: the experience of the German Centre for Multiple Sclerosis in Childhood and Adolescence. J Neurol 2008; 255 Suppl 6 119-122.
• 56 Trapp BD, Nave KA. Multiple sclerosis: an immune or neurodegenerative disorder?. Annu Rev Neurosci 2008; 31: 247-269.
• 57 Trapp BD, Stys PK. Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol 2009; 08: 280-291.
• 58 van der GA. et al. Determination of the sequential degradation of myelin proteins by macrophages. J Neuroimmunol 2005; 161: 12-20.
• 59 Vercellino M. et al. Grey matter pathology in multiple sclerosis. J Neuropathol Exp Neurol 2005; 64: 1101-1107.
• 60 Wegner C. et al. Neocortical neuronal, synaptic, and glial loss in multiple sclerosis. Neurology 2006; 67: 960-967.
• 61 Wolswijk G. Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells. J Neurosci 1998; 18: 601-609.
• 62 Wolswijk G. Oligodendrocyte regeneration in the adult rodent CNS and the failure of this process in multiple sclerosis. Prog Brain Res 1998; 117: 233-247.