Nervenheilkunde 2007; 26(07): 572-577
DOI: 10.1055/s-0038-1626899
Original Article
Schattauer GmbH

Fortschritte in der Pathogeneseforschung der Multiplen Sklerose

Recent advances in pathogenesis of multiple sclerosis
R. Gold
1   Neurologische Klinik, St. Josef Hospital, Klinikum der Ruhr-Universität Bochum
,
W. Brück
2   Institut für Neuropathologie, Bereich Humanmedizin, Georg-August-Universität Göttingen
› Author Affiliations
Further Information

Publication History

Eingegangen am: 27 April 2007

angenommen am: 02 May 2007

Publication Date:
20 January 2018 (online)

Zusammenfassung

In dieser Übersichtsarbeit stellen wir die in den letzten Jahren erzielten Fortschritte im Verständnis der Multiplen Sklerose (MS) dar. Aus molekularen, pathologischen, immunologischen und tierexperimentellen Studien resultierten neue Erkenntnisse zur Pathogenese, die durch bildgebende Verfahren und klinische Studien ergänzt wurden. Schwerpunkte liegen insbesondere auf neurodegenerativen Aspekten der Erkrankung sowie auf therapierelevanten Befunden, die bereits zu einer deutlichen Verbesserung der Immuntherapie im letzten Jahrzehnt führten. Vor allem bei der schubförmig verlaufenden MS kann seit der Einführung moderner Immuntherapien in vielen Fällen die Krankheit früh stabilisiert werden. Bei der primär progredienten Verlaufsform sind unsere pathogenetischen Fortschritte leider deutlich begrenzt, vor allem auch durch den limitierten Zugang zu Gewebeproben und Fehlen adäquater Modelle. Die weitere Entwicklung neurobiologisch-protektiver Strategien soll gezielt das Überleben von Gliaund Nervenzellen fördern.

Summary

In this article, recent advances in the research on pathogenesis of multiple sclerosis (MS) will be summarized. New evidence from molecular histopathology, immunology and experimental models are discussed with a focus on neurodegenerative aspects; in addition evidence from imaging and recent clinical studies is analysed. During the last decade, important advances in immunotherapy have been achieved, which proved especially useful for patients with relapsing remitting MS. Limitations are given for primary progressive MS, due to the lack of suitable tissue specimens and experimental models. The pathogenetic insights presented here may open new avenues for novel immunotherapies and lead to an individualized MS therapy in the future. Neuroprotective treatment strategies aim at the protection of glial and neuronal cells.

 
  • Literatur

  • 1 Aboul-Enein F, Rauschka H, Kornek B. 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 Babbe H, Roers A, Waisman A. 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 2000; Aug 7; 192: 393-404.
  • 3 Bailey SL, Schreiner B, McMahon EJ, Miller SD. CNS myeloid DCs presenting endogenous myelin peptides ‘preferentially’ polarize CD4(+) T-H-17 cells in relapsing EAE. Nat Immunol 2007; 08: 172-180.
  • 4 Bechtold DA, Kapoor R, Smith KJ. Axonal protection using flecainide in experimental autoimmune encephalomyelitis. Ann Neurol 2004; 55: 607-616.
  • 5 Ben-Nun A, Wekerle H, Cohen IR. The rapid isolation of clonable antigen-specific T lymphocyte lines capable of mediating autoimmune encephalomyelitis. Eur J Immunol 1981; 11: 195-199.
  • 6 Bettelli E, Carrier YJ, Gao WD. et al. Reciprocal developmental pathways for the generation of pathogenic effector T(H)17 and regulatoryT cells. Nature 2006; 441: 235-238.
  • 7 Bettelli E, Oukka M, Kuchroo VK. T-H-17 cells in the circle of immunity and autoimmunity. Nat Immunol 2007; 08: 345-350.
  • 8 Bitsch A, Kuhlmann T, Stadelmann C, Lassmann H, Lucchinetti C, Bruck W. A longitudinal MRI study of histopathologically defined hypointense multiple sclerosis lesions. Ann Neurol 2001; 49: 793-796.
  • 9 Bitsch A, Schuchardt J, Bunkowski S, Kuhlmann T, Brück W. Acute axonal injury in multiple sclerosis – Correlation with demyelination and inflammation. Brain 2000; Jun; 123: 1174-1183.
  • 10 Bo L, Vedeler CA, Nyland H, Trapp BD, Mork SJ. Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration. Mult Scler 2003; 09: 323-331.
  • 11 Bruck W, Kuhlmann T, Stadelmann C. Remyelination in multiple sclerosis. J Neurol Sci 2003; 206: 181-185.
  • 12 Derfuss T, Gurkov R, Bergh FT. et al. Intrathecal antibody production against Chlamydia pneumoniae in multiple sclerosis is part ofa polyspecific immune response. Brain 2001; 124: 1325-1335.
  • 13 Diem R, Sattler MB, Merkler D. et al. Combined therapy with methylprednisolone and erythropoietin in a model of multiple sclerosis. Brain 2005; Feb; 128: 375-385.
  • 14 Flugel A, Berkowicz T, Ritter T. et al. Migratory activity and functional changes of green fluorescent effector cells before and during experimental autoimmune encephalomyelitis. Immunity 2001; 14: 547-560.
  • 15 Goebels N, Hofstetter H, Schmidt S, Brunner C, Wekerle H, Hohlfeld R. Repertoire dynamics of autoreactiveT cells in multiple sclerosis patients and healthy subjects – Epitope spreading versus clonal persistence. Brain 2000; Mar; 123: 508-518.
  • 16 Gold R, Linington C, Lassmann H. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 2006; 129: 1953-1971.
  • 17 Kawakami N, Nagerl UV, Odoardi F, Bonhoeffer T, Wekerle H, Flugel A. Live imaging of effector cell trafficking and autoantigen recognition within the unfolding autoimmune encephalomyelitis lesion. J Exp Med 2005; 201: 1805-1814.
  • 18 Keegan M, Konig F, McClelland R. et al. Relation between humoral pathological changes in multiple sclerosis and response to therapeutic plasma exchange. Lancet 2005; 366: 579-582.
  • 19 Kerschensteiner M, Gallmeier E, Behrens L. et al. Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation?. J Exp Med 1999; Mar 1; 189: 865-870.
  • 20 Kivisakk P, Mahad DJ, Callahan MK. et al. Expression of CCR7 in multiple sclerosis: implications for CNS immunity. Ann Neurol 2004; May; 55: 627-638.
  • 21 Kornek B, Storch MK, Bauer J. et al. Distribution of a calcium channel subunit in dystrophic axons in multiple sclerosis and experimental autoimmune encephalomyelitis. Brain 2001; 124: 1114-1124.
  • 22 Kuhlmann T, Lingfeld G, Bitsch A, Schuchardt J, Bruck W. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 2002; 125: 2202-2212.
  • 23 Lassmann H, Bruck W, Lucchinetti C. Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends Mol Med 2001; 07: 115-121.
  • 24 Lennon VA, Wingerchuk DM, Kryzer TJ. et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004; 364: 2106-2112.
  • 25 Linker RA, Maurer M, Gaupp S. et al. CNTF is a major protective factor in demyelinating CNS disease: A neurotrophic cytokine as modulator in neuroinflammation. Nature Med 2002; 08: 620-624.
  • 26 Losseff NA, Webb SL, O’Riordan JI. et al. Spinal cord atrophy and disability in multiple sclerosis – A new reproducible and sensitive MRI method with potential to monitor disease progression. Brain 1996; 119: 701-708.
  • 27 Lucchinetti CF, Mandler RN, McGavern D. et al. A role for humoral mechanisms in the pathogenesis of Devic’s neuromyelitis optica. Brain 2002; 125: 1450-1461.
  • 28 McMahon EJ, Bailey SL, Castenada CV, Waldner H, Miller SD. Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis. Nature Med 2005; 11: 335-339.
  • 29 Merkler D, Ernsting T, Kerschensteiner M, Bruck W, Stadelmann C. A new focal EAE model of cortical demyelination: multiple sclerosis-like lesions with rapid resolution of inflammation and extensive remyelination. Brain 2006; 129: 1972-1983.
  • 30 Merkler D, Schmelting B, Czeh B, Fuchs E, Stadelmann C, Bruck W. Myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in the common marmoset reflects the immunopathology of pattern II multiple sclerosis lesions. Mult Scler 2006; Aug; 12: 369-374.
  • 31 Meyer R, Weissert R, Diem R. et al. Acute neuronal apoptosis in a rat model of multiple sclerosis. J Neurosci 2001; 21: 6214-6220.
  • 32 Nitsch R, Pohl EE, Smorodchenko A, Infante-Duarte C, Aktas O, Zipp F. Direct impact of T cells on neurons revealed by two-photon microscopy in living brain tissue. J Neurosci 2004; Mar 10; 24: 2458-2464.
  • 33 Ota K, Matsui M, Milford EL, Mackin GA, Weiner HL, Hafler DA. T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature 1990; 346: 183-187.
  • 34 Owens T, Wekerle H, Antel S. Genetic models for CNS inflammation. Nature Med 2001; 07: 161-166.
  • 35 Ozawa K, Suchanek G, Breitschopf H. et al. Patterns of oligodendroglia pathology in multiple sclerosis. Brain 1994; 117: 1311-1322.
  • 36 Patrikios P, Stadelmann C, Kutzelnigg A. et al. Remyelination is extensive in a subset of multiple sclerosis patients (vol 129, pg 3165, 2006). Brain 2007; 130: 879.
  • 37 Peterson JW, Bo L, Mork S, Chang A, Trapp BD. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 2001; 50: 389-400.
  • 38 Pette M, Fujita K, Wilkinson D. et al. Myelin autoreactivity in multiple sclerosis: recognition of myelin basic protein in the context of HLA-DR2 products by T lymphocytes of multiple-sclerosis patients and healthy donors. Proc Natl Acad Sci USA 1990; Oct; 87: 7968-7972.
  • 39 Reddy H, Narayanan S, Arnoutelis R. et al. Evidence for adaptive functional changes in the cerebral cortex with axonal injury from multiple sclerosis. Brain 2000; Nov; 123 ( Pt 11): 2314-2320.
  • 40 Reddy H, Narayanan S, Woolrich M. et al. Functional brain reorganization for hand movement in patients with multiple sclerosis: defining distinct effects of injury and disability. Brain 2002; Dec; 125: 2646-2657.
  • 41 Rivers TM, Sprunt DH, Berry GP. Observations on attempts to produce acute disseminated encephalomyelitis in monkeys. J Exp Med 1933; 58: 39-53.
  • 42 Sabatos CA, Chakravarti S, Cha E. et al. Interaction of Tim-3 and Tim-3 ligand regulatesT helper type 1 responses and induction of peripheral tolerance. Nature Immunol 2003; 04: 1102-1110.
  • 43 Schilling S, Linker R, Konig F. et al. Plasma exchange therapy for steroid-unresponsive multiple sclerosis relapses. Clinical experience with 16 patients. Nervenarzt 2006; 77: 430.
  • 44 Shevach EM. CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2002; Jun; 02: 389-400.
  • 45 Skulina C, Schmidt S, Dornmair K. et al. Multiple sclerosis: Brain-infiltrating CD8(+)T cells persist as clonal expansions in the cerebrospinal fluid and blood. Proc Natl Acad Sci USA 2004; 101: 2428-2433.
  • 46 Stadelmann C, Kerschensteiner M, Misgeld T, Bruck W, Hohlfeld R, Lassmann H. BDNF and gp145trkB in multiple sclerosis brain lesions: Neuroprotective interactions between immune and neuronal cells?. Brain 2002; 125: 75-85.
  • 47 Stasiolek M, Bayas A, Wieczarkowiecz A, Toyka KV, Gold R, Selmaj K. Impaired maturation and altered regulatory function of plasmacytoid dendritic cells in multiple sclerosis. Brain 2006; 129: 1293-1305.
  • 48 Steinman L. Multiple sclerosis: a two-stage disease. Nature Immunol 2001; 02: 762-764.
  • 49 Storch MK, Stefferl A, Brehm U. et al. Autoimmunity to myelin oligodendrocyte glycoprotein in rats mimics the spectrum of multiple sclerosis pathology. Brain Pathol 1998; Oct; 08: 681-694.
  • 50 Sundvall M, Jirholt J, Yang HT. et al. Identification of murine loci associated with susceptibility to chronic experimental autoimmune encephalomyelitis. Nat Genet 1995; 10: 313-317.
  • 51 T’Hart BA, Laman JD, Bauer J, Blezer E, Van Kooyk Y, Hintzen RQ. Modelling of multiple sclerosis: lessons learned in a non-human primate. Lancet Neurol 2004; 03: 588-597.
  • 52 Takahashi K, Miyake S, Kondo T. et al. Natural killer type 2 bias in remission of multiple sclerosis. J Clin Invest 2001; Mar; 107: R23-R29.
  • 53 Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol 2003; 21: 335-76.
  • 54 Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338: 278-285.
  • 55 Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4(+)CD25(+) regulatory T cells in patients with multiple sclerosis. J Exp Med 2004; 199: 971-979.
  • 56 Weinshenker BG, O’Brien PC, Petterson TM. et al. A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol 1999; Dec; 46: 878-886.
  • 57 Zhou D, Srivastava R, Nessler S. et al. Identification of a pathogenic antibody response to native myelin oligodendrocyte glycoprotein in multiple sclerosis. Proc Natl Acad Sci US A 2006; Dec 12; 103: 19057-19062.
  • 58 Brück W. et al. In Vorbereitung zur Publikation