Oligodendrocyte apoptosis and primary demyelination induced by local TNF/p55TNF receptor signaling in the central nervous system of transgenic mice - Models for multiple sclerosis with primary oligodendrogliopathy

被引:275
作者
Akassoglou, K
Bauer, J
Kassiotis, G
Pasparakis, M
Lassmann, H
Kollias, G
Probert, L
机构
[1] Hellen Pasteur Inst, Dept Mol Genet, GR-11521 Athens, Greece
[2] Univ Vienna, Inst Neurol, Dept Expt Neuropathol, Vienna, Austria
关键词
D O I
10.1016/S0002-9440(10)65622-2
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
The scientific dogma that multiple sclerosis (MS) is a disease caused by a single pathogenic mechanism has been challenged recently by the heterogeneity observed in MS lesions and the realization that not all patterns of demyelination can be modeled by auto-immune-triggered mechanisms. To evaluate the contribution of local tumor necrosis factor (TNF) ligand/ receptor signaling pathways to MS immunopathogenesis we have analyzed disease pathology in central nervous system-expressing TNF transgenic mice, with or without p55 or p75TNF receptors, using combined in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling and cell identification techniques, Vile demonstrate that local production of TNF by central nervous system glia potently and selectively induces oligodendrocyte apoptosis and myelin vacuolation in the context of an intact blood-brain barrier and absence of immune cell infiltration into the central nervous system parenchyma, Interestingly, primary demyelination then develops in a classical manner in the presence of large numbers of recruited phagocytic macrophages, possibly the result of concomitant pro-inflammatory effects of TNF in the central nervous system, and lesions progress into acute or chronic MS-type plaques with axonal damage, focal blood-brain barrier disruption, and considerable oligodendrocyte loss. Both the cytotoxic and inflammatory effects of TNF were abrogated in mice genetically deficient for the p55TNF receptor demonstrating a dominant role for p55TNF receptor-signaling pathways in TNF-mediated pathology, These results demonstrate that aberrant local TNF/p55TNF receptor signaling in the central nervous system can have a potentially major role ia the aetiopathogenesis of MS demyelination, particularly in MS subtypes in which oligodendrocyte death is a primary pathological feature, and provide new models for studying the basic mechanisms underlying oligodendrocyte and myelin loss.
引用
收藏
页码:801 / 813
页数:13
相关论文
共 70 条
  • [1] Akassoglou K, 1997, J IMMUNOL, V158, P438
  • [2] CONTROL OF ESTABLISHED EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS BY INHIBITION OF TUMOR-NECROSIS-FACTOR (TNF) ACTIVITY WITHIN THE CENTRAL-NERVOUS-SYSTEM USING MONOCLONAL-ANTIBODIES AND TNF RECEPTOR IMMUNOGLOBULIN FUSION PROTEINS
    BAKER, D
    BUTLER, D
    SCALLON, BJ
    ONEILL, JK
    TURK, JL
    FELDMANN, M
    [J]. EUROPEAN JOURNAL OF IMMUNOLOGY, 1994, 24 (09) : 2040 - 2048
  • [3] TUMOR-NECROSIS-FACTOR-ALPHA AND TUMOR-NECROSIS-FACTOR-BETA PROTECT NEURONS AGAINST AMYLOID BETA-PEPTIDE TOXICITY - EVIDENCE FOR INVOLVEMENT OF A KAPPA-B-BINDING FACTOR AND ATTENUATION OF PEROXIDE AND CA2+ ACCUMULATION
    BARGER, SW
    HORSTER, D
    FURUKAWA, K
    GOODMAN, Y
    KRIEGLSTEIN, J
    MATTSON, MP
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (20) : 9328 - 9332
  • [4] THE LONGSTANDING MS LESION - A QUANTITATIVE MRI AND ELECTRON-MICROSCOPIC STUDY
    BARNES, D
    MUNRO, PMG
    YOUL, BD
    PRINEAS, JW
    MCDONALD, WI
    [J]. BRAIN, 1991, 114 : 1271 - 1280
  • [5] An essential role for NF-kappa B in preventing TNF-alpha-induced cell death
    Beg, AA
    Baltimore, D
    [J]. SCIENCE, 1996, 274 (5288) : 782 - 784
  • [6] Bonetti B, 1997, J IMMUNOL, V159, P5733
  • [7] Multiple sclerosis: Oligodendrocytes display cell death-related molecules in situ but do not undergo apoptosis
    Bonetti, B
    Raine, CS
    [J]. ANNALS OF NEUROLOGY, 1997, 42 (01) : 74 - 84
  • [8] BREITSCHOPF H, 1992, ACTA NEUROPATHOL, V84, P581
  • [9] Mechanisms of immune injury in multiple sclerosis
    Brosnan, CF
    Raine, CS
    [J]. BRAIN PATHOLOGY, 1996, 6 (03) : 243 - 257
  • [10] Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors
    Bruce, AJ
    Boling, W
    Kindy, MS
    Peschon, J
    Kraemer, PJ
    Carpenter, MK
    Holtsberg, FW
    Mattson, MP
    [J]. NATURE MEDICINE, 1996, 2 (07) : 788 - 794