Review article
Inflammation, demyelination, neurodegeneration and neuroprotection in the pathogenesis of multiple sclerosis

https://doi.org/10.1016/j.jneuroim.2006.11.015Get rights and content

Abstract

Although axonal loss has been observed in demyelinated multiple sclerosis (MS) lesions, there has been a major focus on understanding mechanisms of demyelination. However, identification of markers for axonal damage and development of new imaging techniques has enabled detection of subtle changes in axonal pathology and revived interest in the neurodegenerative component of MS. Axonal loss is generally accepted as the main determinant of permanent clinical disability. However, the role of axonal loss early in disease or during relapsing–remitting disease is still under investigation, as are the interactions and interdependency between inflammation, demyelination, neurodegeneration and neuroprotection in the pathogenesis of MS.

Introduction

Multiple sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS). It is the most common demyelinating disease in young adults. Although Charcot noted axonal loss in demyelinated MS lesions over a century ago, the majority of MS research has focused on the process of demyelination with significantly less attention paid to the neurodegenerative component (Bjartmar and Trapp, 2001, Charcot, 1868). There is little doubt that axonal loss is the main determinant of permanent clinical disability. However, the role of axonal loss early in the disease course or during relapsing–remitting (RR) disease is still unclear, as are the interactions and interdependency of inflammation, demyelination and neurodegeneration.

Section snippets

Inflammation in MS and its animal models

The CNS has long been considered to be an immunoprivileged site with few if any lymphocytes present in the absence of active or ongoing infection. However, accumulating evidence has demonstrated that a small number of T cells traffic through the CNS surveying for infection or injury and that T cells activated in the periphery can penetrate the blood–brain barrier (BBB) and enter the CNS (Hickey et al., 1991, Wekerle et al., 1987).

Autoreactive T and B cells are normal constituents of the immune

Neurodegeneration in MS and its animal models

Neurodegeneration, axonal and/or neural damage, has been recognized as a component of MS for more than a century (Charcot, 1868). However, the axon has primarily been considered an innocent bystander in the disease process occurring secondary to inflammation and demyelination rather than as a specific target for immune attack. Early studies employed silver impregnation of sections and electron microscopy to detect axonal degeneration in MS (Suzuki et al., 1969). Recently the use of

Inflammation and neurodegeneration in MS and its animal models

Several possibilities exist for the relationship between inflammation and neurodegeneration: (1) that inflammation induces neurodegeneration; (2) that neurodegeneration causes inflammation; (3) other factors contribute to the development of inflammation and/or neurodegeneration; (4) inflammation and neurodegeneration participate in a cycle or a cascade in which they augment one another; and (5) that inflammation can protect against neurodegeneration. In the context of MS and its animal models

Animal model for investigating the relationship between inflammation and neurodegeneration

Several hypotheses exist to explain the relationship between inflammation and neurodegeneration in MS. One theory is that the pathogenesis of MS occurs in two distinct phases, an initial inflammatory autoimmune phase with a RR disease course followed by a progressive neurodegenerative phase in which axonal loss and permanent neurological disability occur (Steinman, 2001). Another hypothesis is that the different forms of MS represent different types of pathology with RR disease classified as an

Conclusions and future directions

Several hypotheses exist to explain the relationship between inflammation and neurodegeneration in MS. Examples exist in which inflammation causes neurodegeneration, neurodegeneration causes inflammation, inflammation and neurodegeneration appear to occur independently of one another and in which inflammation protects against neurodegeneration (Table 1). Further studies need to focus on the relevance of these hypotheses to MS in general, or with respect to different disease courses in MS, as

Acknowledgements

We thank Ikuo Tsunoda MD, PhD and Jane E. Libbey, MS for many helpful discussions. We are grateful to Ms. Kathleen Borick for the preparation of the manuscript. This work was supported by NIH grant 5RO1NS40350.

References (81)

  • P. Matsiota et al.

    Comparative study of natural autoantibodies in the serum and cerebrospinal fluid of normal individuals and patients with multiple sclerosis and other neurological diseases

    Ann. Inst. Pasteur., Immunol.

    (1988)
  • H. Neumann et al.

    Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases

    Trends Neurosci.

    (2002)
  • D. Papadopoulos et al.

    Axon loss is responsible for chronic neurological deficit following inflammatory demyelination in the rat

    Exp. Neurol.

    (2006)
  • E. Silber et al.

    Axonal degeneration in the pathogenesis of multiple sclerosis

    J. Neurol. Sci.

    (1999)
  • J.H. Simon

    From enhancing lesions to brain atrophy in relapsing MS

    J. Neuroimmunol.

    (1999)
  • I. Tsunoda et al.

    Axonal injury heralds virus-induced demyelination

    Am. J. Pathol.

    (2003)
  • S.S. Zamvil et al.

    Diverse targets for intervention during inflammatory and neurodegenerative phases of multiple sclerosis

    Neuron

    (2003)
  • H. Babbé 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)
  • D.A. Bechtold et al.

    Axonal protection using flecainide in experimental autoimmune encephalomyelitis

    Ann. Neurol.

    (2004)
  • C. Bjartmar et al.

    Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences

    Curr. Opin. Neurol.

    (2001)
  • M. Charcot

    Histology of sclerotic plaques

    Gaz. Hôsp.

    (1868)
  • C. Confavreux et al.

    Relapses and progression of disability in multiple sclerosis

    N. Engl. J. Med.

    (2000)
  • D.B. Constam et al.

    Differential expression of transforming growth factor-β1, -β2, and -β3 by glioblastoma cells, astrocytes, and microglia

    J. Immunol.

    (1992)
  • M.J. Craner et al.

    Co-localization of sodium channel Nav1.6 and the sodium–calcium exchanger at sites of axonal injury in the spinal cord in EAE

    Brain

    (2004)
  • M.J. Craner et al.

    Sodium channels contribute to microglia/macrophage activation and function in EAE and MS

    Glia

    (2005)
  • B. Ferguson et al.

    Axonal damage in acute multiple sclerosis lesions

    Brain

    (1997)
  • A. Flügel et al.

    Neuronal FasL induces cell death of encephalitogenic T lymphocytes

    Brain Pathol.

    (2000)
  • R.S. Fujinami

    Neurons tame T cells

    Nat. Med.

    (2006)
  • R. Gold et al.

    Antigen presentation by astrocytes primes rat T lymphocytes for apoptotic cell death. A model for T-cell apoptosis in vivo

    Brain

    (1996)
  • P.G. Haydon

    GLIA: listening and talking to the synapse

    Nat. Rev., Neurosci.

    (2001)
  • W.F. Hickey et al.

    T-lymphocyte entry into the central nervous system

    J. Neurosci. Res.

    (1991)
  • M. Hobom et al.

    Mechanisms and time course of neuronal degeneration in experimental autoimmune encephalomyelitis

    Brain Pathol.

    (2004)
  • E.S. Huseby et al.

    A pathogenic role for myelin-specific CD8+ T cells in a model for multiple sclerosis

    J. Exp. Med.

    (2001)
  • A. Iglesias et al.

    T- and B-cell responses to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis and multiple sclerosis

    Glia

    (2001)
  • S. Issazadeh et al.

    Kinetics of expression of costimulatory molecules and their ligands in murine relapsing experimental autoimmune encephalomyelitis in vivo

    J. Immunol.

    (1998)
  • M. Jacobsen et al.

    Oligoclonal expansion of memory CD8+ T cells in cerebrospinal fluid from multiple sclerosis patients

    Brain

    (2002)
  • A.H. Kim et al.

    Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1

    Mol. Cell. Biol.

    (2001)
  • E.A. Ling et al.

    The origin and nature of ramified and amoeboid microglia: a historical review and current concepts

    Glia

    (1993)
  • C. Linington et al.

    T cells specific for the myelin oligodendrocyte glycoprotein mediate an unusual autoimmune inflammatory response in the central nervous system

    Eur. J. Immunol.

    (1993)
  • Y. Liu et al.

    Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE

    Nat. Med.

    (2006)

    • Cited by (0)

    View full text
    Copyright © 2006 Elsevier B.V. All rights reserved.