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The role of TNFα and lymphotoxin in demyelinating disease
  1. Christopher Locka,
  2. Jorge Oksenbergb,
  3. Lawrence Steinmana
  1. aDepartment of Neurology and Neurological Sciences, Stanford University, Beckman Center B002, Stanford, CA 94305, USA, bDepartment of Neurology, University of California at San Francisco, School of Medicine, San Francisco, USA
  1. Dr L Steinman.

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Multiple sclerosis (MS) is an inflammatory demyelinating disease of central nervous system (CNS) white matter.1 The aetiology is unknown but the condition is probably the result of a misdirected immune response against myelin antigens. Pathologically there are multiple plaques or areas of white matter inflammation, demyelination, and glial scarring or sclerosis. In addition to myelin damage, axon loss may occur as there is a close relation between myelin and axon.2 The inflammatory lesions are disseminated in time and space, and clinically the illness is characterised by relapsing episodes of neurological dysfunction.

In a commonly proposed sequence of events, autoreactive myelin specific CD4+ Th1 are activated in the periphery, probably by non-self antigens with a resemblance to myelin proteins.3 T cells interact with adhesion molecules, such as selectins and integrins, on the capillary endothelium and then migrate into the brain parenchyma in response to chemotactic signals. Matrix metalloproteases (MMPs) are important in facilitating T cell penetration through the endothelial basement membrane. Microglia and astrocytes reactivate T cells locally in the CNS by presentation of myelin proteins bound to class II MHC molecules. T cells stimulate macrophage activity by release of proinflammatory cytokines such as IL2, IFNγ, tumour necrosis factor α (TNFα) and lymphotoxin (LT). Activated macrophages phagocytose myelin, and damage myelin by release of proteases, nitric oxide metabolites, reactive oxygen species, eicosanoids, complement components and TNFα. Autoantibodies directed against myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) are involved in myelin damage.4 ,5

Experimental allergic (or autoimmune) encephalomyelitis (EAE) can be induced in a variety of animal species, including non-human primates, by immunisation with spinal cord homogenates, myelin proteins or their peptide derivatives. A number of different myelin proteins can induce EAE, including proteolipid protein (PLP), MBP, MOG, myelin associated glycoprotein (MAG), and 2'3' cyclic …

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