THE DALE-E-MCFARLIN-MEMORIAL-LECTURE - THE IMMUNOLOGY OF THE MULTIPLE-SCLEROSIS LESION

This review surveys the structural terrain of the multiple sclerosis ( MS) lesion from the standpoint of its immunologic responsiveness. Simi larities in lymphocyte trafficking patterns are noted between MS and i ts laboratory model, experimental allergic encephalomyelitis (EAE), an d in both conditions, the inflammatory response is selective for the c entral nervous system (CNS). While adhesion molecules abound during th e genesis of the MS lesion, none has yet been found that is unusual to this condition and, indeed, many occur in other neurodegenerative sta tes in which inflammation is not a component of the lesion. Cytokines are effective regulators of lymphocyte traffic and adhesion events and most can be located in MS lesions. Of these, tumor necrosis factor-al pha (TNF-alpha) occurs in abundance. Together with its known affinity to effect myelin and oligodendrocyte destruction and to up-regulate ad hesion molecule expression, the presence of TNF-alpha renders it an im portant player in lesion pathogenesis. Demyelination is described as a rapid lytic event, perhaps involving cytokines and immunoglobulin, an d structural similarities are common in the patterns seen in MS and EA E. Oligodendrocytes survive the initial stages of lesion formation. Mo reover, they are now known to proliferate and elaborate new myelin at the same time as myelin is being degraded. This paradoxical reparatory scenario is apparently a transient event although rims of remyelinati on persist about the margins of chronic lesions. The speculation is re iterated that the demise of the oligodendrocyte in MS may occur late i n lesion formation and may be in part related to the expression of hea t shock proteins (specifically, members of the hsp 60 family), potent stimulators of T-cell receptor-gamma delta T cells that have been clai med to have cytolytic activity and that have been located in chronic a ctive MS lesions. In sum, while no single immune system molecule can b e assigned as unusual to the CNS in MS, and while there appears to be nothing unique about the manner in which the CNS responds to the infla mmation, the true uniqueness of the situation in MS is probably relate d to the many, normally sequestered, specific antigens within the myel in sheath and the biology of the myelinating cell, the oligodendrocyte .