R. Martin, B. Gran, B. Bielekova, S. Markovic-Plese, I. Cortese,

Proinflammatory CD4+ T lymphocytes with specificity for myelin autoantigens play a central role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). While research during the last two decades focused on the most abundant myelin components, namely myelin basic protein (MBP) and proteolipid protein (PLP), it is becoming well recognized that minor myelin components such as myelin oligodendroglia glycoprotein (MOG) or myelin oligodendrocyte basic protein (MOBP) or even non-myelin constituents such as heat shock proteins, S-100, or ion channel components may also induce a demyelinating or inflammatory disease. Along with a better understanding of the T cell response to these proteins, elegant animal studies suggest that the combination of a particular encephalitogen and the genetic background of susceptible animals may lead to phenotypically distinct disaeses. Thus, a similar, though not as extensive heterogeneity of disease is not only appreciated in MS, but also in the experimental animal systems. Furthermore, the development of transgenic mice that express MS-associated HLA molecules as well as human, myelin-specific T cell receptors and other equally interesting approaches provide firm evidence that myelin-specific T cells are important in MS and EAE. A recent phase II clinical trial of MS with an altered peptide ligand based on the immunodominant MBP peptide (83-99) showed that such a peptide may induce disease exacerbations in a subset of patients, and thus strongly supports the above notion. Observations from animal systems and human in vitro studies are therefore not only valid with respect to disease pathogenesis, but will also be useful for the design of specific immunotherapies.