Restricted immune responses lead to CNS demyelination and axonal damage

Although autoreactive T-cells have a pivotal role in initiating the inflamm atory process in experimental autoimmune encephalomyelitis (EAE) and multip le sclerosis (MS). recent evidence suggests a relevant role for autoantibod ies specific for myelin proteins as well. To examine the role of B-cells in the cerebrospinal fluid of patients with MSI we analyzed the V-H gene usag e in ten MS patients by PCR technologies. Analysis of HCDR3 length revealed an oligoclonal accumulation of B-cells. Sequence analysis of the V(H)3 and V(H)4 gamma transcripts of two MS individuals demonstrated that this accum ulation was related to the expansion and somatic diversification of a limit ed groups of B-cell clones. These findings are indicative of a chronic and intense antigenic stimulation occurring in the CNS. Animal models, such as EAE. are of particular importance in order to elucidate the pathogenetic ef fector mechanisms in autoimmune demyelination. in a non-human primate model of EAE, we describe that the immunodominant T-cell epitope is presented ex clusively by a monomorphic DRB1 allele, suggesting that susceptibility to E AE may be linked to this unique restriction and, therefore, providing a pos sible mechanism for MHC linkage to diseases. Moreover, we report on the pre sence of inflammation, sharp demyelination and axonal damage in EAE induced with whole myelin as well as with recombinant myelin oligodendrocyte glyco protein (MOG), but not with myelin basic protein alone. The presence of axo nal pathology was supported by immunohistochemistry with anti-amyloid precu rsor protein and anti-non phosphorilated neurofilaments monoclonal antibodi es within early active demyelinated plaques. These findings suggest that ax onal damage may be an early event in the pathogenesis of autoimmune demyeli nating diseases of the CNS and highlights the importance of animal models i n which therapies targeting repair and axonal survival may be exploited. (C ) 2000 Elsevier Science B.V. All rights reserved.