Mistaken self, a novel model that links microbial infections with myelin-directed autoimmunity in multiple sclerosis

Several findings indicate that infectious events play a role in the pathoge nesis of multiple sclerosis (MS). At the same time, T-cell autoimmunity to myelin antigens is widely believed to be crucial to the development of MS l esions. Several mechanisms have been put forward to explain the presumed li nk between microbial infections and myelin-directed autoimmunity. These inc lude molecular mimicry, bystander activation including epitope spreading an d superantigenic activation of T cells. Evidence that either one of these m echanisms actually occurs in MS patients, however, is still weak. Also, non e of the above mechanisms explain why MS is unique to humans. We propose an alternative link between microbial infection and myelin autoimmunity, whic h we refer to as 'mistaken self'. In this mechanism, peripheral microbial i nfections of lymphoid cells prime the human T-cell repertoire not only to m icrobial antigens but also to the stress protein alpha B-crystallin that is expressed de novo in infected lymphoid cells. Subsequently, stress-induced accumulation of this self antigen in oligodendocytes/myelin can provoke pr o-inflammatory responses as the recruited memory T-cell repertoire then mis takes the self protein for a microbial antigen. In this paper we review the currently available evidence that 'mistaken self' centering on alpha B-cry stallin represents a powerful source of anti-myelin autoimmunity in a way t hat is unique to humans. (C) 2000 Elsevier Science B.V. All rights reserved .