T-cell recognition of an immuno-dominant myelin basic protein epitope in multiple sclerosis

Abstract

Multiple sclerosis is thought to be an autoimmune disease of the central nervous system mediated by T cells specific for a myelin antigen. Myelin basic protein has been studied as a potential autoantigen in the disease because of its role as an encephalitogen in experimental autoimmune encephalomyelitis and post-viral encephalomyelitis and because of the presence in the blood of multiple sclerosis patients of in vivo-activated T cells reactive to myelin basic protein. Immune involvement in multiple sclerosis has been further suggested by the association with the major histocompatibility complex class II phenotype DR2, DQw1. To define the T-cell specificity toward myelin basic protein, 15,824 short-term T-cell lines were established from multiple sclerosis subjects, subjects with other neurological diseases, and normal controls. Here we report a higher frequency of T-cell lines reactive with a DR2-associated region of myelin basic protein between residues 84-102 in patients with multiple sclerosis compared with controls. A second region, identified between residues 143-168, was recognized equally in multiple sclerosis patients and controls and was associated with the DRw11 phenotype. These DR2 and DRw11 associations were also observed among T-cell lines generated from family members of a multiple sclerosis patient. The immunodominant 84-102 peptide from myelin basic protein was both DR2- and DQw1-restricted among different T-cell lines. These results raise the possibility that this immunodominant region may be encephalitogenic in some DR2+ individuals.

Oligodendrocyte‐specific protein is encephalitogenic in rhesus macaques and induces specific demyelination of the optic nerve

“…The autoantigen(s) probably reside in CNS myelin, the target of the immune response. In addition to the wellcharacterized autoreactivity to the quantitatively major proteins of CNS myelin, myelin basic protein and proteolipid protein [3][4][5][6], autoreactivity to other myelin proteins such as myelin oligodendrocyte glycoprotein (MOG) [7,8], myelin-associated glycoprotein (MAG) [9,10] and oligodendrocyte-specific protein (OSP) [11,12], as well as myelin-associated proteins like aB-crystallin [13,14] have more recently been detected in MS patients.…”

Cell-based gene therapy experiments in murine experimental autoimmune encephalomyelitis

“…33,35,[62][63][64] The fact that we can treat EAE successfully, without the requirement that all epitopes recognized by pathogenic T cells be secreted, suggests that treatment of MS patients need not be individualized despite extensive MHC polymorphism and epitope diversity. In the clinic, initial screening of the myelin-specific T-cell reactivities of the patient may indicate that expressing epitopes other than MBP 84-101 and PLP 139-151 may be more efficacious, and our mini-gene construct has, in fact, been designed as a cassette to facilitate exchange of epitope sequences.…”

“…31 This is of critical importance, since T cells responding to this epitope have been detected in many MS patients. 21,[32][33][34][35] To address clinical practicality and safety concerns, we have sequestered the transduced cells within a chamber that is implanted subcutaneously (s.c.). Use of the chamber not only enables us to use allogeneic cells for treatment, thus allowing for development of a 'universal' treatment cell line, but also permits us to terminate the treatment should any exacerbation occur.…”

A new approach for evaluating antigen-specific T cell responses to myelin antigens during the course of multiple sclerosis

“…However, auto-reactive T cells are also frequently part of the mature immune repertoire of healthy non-MS humans (Burns et al, 1983(Burns et al, , 1986Jingwu et al, 1992;Kerlero de Rosbo et al, 1993;Lindert et al, 1999;Markovic-Plese et al, 1995;Ota et al, 1990) as well as of nonimmunized animals (Schluesener and Wekerle, 1985). Thus, humans often show comparable frequencies of myelin [myelin basic protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG)]-reactive T cells in their blood, whether they are MS patients or healthy controls (Burns et al, 1983(Burns et al, , 1986Jingwu et al, 1992;Kerlero de Rosbo et al, 1993;Lindert et al, 1999;Markovic-Plese et al, 1995;Ota et al, 1990). These findings suggest that the more important factor in disease development may be activation; that is a greater frequency of activated myelin-reactive cells in MS patients as compared to healthy individuals (Zhang et al, 1994).…”