The T‐cell response to myelin basic protein in familial multiple sclerosis: Diversity of fine specificity, restricting elements, and T‐cell receptor usage

Abstract

Indirect evidence suggests that an autoimmune response to myelin basic protein (MBP) may be involved in the pathogenesis of multiple sclerosis (MS). In MS, several reports have suggested that restricted T-cell populations respond to MPB, as in inbred rodents with the MS disease model experimental allergic encephalomyelitis. In experimental allergic encephalomyelitis, the T-cell repertoire to MBP varies between strains, and in MS it is likely that the response to MBP is also best defined under conditions where genetic differences between subjects are controlled. In this report, the fine specificity of the T-cell response to MBP was assessed in three families, each with multiple individuals affected with MS. We found that (1) comparable frequencies of MBP-reactive T-cell lines were obtained from peripheral blood of MS patients and their healthy siblings. Human leukocyte antigen (HLA) identical sibling pairs discordant for MS had similar frequencies of MBP-reactive T-cell lines. (2) A broad spectrum of MBP epitopes was recognized by T-cell lines from all individuals studied. Within a family, the fine specificity of MBP recognition showed little or no overlap between individuals, even between HLA identical siblings. (3) Recognition of MBP epitopes occurred in the context of different HLA class II alleles. At least four DR alleles each served as restricting elements for recognition of P82-101 or the carboxy terminal region of MBP, two regions thought to be important in the human T-cell response to the molecule. No relationship between the use of a particular DR allele and a response to a particular region of MBP could be established.(ABSTRACT TRUNCATED AT 250 WORDS)

In healthy primates, circulating autoreactive T cells mediate autoimmune disease.

“…The frequency of MBP-reactive T cell clones in circulat- ing PBMC of normal C. jacchus ranged between 3 and 7 per lo-, similar to the frequency estimated to be present in the circulation of healthy humans (8)(9)(10)(11)(12). Mapping of the antigenic peptides recognized by individual clones indicated that multiple regions of the MBP molecule were recognized by naturally occurring T cells (Fig.…”

“…They were similar in several respects to the repertoire of circulating MBP-reactive cells described in human blood (8)(9)(10)(11)(12). First, circulating MBP-reactive T cells occur at similar frequencies in the two species.…”

“…In humans, MBP-reactive T cells are thought to play a role in acute disseminated encephalomyelitis that follows infection or vaccination (5,6) and have long been suspected as effector cells in MS (7). MBP-reactive T cells are present in the circulation of patients with MS but are also present in healthy individuals (8)(9)(10)(11)(12). The role of these circulating T cell populations in the induction of human MS is unknown.…”

The Human T Cell Response to Myelin Oligodendrocyte Glycoprotein: A Multiple Sclerosis Family-Based Study

“…In contrast to MOG, relatively low frequencies of MBP-reactive T cells, generally in the range of 10 Ϫ5 -10 Ϫ6 , have been described by traditional limiting dilution methods in MS patients (31,32,68). A similar low frequency has been reported against another quantitatively major myelin protein, proteolipid protein (32).…”

Treatment of experimental encephalomyelitis with a novel chimeric fusion protein of myelin basic protein and proteolipid protein.

“…Two hydrophilic regions of PLP, residues 30-49 and 180-199, were recently demonstrated to be immunodominant regions recognized by human peripheral T cell populations after primary in vitro stimulation with native PLP (33). However, results from several laboratories have further revealed a marked heterogeneity of human T cell proliferative responses to MBP and PLP with respect to epitope recognition, MHC restriction, and T cell receptor usage (13, 28,30,[34][35][36][37][38][39][40][41][42][43][44][45][46][47]. Furthermore, there is evidence for progressive diversification of the T cell repertoire during the course of autoimmune disease.…”