Myelin basic protein–specific T lymphocytes in multiple sclerosis and controls: Precursor frequency, fine specificity, and cytotoxicity

Abstract

A panel of 90 myelin basic protein (MBP)-specific T-cell lines were derived from peripheral blood of eight patients with multiple sclerosis and four normal subjects. The precursor frequency of MBP-reactive T cells in peripheral blood mononuclear cells ranged from 10(-7) to 9 x 10(-7) (mean, 6.7 x 10(-7)) in the group of patients with multiple sclerosis and from 0.5 x 10(-7) to 9.8 x 10(-7) (mean, 5.6 x 10(-7)) in the control subjects. This difference between the two groups was not statistically significant (p greater than 0.1). These T-cell lines expressed exclusively CD3+CD4+CD8- phenotypes and were restricted predominantly by HLA-DR molecules. When tested with fragments and synthetic peptides of human MBP, these MBP-specific T-cell lines (45 lines for each group) displayed a limited heterogeneous pattern with a biased recognition to peptide 84-102 and the C-terminal peptide 149-171. The reactivity to the 84-102 region of MBP was associated with the HLA-DR2, DRw15 (DRw15,2) haplotype, whereas the recognition to peptide 149-171 did not correlate with a particular HLA-DR allele(s). Furthermore, the majority of T-cell lines (greater than 75%) were found to exhibit substantial cytotoxic activity against MBP-coated target cells, but showing no significant difference between these two groups. This MBP-dependent cytotoxicity was not associated with epitope specificities of the T-cell lines tested.

Thymic Export Function and T Cell Homeostasis in Patients with Relapsing Remitting Multiple Sclerosis

“…We cannot exclude that ongoing autoantigen-driven T cell proliferation associated with acute MS relapses primarily impairs the TREC content of peripheral lymphocytes. However, autoreactive T cells represent a minor portion within the peripheral T cell repertoire (26,27), and it is unlikely that an increased turnover of autoaggressive T cell clones alone mediates such a pronounced reduction of circulating TRECexpressing T cells in patients with early stage MS. In our study population, the TREC content was not influenced by the frequency or severity of prior relapses, and even patients with extremely low TREC numbers in PBLs (Ͻ1 ϫ 10 3 /10 6 cells) did not differ from the remaining study population with respect to disease duration, relapse rate, and disability, as determined by the expanded disability status scale (28).…”

Activation of APCs Through CD40 or Toll-Like Receptor 9 Overcomes Tolerance and Precipitates Autoimmune Disease

“…Autoreactive T cells regularly escape into the periphery. This includes CD4 ϩ T cells specific for myelin Ags, the mediators of experimental autoimmune encephalomyelitis (EAE) 3 and presumably of multiple sclerosis (MS) (1)(2)(3)(4)(5)(6). Furthermore, candidate autoantigens, including isoforms of myelin basic protein and proteolipid protein (PLP), have been detected in secondary lymphoid tissues, where they might be accessible for processing and presentation by professional APCs (7)(8)(9)(10)(11)(12).…”

Ex vivo detection of myelin basic protein‐reactive T cells in multiple sclerosis and controls using specific TCR oligonucleotide probes

“…In that study, the authors demonstrated that MBP-reactive T cells occurred at a range of 1/300-1/1,000 total T cells in MS patients using oligonucleotide probes and cDNA cloning [24]. The precursor frequency of MBP-reactive T cells as reported by Bieganowska and colleagues [24] is higher than that measured by cell culture-based assay or ELISPOT assay by two to three logs [4,5,10,11,[21][22][23]. The study has raised the important issue that the precursor frequency of MBPreactive T cells is significantly underestimated in MS patients, as well as some confusion as to whether these clonal populations of MBP-reactive T cells truly occur at such high precursor frequency (1/300 total T cells) in MS patients.…”

“…Although the etiology and pathogenesis of the disease remain elusive, there is evidence suggesting that the T cell responses to certain myelin autoantigens may play an important role in the disease processes [1]. Among the candidate myelin proteins identified so far that are capable of inducing EAE, myelin basic protein (MBP) has been studied most extensively with respect to the complete profile of the T cell reactivity to various epitopes of the protein in both EAE models and humans [2][3][4][5][6][7]. In humans, there is evidence indicating that MBP-reactive T cells undergo in vivo activation and clonal expansion in MS patients as opposed to control subjects [8][9][10][11] and occur at an increased frequency during clinical exacerbation [12].…”