Diversity and dynamics of the T-cell response to MBP in DR2+ve individuals

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease characterized by multiple demyelinating lesions disseminated throughout the CNS white matter, occurring at various sites and times [1,2]. MS is thought to be mediated by autoreactive T cells and, amongst the myelin components that represent the putative autoantigens, myelin basic protein (MBP) has been the most extensively studied. This is partly due to the finding that MBP is immunogenic and that MBP-specific T lymphocytes have encephalitogenic activity in experimental animals [3][4][5]. Furthermore, recent evidence arising from a clinical trial using an MBP-TCR antagonist has shown a clear correlation between exacerbation of disease and an increased precursor frequency of MBP-specific T cells [6]. This clearly demonstrates that MBPspecific T lymphocytes can contribute to MS in humans.It is well established that MBP-specific T cells are present in the peripheral blood of MS patients as well as in healthy individuals. Therefore, the mere presence of autoreactive cells in the periphery is not sufficient for the development of MS. We and others [7][8][9] have shown that one of the differences between healthy individuals and MS patients lies in the activation state of the autoreactive T cells. That is, MBP-specific T cells in MS patients are more likely to have been activated in vivo and to have differentiated into memory cells compared with control subjects.Early studies using T-cell lines (TCL) and T-cell clones (TCC) revealed that MS patients recognize three immunodominant regions within human MBP (amino acid (aa) 13-32, aa 84-103 and aa 144-163) [10][11][12][13][14]. This restricted epitope recognition was thought to persist for several months irrespective of clinical disease activity [13]. To date, the profile of MBP reactivity in MS patients and healthy individuals has been defined largely through the use of TCL and TCC. However, recent work showing that some TCC are susceptible to apoptosis in cell culture conditions suggests that surviving MBP-reactive TCL and TCC may represent a skewed repertoire with respect to the pattern of peptide reactivity [15]. Few studies have carried out direct ex vivo analyses involving peripheral blood mononuclear cell (PBMC) cultures to examine (a) whether MS patients respond to a broad spectrum of MBP peptides and (b) how anti-MBP T-cell responses evolve and whether such responses are stable over time. SUMMARYIt is generally accepted that multiple sclerosis (MS) is mediated by autoreactive T cells and that myelin basic protein (MBP) is one of the target autoantigens. The T-cell response to MBP has been analysed extensively, largely through the use of T-cell lines (TCL) and T-cell clones (TCC), and to date, three immunodominant regions (13-32, 84-103 and 144-163) have been described. However, given that TCL may represent a skewed pattern of peptide reactivity, we have developed a kinetic response assay in which the proliferation of peripheral blood mononuclear cells (PBMC) from MS patients and healthy individuals was me...

Mapping helper T-cell epitopes on platelet membrane glycoprotein IIIa in chronic autoimmune thrombocytopenic purpura

“…Such gain or loss of stimulation by peptides can reflect changes in the frequency of the corresponding Th cells in the circulation, attributable to the respective effects of epitope spreading and clonal exhaustion. 28,40,41,51 Similar diversity, plasticity, evolution and cyclical changes in self-recognition have been reported for Th cells reactive with autoantigen in other diseases, including AIHA 28 and multiple sclerosis, 40,41 and, as here, do not necessarily correlate with the severity or clinical course of disease.…”

“…First, multiple peptides from GPIIIa stimulated proliferation by Th cells from most patients with AITP, a diversity of fine specificity that mirrors the results of epitope mapping studies in human type 1 diabetes, 49 rheumatoid arthritis, 50 autoimmune glomerulonephritis, 30 multiple sclerosis, 40,41 and autoimmune hemolytic anemia (AIHA). 28 Animal models of these diseases, including AIHA in the NZB mouse, reveal that such diversity may follow the phenomenon of epitope spreading.…”

“…12,51 This occurs when the autoimmune helper response initially targets very few, or only one, self-determinant(s), but further Th clones with new specificities for the same, or associated, autoantigens are recruited over time as pathology develops. 44 The second, related feature of GPIIIa recognition that resembles other autoaggressive responses 28,40,41 is the variation, seen in individual patients with AITP over time, in the peptides that induce proliferation by peripheral blood Th cells in vitro. Such gain or loss of stimulation by peptides can reflect changes in the frequency of the corresponding Th cells in the circulation, attributable to the respective effects of epitope spreading and clonal exhaustion.…”

High Incidence of Spontaneous Disease in an HLA-DR15 and TCR Transgenic Multiple Sclerosis Model

“…The response is hierarchical and progressive: as mice age and become sicker, responses to more epitopes are found. The MOG 82-96 and MBP 38 -59 spread responses echo the finding that these are key HLA-DR15-restricted epitopes in MS (14,15,24,27). However, from the studies with human PBL, it is uncertain how and whether the responses are associated with pathogenesis.…”

Peptide immunotherapy in experimental autoimmune encephalomyelitis

“…Bystander suppression is particularly appealing given that, although several autoantigenic epitopes are characterized in MS, [46][47][48][49][50] we do not know which (if any) of these are the key targets recognized by T cells driving disease. Therefore, a suppressive T-cell population recognizing a defined myelin epitope could suppress a proinflammatory population recognizing other (perhaps unknown) myelin epitopes, if their localization was sufficiently close.…”