Impaired apoptotic deletion of myelin basic protein-reactive T cells in patients with multiple sclerosis

Abstract

T cell responses to myelin basic protein (MBP) may play an important role in the pathogenesis of multiple sclerosis (MS). If MBP-reactive T cells are involved in the disease processes and undergo clonal activation and expansion, their precursor frequency would be increased in patients with MS. The frequency of MBP-reactive T cells is also influenced by regulatory mechanisms in vivo, including apoptotic deletion. In this study, we examined changes in the frequency of MBP-reactive T cells in patients with MS as a function of the apoptotic deletional mechanism in vivo, using a cell culture-based assay. A significantly increased frequency of MBP-reactive T cells was found in patients with MS relative to healthy individuals only when Fas-ligand antibody was used to block apoptosis. This result indicates that a significant proportion of MBP-reactive T cells are sensitive to apoptosis and are not deleted in vivo in patients with MS, as opposed to healthy individuals, thus suggesting a functional deficit in apoptotic deletional mechanism. Surviving Fas-sensitive MBP-reactive T cell lines represent distinct subpopulations preferentially recognizing the 111-139 region of MBP and exhibiting a Th2 cytokine profile. The findings are relevant to our understanding of regulation of MBP-reactive T cells in vivo in MS.

Atorvastatin does not alter serum levels of sCD95 and sCD95L in multiple sclerosis

“…Among several hypotheses on the pathogenesis of MS, defective AICD of myelin-reactive T cells may play a central role. Interference of IFN-b with this hindered CD95L-induced apoptosis is a possible mechanism of action, and the increase of CD95L by IFN-b may support increased apoptosis of autoreactive T cells [20]. Statins would be desirable candidates for a long-term treatment in MS with regard to potentially favourable immunoregulatory effects, oral administration, safety profile and advantageous cost/benefit profile.…”

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

“…It may be relevant that a proportion of MBP-reactive TCL, specific for region 111-139, were susceptible to apoptosis in vitro following stimulation with MBP [15]. Furthermore, these Fas-sensitive MBP-specific T cells were not deleted in vivo in patients with MS as opposed to healthy individuals [15]. This argument clearly does not hold for all epitopes since we have managed to obtain TCC for many different MBP epitopes.…”

“…Interestingly, even though residues 90-114 and, to a lesser extent, 15-39 were recognized frequently by MS patients, TCC specific for these determinants have yet to be developed in vitro. It may be relevant that a proportion of MBP-reactive TCL, specific for region 111-139, were susceptible to apoptosis in vitro following stimulation with MBP [15]. Furthermore, these Fas-sensitive MBP-specific T cells were not deleted in vivo in patients with MS as opposed to healthy individuals [15].…”

“…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.…”

Theiler's Virus Infection: a Model for Multiple Sclerosis

“…Several reports published recently suggested impaired apoptotic deletion of MBP-reactive T cells in the peripheral blood of patients with MS. Zang et al (514) demonstrated that a significant proportion of T cells in the peripheral blood of patients with MS, which are specific for MBP, are sensitive to FasL-mediated apoptosis but are not deleted in vivo. Defective apoptotic deletion of mitogen-stimulated T lymphocytes in the peripheral blood of patients with MS has been reported by several groups of investigators.…”