Impaired apoptotic deletion of myelin basic protein-reactive T cells in patients with multiple sclerosis.
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.
Zang
Y C
YC
Department of Neurology, Baylor College of Medicine, and Baylor-Methodist Multiple Sclerosis Center, Houston 77030, USA. jzang@bcm.tmc.edu
Kozovska
M M
MM
Hong
J
J
Li
S
S
Mann
S
S
Killian
J M
JM
Rivera
V M
VM
Zhang
J Z
JZ
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis; D002460:Cell Line; D016207:Cytokines / Q000276:immunology; D053222:Fas Ligand Protein; D006801:Humans; D008562:Membrane Glycoproteins / Q000276:immunology; D009103:Multiple Sclerosis / Q000276:immunology*; D004676:Myelin Basic Protein / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology
D000911:Antibodies, Monoclonal; D016207:Cytokines; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D004676:Myelin Basic Protein; D019014:fas Receptor