Unique T-cell receptor junctional sequences found in multiple sclerosis and T-cells mediating experimental allergic encephalomyelitis.
We have used two approaches to isolate TCR sequences that are unique to patients with multiple sclerosis. One strategy was to sequence TCR gene rearrangements directly from MS lesions. The second strategy utilized T-cell clones with a selectable mutation that are found only in MS patients. The selection of T-cell clones with mutations in the hypoxanthine guanine phosphoribosyltransferase (hprt) gene was used to isolate T-cells reactive to myelin basic protein (MBP) in patients with multiple sclerosis (MS). These T-cell clones are activated in vivo, and are not found in healthy individuals. The third complementarity determining regions (CDR3) of the T-cell receptor (TCR) alpha and beta chains are the putative contact sites for peptide fragments of MBP bound in the groove of the HLA molecule. The TCR V gene usage and CDR3s of these MBP-reactive hprt- T-cell clones are homologous to TCRs from other T-cells relevant to MS, including T-cells causing experimental allergic encephalomyelitis (EAE) and T-cells found in brain lesions and in the cerebrospinal fluid (CSF) of MS patients. In vivo activated MBP-reactive T-cells in MS patients may be critical in the pathogenesis of MS.
Allegretta
M
M
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Beckman Center for Molecular and Genetic Medicine (B002), California 94305, USA.
Steinman
L
L
D000595:Amino Acid Sequence; D001483:Base Sequence; D001921:Brain / Q000276:immunology / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015329:Gene Rearrangement, T-Lymphocyte; D006801:Humans; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004676:Myelin Basic Protein / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
D004676:Myelin Basic Protein; D016693:Receptors, Antigen, T-Cell, alpha-beta