title: Selection for T-cell receptor V beta-D beta-J beta gene rearrangements with specificity for a myelin basic protein peptide in brain lesions of multiple sclerosis.
abstract: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system in which a restricted cellular immune response has been observed. In order to establish whether such T cell responses are likely to be antigen-specific particularly with regard to myelin basic protein (MBP), we analysed T-cell receptor (TCR) gene rearrangements directly from MS brain plaques, using the polymerase chain reaction on reverse transcribed messenger RNA, and compared these with TCR of previously described MBP-specific T cell clones from MS and the rat model experimental allergic encephalomyelitis. Rearranged V beta 5.2 genes were detected in the brains of all patients who were HLA DRB1*1501, DQA1*0102, DQB1*0602, DPB1*0401. The V beta 5.2-D beta-J beta sequences in these MS brain plaques revealed five motifs. One of the common motifs was identical to that described for the VDJ region of a V beta 5.2 T-cell clone. This clone was from an MS patient who was HLA DRB1*1501, DQB1*0602, DPB1*0401, and it was cytotoxic towards targets containing the MBP peptide 89-106 (ref. 1). The deduced amino-acid sequence of this VDJ rearrangement, Leu-Arg-Gly, has also been described in rat T cells cloned from experimental allergic encephalomyelitis lesions, which are specific for MBP peptide 87-99 (ref. 2). VDJ sequences with specificity for this MBP epitope constitute a large fraction (40%) of the TCR V beta 5.2 N(D)N rearrangements in MS lesions. The capacity of rat T cells with these VDJ sequences to cause experimental allergic encephalomyelitis and the prevalence of such sequences in demyelinated human lesions indicate that T cells with this rearranged TCR may be critical in MS.
authors.affiliation: Department of Neurology and Neurological Science, Stanford University School of Medicine, California 94305-5235.
authors.forename: J R
authors.initials: JR
authors.lastname: Oksenberg
authors.forename: M A
authors.initials: MA
authors.lastname: Panzara
authors.forename: A B
authors.initials: AB
authors.lastname: Begovich
authors.forename: D
authors.initials: D
authors.lastname: Mitchell
authors.forename: H A
authors.initials: HA
authors.lastname: Erlich
authors.forename: R S
authors.initials: RS
authors.lastname: Murray
authors.forename: R
authors.initials: R
authors.lastname: Shimonkevitz
authors.forename: M
authors.initials: M
authors.lastname: Sherritt
authors.forename: J
authors.initials: J
authors.lastname: Rothbard
authors.forename: C C
authors.initials: CC
authors.lastname: Bernard
authors.forename: L
authors.initials: L
authors.lastname: Steinman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000276:immunology* / Q000473:pathology; D017252:CD3 Complex / Q000235:genetics*; D003001:Cloning, Molecular; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D006681:HLA-D Antigens / Q000032:analysis / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D004676:Myelin Basic Protein / Q000276:immunology*; D009838:Oligodeoxyribonucleotides; D010641:Phenotype; D016133:Polymerase Chain Reaction / Q000379:methods; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D013116:Spinal Cord / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D017252:CD3 Complex; D006681:HLA-D Antigens; D004676:Myelin Basic Protein; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger