Selection for T-cell receptor Vβ–Dβ–Jβ 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.

Increased proinflammatory cytokine gene expression in the colonic mucosa of coeliac disease patients in the early period after gluten challenge

“…Although skewing of the TCRBV repertoire and sharing of common amino acid motifs in the CDR3 region have been reported in other HLA class II D region-associated diseases (e.g. rheumatoid arthritis, multiple sclerosis) [39,40], our analysis revealed no skewing of the TCRBV repertoire in coeliac disease patients in the early period after gluten challenge. Our analysis would not, however, detect minor changes that might occur in the representation of antigenspecific clones within V families.…”

Skewed T-cell receptor BV14 and BV16 expression and shared CDR3 sequence and common sequence motifs in synovial T cells of rheumatoid arthritis

“…Immunoscope analysis was performed with a modified protocol. 27,35 A measure of 2 ml of BV14-BC or BV16-BC PCR products were used as templates and run-off reactions were performed with a single internal fluorescent label for each of the 6FAM (expand)-labeled BC or BJ primers ( Table 5). The reaction profile consisted of 30 s at 941C denaturation temperature and 15 cycles at 941C for 45 s; at 551C for 45 s, at 721C for 1 min, followed by 721C for 5 min as an extension step.…”

A Journey in Science: The Privilege of Exploring the Brain and the Immune System

“…With an outstanding postdoc Jorge Oksenberg, now a professor at UCSF, and with a renowned collaborator Claude Bernard from Australia, we also showed that, even in lesions in MS brain, there was evidence of restricted T-cell receptor expression (54,55). Tomas Olsson and colleagues took these results forward into the clinic, targeting T cells with VB5.2 T-cell receptors.…”