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Myelin basic protein-specific T lymphocyte repertoire in multiple sclerosis. Complexity of the response and dominance of nested epitopes due to recruitment of multiple T cell clones

Item Type:Article
Title:Myelin basic protein-specific T lymphocyte repertoire in multiple sclerosis. Complexity of the response and dominance of nested epitopes due to recruitment of multiple T cell clones
Creators Name:Meinl, E. and Weber, F. and Drexler, K. and Morelle, C. and Ott, M. and Saruhan-Direskeneli, G. and Goebels, N. and Ertl, B. and Jechart, G. and Giegerich, G. and Schoenbeck, S. and Bannwarth, W. and Wekerle, H. and Hohlfeld, R.
Abstract:The human T cell response to the myelin basic protein (MBP) has been studied with respect to T cell receptor (TCR) usage, HLA class II restriction elements, and epitope specificity using a total of 215 long-term MBP-specific T cell lines (TCL) isolated from the peripheral blood of 13 patients with multiple sclerosis (MS) and 10 healthy donors. In most donors, the anti-MBP response was exceedingly heterogeneous. Using a panel of overlapping synthetic peptides spanning the entire length of human MBP, at least 26 epitopes recognized by human TCL could be distinguished. The MBP domain most commonly recognized was sequence 80-105 (31% of MS TCL, and 24% of control TCL). Sequence 29-48 was recognized more frequently by control-derived TCL (24%) than by TCL from MS patients (5%). The MBP epitopes were recognized in the context of DRB1 *0101, DRB5*0101, DRB1*1501, DRB1*0301, DRB1*0401, DRB1*1402, and DRB3*0102, as demonstrated using a panel of DR gene-transfected L cells. The TCR gene usage was also heterogeneous. V beta 5.2, a peptide of which is currently being used in a clinical trial for treatment of MS patients, was expressed by only one of our TCL. However, within this complex pattern of MBP-specific T cell responses, a minority of MS patients were found to exhibit a more restricted response with respect to their TCL epitope specificity. In these patients 75-87% of the TCL responded to a single, patient-specific cluster of immunodominant T cell epitopes located within a small (20-amino acid) domain of MBP. These nested clusters of immunodominant epitopes were noted within the amino acids 80-105, 108-131, and 131-153. The T cell response to the immunodominant epitopes was not monoclonal, but heterogeneous, with respect to fine specificity, TCR usage, and even HLA restriction. In one patient (H.K.), this restricted epitope profile remained stable for > 2 yr. The TCR beta chain sequences of TCL specific for the immunodominant region of HK are consistent with an oligoclonal response against the epitopes of this region (80-105). Further, two pairs of identical sequences were established from TCL generated from this patient at different times (June 1990 and June 1991), suggesting that some TCL specific for the immunodominant region persisted in the peripheral repertoire. The possible role of persistent immunodominant epitope clusters in the pathogenesis of MS remains to be established.
Keywords:Amino Acid Sequence, Base Sequence, Brain Chemistry, DNA, DNA Primers, Epitopes, HLA Antigens, HLA-D Antigens, Lymphocyte Activation, Molecular Sequence Data, Multiple Sclerosis, Myelin Basic Proteins, Polymerase Chain Reaction, T-Cell Antigen Receptors , Alpha-Beta T-Cell Antigen Receptors, Reference Values, T-Lymphocytes, Thymidine
Source:Journal of Clinical Investigation
ISSN:0021-9738
Publisher:American Society for Clinical Investigation (U.S.A.)
Volume:92
Number:6
Page Range:2633-2643
Date:December 1993
Official Publication:https://doi.org/10.1172/JCI116879
PubMed:View item in PubMed

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