Autoimmune T cell recognition of human acetylcholine receptor: the sites of T cell recognition in myasthenia gravis on the extracellular part of the α subunit

Abstract

Autoimmune T cell lines were prepared from peripheral blood lymphocytes of five myasthenia gravis patients by passage in vitro with an equimolar mixture of 18 overlapping synthetic peptides corresponding to the entire extracellular region (residues alpha 1-210) of the alpha subunit of human acetylcholine receptor (AChR). The proliferative responses of the human AChR-specific T cell lines to each of the individual peptides were determined. It was found that the profiles of the peptides recognized by the T cells were different among the five T cell lines, consistent with genetic control operating at the recognition site level. However, other regulatory influences may play important roles in the triggering of the autoimmune responses. These results suggest that the pathogenesis of this autoimmune disease is variable at the cellular-molecular level.

Animal Models of Myasthenia Gravis

“…Lymphocytes derived from human MG patients respond to an array of T-cell epitopes in the AChR molecule (61). In one study, MG patients' T cells responded to the human AChR ␣146 -162 and ␣182-198 sequences (70). Unique autoantigenic determinants might reside within these sequences of Torpedo and human AChR ␣-subunit involved in the development of MG.…”

“…The first direct genetic evidence for the importance of the MHC class II molecule in EAMG came from studies of B6.C-H-2 bml2 (bml2) and B6 mice (26,28). The bml2 is the first and only I-A locus mutant, and it differs from B6 mice by only three amino acids in the ␤ chain of the I-A molecule (Ile 67 3 Phe, Arg 70 3 Gln, Thr 71 3 Lys). The A␤ mutation (gene conversion) in bml2 mice suppressed both the cellular and the humoral immune responses to AChR and led to a decreased incidence of clinical EAMG (26,33).…”

The Intrathymic Pathogenesis of Myasthenia Gravis

“…In the analysis of nAChRs in the thymus, many investigators have focused on the nAChR alpha subunit (nAChRa) since it is the source of the important pathogenic T and B cell epitopes for the pathogenic autoimmune response in MG (Oshima et al, 1990;Zhang et al, 1990;Conti-Fine et al, 1998;Fuji and Lindstrom, 1988). Expression of this subunit was originally reported on a variety of thymic cells including epithelial cells (Engel et al, 1977), thymocytes (Fuchs et al, 1980), and myoid cells (Kao and Drachman, 1977;Schluep et al, 1987).…”

Acetylcholine Receptor Peptide Recognition in HLA DR3-Transgenic Mice: In Vivo Responses Correlate with MHC-Peptide Binding

“…Peptide 141-160 was previously identified by others as a dominant sequence in human MG. T cell lines and clones generated to recombinant AChR ␣ subunit using blood from MG patients were specific to 141-160 (9,(21)(22)(23)(24). These T cells were restricted to DR4, DR3, and DR52a.…”