| Abstract: | No immunodominant T-cell epitopes have yet been reported in the human acetylcholine receptor (AChR), the target of the pathogenic autoantibodies in myasthenia gravis (MG). We have selected and characterized T cells from MG patients by restimulation in culture with recombinant human AChR α, γ, and ε subunits; the γ and ε distinguish the fetal and adult AChR isoforms, respectively. We obtained clones specific for the ε, rather than the α or γ, subunit in 3 of the first 4 early-onset MG cases tested. They all responded to peptide ε201–219 and to low concentrations of adult but not fetal AChR. Moreover, although using different T-cell receptor genes, they were all restricted to HLA-DR52a (DRB3*0101), a member of the strongly predisposing HLA-A1-B8-DR3 haplotype. This apparently immunodominant ε201–219 epitope (plus DR52a) was also recognized by clones from an elderly patient whose MG had recently been provoked by the drug D -penicillamine. In all 4 cases, however, the serum antibodies reacted better with fetal than adult AChR and may thus be end products of determinant spreading initiated by adult AChR-specific T cell responses. Furthermore, as these T cells had a pathogenic Th1 phenotype, with the potential to induce complement-activating antibodies, they should be important targets for selective immunotherapy. Ann Neurol 1999;45:224–231 |
