Early-onset myasthenia gravis: A recurring T-cell epitope in the adult-specific acetylcholine receptor epsilon subunit presented by the susceptibility allele HLA-DR52a

No immunodominant T-cell epitopes have yet been reported in the human acety lcholine receptor (AChR), the target of the pathogenic autoantibodies in tn yasthenia gravis (MG). We have selected and characterized T cells from MG p atients by restimulation in culture with recombinant human AChR alpha, gamm a, and epsilon subunits; the gamma and epsilon distinguish the fetal and ad ult AChR isoforms, respectively. We obtained clones specific for the epsilo n, rather than the alpha or gamma, subunit in 3 of the first 4 early-onset MG cares tested They all responded to peptide epsilon 201-219 and to low co ncentrations of adult but not fetal AChR. Moreover, although using differen t T-cell receptor genes, they were all restricted to HKA-DR52a (DRB3*0101), a member of the strongly predisposing HLA-A1-B8-DR3 haplotype. This appare ntly immunodominant epsilon 201-219 epitope (plus DR52a) was also recognize d 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 rea cted better with fetal than adult AChR and map thus be end products of dete rminant spreading initiated by adult AChR-specific T cell responses. Furthe rmore, as these T cells had a pathogenic Th1 phenotype, with the potential to induce complement-activating antibodies, they should be important target s for selective immunotherapy.