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 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 to alpha, gamma and epsilon subunits; the gamma and epsilon distinguish the fetal and adult AChR isoforms, respectively. We obtained clones specific for the epsilon, rather than the alpha or gamma, subunit in 3 of the first 4 early-onset MG cases tested. They all responded to peptide epsilon201-219 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 epsilon201-219 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.
Hill
M
M
Neurosciences Group, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, England, UK.
Beeson
D
D
Moss
P
P
Jacobson
L
L
Bond
A
A
Corlett
L
L
Newsom-Davis
J
J
Vincent
A
A
Willcox
N
N
D000595:Amino Acid Sequence; D001483:Base Sequence; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D009157:Myasthenia Gravis / Q000235:genetics* / Q000276:immunology*; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011950:Receptors, Cholinergic / Q000276:immunology*; D013997:Time Factors