T cell responses to D-penicillamine in drug-induced myasthenia gravis: recognition of modified DR1:peptide complexes.
The anti-rheumatoid drug D-penicillamine (D-pen) has a reactive sulfhydryl group capable of modifying self antigens, and can provoke typical autoantibody-mediated myasthenia gravis (MG), especially in DR1+ individuals. We have selected T cell clones from one such patient that were highly specific for D-pen but not its L-isomer or D-cysteine. Moreover, they were restricted to HLA-DR1, had a Th1 phenotype and used TCR V alpha4.1, V beta6.1. They responded well to blood mononuclear cells prepulsed with D-pen either in the absence of serum or after chloroquine treatment, but not to autologous D-pen-pulsed B cell lines. Thus, D-pen may directly couple to distinctive peptides resident in surface DR1 molecules on circulating macrophages or dendritic cells.
Hill
M
M
Neurosciences Group, Institute of Molecular Medicine, The John Radcliffe Hospital, Headington, Oxford, UK.
Moss
P
P
Wordsworth
P
P
Newsom-Davis
J
J
Willcox
N
N
D000368:Aged; D000595:Amino Acid Sequence; D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000276:immunology / Q000378:metabolism; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000276:immunology; D001483:Base Sequence; D001798:Blood Proteins / Q000378:metabolism / Q000494:pharmacology; D017252:CD3 Complex / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology; D004342:Drug Hypersensitivity / Q000276:immunology; D000939:Epitopes; D005260:Female; D015798:HLA-DR1 Antigen / Q000032:analysis / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D006801:Humans; D008969:Molecular Sequence Data; D009157:Myasthenia Gravis / Q000139:chemically induced / Q000276:immunology*; D010396:Penicillamine / Q000009:adverse effects* / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology; D013936:Thymidine / Q000494:pharmacology; D014316:Tritium
D018501:Antirheumatic Agents; D001798:Blood Proteins; D017252:CD3 Complex; D000939:Epitopes; D015798:HLA-DR1 Antigen; D000949:Histocompatibility Antigens Class II; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014316:Tritium; D002738:Chloroquine; D010396:Penicillamine; D013936:Thymidine