PATHOGENETIC ROLE FOR THE THYMOMA IN MYASTHENIA-GRAVIS - AUTOSENSITIZATION OF IL-4-PRODUCING T-CELL CLONES RECOGNIZING EXTRACELLULAR ACETYLCHOLINE-RECEPTOR EPITOPES PRESENTED BY MINORITY CLASS-II ISOTYPES

Myasthenia gravis (MG) is caused by helper T cell-dependent autoantibo dies against the muscle acetylcholine receptor (AChR). Thymic epitheli al tumors (thymomas) occur in 10% of MG patients, but their autoimmuni zing potential is unclear. They express mRNAs encoding AChR alpha and epsilon subunits, and might aberrantly select or sensitize developing thymocytes or recirculating peripheral T cells against AChR epitopes, Alternatively, there could be defective self-tolerance induction in th e abundant maturing thymocytes that they usually generate. For the fir st time, we have isolated and characterized AChR-specific T cell clone s from two MG thymomas, They recognize extracellular epitopes (alpha 7 5-90 and alpha 149-158) which are processed very efficiently from musc le AChR. Both clones express CD4 and CD8 alpha, and have a Th-0 cytoki ne profile, producing IL-4 as well as IFN-gamma. They are restricted t o HLA-DP14 and DR52a; expression of these minority isotypes was strong on professional antigen-presenting cells in the donors' tumors, altho ugh it is generally weak in the periphery. The two clones' T cell rece ptor beta chains are different, but their a chain sequences are very s imilar. These resemblances, and the striking contrasts with T cells pr eviously cloned from nonthymoma patients, show that thymomas generate and actively induce specific T cells rather than merely failing to tol erize them against self antigens.