Thymocyte Fas expression is dysregulated in myasthenia gravis patients with anti-acetylcholine receptor antibody

Myasthenia gravis (MG) is a human autoimmune disease mediated by anti-acetylcholine receptor (AChR) antibodies. The thymus is probably the site where the autoimmune response is triggered and maintained. Recent reports have linked various autoimmune disease with defective Fas expression. We thus analyzed Fas expression in thymocytes and peripheral blood lymphocytes (PBL) from MG patients. The proportion of a thymocyte subpopulation with strong Fas expression (Fas(hi)) was markedly enhanced in MG patients with anti-AChR antibodies (P < .0003, compared with controls). In this group of patients, the proportion of CD4+ Fas(hi) and CD4+ CD8+ Fas(hi) thymocytes were significantly increased (P < .002 for both subsets). Fas(hi) thymocytes were enriched in activated cells and showed intermediate CD3 expression. They were preferentially Vbeta5.1-expressing cells, previously shown to be enriched in potentially autoreactive cells. The proliferative response of thymocytes from MG patients to peptides from the AChR was abolished after depletion of Fas(hi) cells. Fas(hi) thymocytes were sensitive to an agonistic anti-Fas antibody. In peripheral blood, Fas(hi) lymphocytes proportion was not significantly modified in MG patients whatever their anti-AChR antibody titer, compared with controls. Altogether, these results indicate that Fas(hi) thymocytes, which accumulate in MG patients with anti-AChR antibodies, could be involved in the autoimmune response that targets the AChR.