Peter Špalek1, Milan Schnorrer2, Tibor Krajč3
Myasthenia gravis (MG) is a heterogeneous autoimmune disease mediated by autoantibodies that interfere with the function of the neuromuscular junction. In seropositive MG, the pathogenic, high-affinity autoantibodies are directed against nicotinic acetylcholine receptor (AChR). In seropositive early-onset MG with thymic lympho-follicular hyperplasia (LFH) all patients have AChR-expressing myoid cells and the autoimmune regulator (AIRE) in the thymus. It is generally accepted that LFH-associated seropositive MG results from an intrathymic pathogenesis with AChR on myoid cells being primarily involved as triggering autoantigens. In about 10 % of anti-AChR-seropositive cases, MG is a paraneoplastic phenomenon caused by epithelial neoplasms of the thymus called thymomas. AChR-expressing myoid cells and AIRE are absent in thymomas. The most important thymus-like organoid feature of thymomas is the capacity to promote intratumorous T-cell development. The paraneoplastic MG starts with abnormal, non-tolerogenic T-cells selection inside thymomas with specifity for AChR. Next step is the export of intolerant T-cells to the „peripheral“ extratymomatous immmune system, i.e., to lymph nodes, normal thymus, spleen and bone marrow. At these sites, T-cells activation, interactions of T-cells and B-cells, and, finally, the production of AChR autoantibodies occur. The immunopathogenic significance of peripheral immune system in thymomaassociated paraneoplastic MG is also underlined by the fact that even complete surgical removal of thymoma (plus residual thymus) is often not followed by a clinical improvement and by a decline of autoantibody titers. Concurrent autoimmunity against four apparently unrelated types of autoantigens is highly characteristic for thymoma-associated paraneoplastic MG. These autoantigens are AChR, striational muscle antigens (titin, ryanodine receptor), neuronal antigens and cytokines.