Thymoma-Associated Paraneoplastic Myasthenia Gravis

Abstract

Since publication of the first edition of this book in 2003, two major new insights into the pathogenesis of thymoma-associated (paraneoplastic) autoimmunities, including myasthenia gravis (MG), have been achieved. First, it has become clear by the analysis of functional single nucleotide polymorphisms that tumor-independent, non-MHC genetic factors contribute to the pathogenesis of paraneoplastic MG at least in a subgroup of patients. Second, thymoma has been identified as a human model of ‘‘localized’’, i.e., tumor-restricted loss of AIRE (‘‘autoimmune regulator’’) expression. AIRE is a transcriptional regulator that controls immunologic tolerance by the pivotal regulation of ‘‘promiscuous’’ expression of tissue-specific self-antigens in the thymic medulla. The finding of AIRE deficiency in thymoma relates to earlier observations (1) that autoantibodies against type I interferons are a conceptionally and diagnostically important hallmark of both thymoma and a germ line-encoded AIRE deficiency syndrome termed autoimmune polyendocrinopathy syndrome type I (APS I). Of note, anti-IFN autoantibodies and APS I symptoms do not occur in AIRE knockout animals. Therefore, the new findings in thymoma patients have implications beyond paraneoplastic MG and underline the importance ofMG(+) compared toMG( ) thymomas as amodel system allowing for the analysis of humanspecific mechanisms leading to autoimmunity. MG is a heterogeneous autoimmune disease mediated by autoantibodies that interfere with the function of the neuromuscular junction. Taking the presence or absence of antibodies against the acetylcholine receptor (AChR) as a criterion, MG has been subdivided into seropositive and seronegative types. In seropositive MG, the pathogenic, high-affinity autoantibodies are directed against the nicotinic acetylcholine receptor (AChR) (2, 3), while so-called seronegative MG (SNMG) is now known to be heterogeneous with respect to autoantibody features: depending on ethnic and geographic backgrounds (4, 5, 6, 7), a quite variable percentage of SNMG cases result from autoantibodies (commonly IgG4) to muscle-specific tyrosine kinases (MuSK) at the neuromuscular endplate (8). Furthermore, a third ‘‘doublenegative’’ subgroup showing neither anti-AChR nor anti-MuSK autoantibodies exists (9). Whether these patients have autoantibodies against other autoantigen targets or whether their anti-AChR or anti-MuSK autoantibodies cannot be detected by current laboratory tests is the subject of ongoing research. In 80 90% of cases, MG is associated with pathologic changes of the thymus. In about 10% of anti-AChR-seropositive cases, MG is a paraneoplastic phenomenon caused by a subgroup of epithelial neoplasms of the thymus called thymomas. There are significant associations between