Myasthenia gravis (MG) is mediated by autoantibodies against the acetylcholine receptor at the muscle endplate. Some MG patients have in addition antibodies (Ab) to the skeletal muscle proteins ryanodine receptor (RyR) and titin. We have examined GM and KM allotypes, RyR and titin Ab in 44 MG patients (37 thymoma patients and 7 non-thymoma, late-onset patients) and 292 non-MG controls to see if GM/KM allotypes associate with differences in autoantibody production. All patients had titin Ab, and 15 thymoma patients had also RyR Ab. The phenotype GM 1, 2, 3 23 5, 21 was significantly increased in the patients with titin Ab compared with the non-MG controls (chi2 = 4.93, p < 0.05). Thymoma patients with RyR Ab had a higher frequency of the GM 3 23 5 phenotype compared with RyR Ab negative patients and controls (chi2 = 7.1, p < 0.05). KM allotypes did not differ between RyR Ab positive or titin Ab positive patients and controls. GM phenotypes may thus be associated with an autoimmune response against the muscle proteins titin and RyR in MG patients.

Titins are a family of gigantic filamentous muscle proteins essential for muscle structure, function and development. Most of their sequence consists of repetitive modules of two superfamily motifs, immunoglobulin and fibronectin, interspersed with unique sequences. A special feature is that many regions are differentially expressed in different muscle types, providing unique characteristics. Titin is evolutionarily old, and many regions are highly conserved. Most mutations that alter titin's characteristics seem to be incompatible with life, since very few associated genetic diseases have been described. The autoimmune response against titin in the paraneoplastic form of myasthenia gravis is discussed.