Pathogenesis of myositis and myasthenia associated with titin and ryanodine receptor antibodies.
Some myasthenia gravis (MG) patients have antibodies against skeletal muscle antigens in addition to the acetylcholine receptor (AChR). Two major antigens for these antibodies are the Ca(2+) release channel of the sarcoplasmic reticulum, the ryanodine receptor (RyR), and titin, a gigantic filamentous muscle protein essential for muscle structure, function, and development. RyR and titin antibodies are found in MG patients with a thymoma and in a proportion of late-onset MG, and they correlate with severe MG disease. The RyR antibodies recognize a region near the N-terminus important for channel regulation. They inhibit Ca(2+) release from sarcoplasmic reticulum in vitro. There is electrophysiological evidence for a disordered excitation-contraction coupling in MG patients. The presence of titin antibodies, which bind to key regions near the A/I junction and in the central I-band, correlates with myopathy in MG patients. However, so far, there is no direct evidence that antibodies against the intracellular antigens RyR and titin are pathogenic in vivo.
Skeie
Geir Olve
GO
Department of Neurology, University of Bergen, Bergen, Norway. gske@haukeland.no
Romi
Fredrik
F
Aarli
Johan A
JA
Bentsen
Pål Tore
PT
Gilhus
Nils Erik
NE
D000818:Animals; D000906:Antibodies / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000276:immunology; D064211:Connectin; D006801:Humans; D009124:Muscle Proteins / Q000276:immunology*; D009157:Myasthenia Gravis / Q000209:etiology / Q000276:immunology*; D009220:Myositis / Q000209:etiology / Q000276:immunology*; D011494:Protein Kinases / Q000276:immunology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000276:immunology*
D000906:Antibodies; D015220:Calcium Channels; D064211:Connectin; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; C577285:TTN protein, human; D011494:Protein Kinases; D002118:Calcium