581P Toxic autophagic vacuolar myopathies and the role of human leukocyte antigen class I molecules and membrane attack complex in its pathogenesis

Colchicine and hydroxycloroquine are supposed to drive their toxic effect according to different pathogenic mechanisms that lead to autophagy impairment. The aim of this study is to investigate the role of human leukocyte antigen (HLA) class I molecules and membrane attack complex (MAC) in toxic autophagic vacuolar myopathies. Three patients presenting with neuromuscular symptoms were referred to the Neuromuscular Morphology Unit of the Myology Institute in Paris for open muscle biopsy. Muscle biopsy specimens obtained from each patient were studied using standard histoenzymatic techniques. Immunolabeling was performed to evaluate the expression of major histocompatibility complex class I and II (MHC-I, MCH-II), P62, LC3 and the complement component C5b9. Patients 1 and 2 were treated for 10 and 3 years with HCQ for Sjogren's disease and Lupus respectively. Patient 3 received colchicine for 7 days for suspected perycarditis. The main histological finding was the presence of a vacuolar autophagic myopathy without inflammation or necrosis. In all patients, immunolabeling with antibodies against MHC-I demonstrated generalised sarcolemmal and sarcoplasmic positivity. C5b9 showed either a punctate or a diffuse sarcolemmal positivity. Punctate cytoplasmic p62 and LC3 positivity was identified. Colchicine and HCG usually have immunomodulatory effects, so overexpression of the MCH-I remains incompletely understood but probably reflects the increased autophagic activity. The accumulation of autophagic substrates, including p62 and LC3, may be the consequence not only of an impairment of the degradation process but also of an enhanced transcription of the corresponding genes. Immunohistochemistry for MCH-I, C5b9, LC3 and p62 are useful markers for toxic autophagic vacuolar myopathies, yet further studies are needed to explore the molecular pathways involved.