Abstract

Necrotizing autoimmune myopathy (NAM) is a newly recognized group of idiopathic inflammatory myopathies, characterized by pathological features of prominent myofiber necrosis without significant inflammation nor HLA re-expression. Although their precise pathogenesis remains unknown, different forms of NAM may be associated to anti-signal recognition particle (SRP) auto- antibodies (Abs), statin therapy with auto-Abs against 3-hydroxy-3-methylglutaryl-coenzyme A reductase, or cancer. Patients with NAM generally present with severe symmetrical proximal deficiency, associated with high blood creatine kinase (CK) levels. Alternatively, NAM with anti-SRP auto-Abs can be very slowly progressive, with clinical and pathological features masquerading limb-girdle muscular dystrophies. NAM generally responds to immunosuppressive therapy but may require more intense treatment than polymyositis or dermatomyositis.

SRP is a ubiquitous protein complex which mediates the transport of newly synthesized proteins to the endoplasmic reticulum (ER). We previously showed that serum titres of anti-SRP Abs closely correlate with CK level and muscle weakness in patients. We are currently investigating a possible direct pathogenic role of anti-SRP Abs. Incubation of muscle sections with different sources of anti-SRP Abs revealed a punctuated intracellular staining within the endomysium with reinforcement at myocyte membranes which disappeared upon preincubation with excess recombinant SRP54. Immunogold staining followed by electron-microscopy revealed immunoreactivity located in the ER. When cultured with purified anti-SRP Abs, myotubes showed a dramatic decrease of their diameter as compared to those cultured with control polyclonal IgG. In vivo injection of anti-SRP positive serum (as compared to normal serum) to mice resulted in weight loss and significant decrease in muscle strength as attested by rotarod and grip tests. Hence, while the mechanisms of how anti-SRP Abs may penetrate into and destroy myofibers remains elusive, these results provide the first experimental evidence that anti-SRP Abs might play a direct role in NAM pathogenesis.