P.14.7 Anti-SRP antibody induces muscle cell lysis through complement mediated pathway

The signal recognition particle (SRP), an intracytoplasmic complex of ribonucleoprotein, binds to the endoplasmic reticulum (ER) localising signal sequences of elongating polypeptide chains during their synthesis and translocates nascent peptides to the ER membrane. Anti-SRP antibodies to one or more of the components have been associated with a necrotising autoimmune myopathy (NAM) characterised by severe subacute progressive proximal muscle weakness with very high serum CK levels. The muscle biopsies from such patients show abundant necrotic and regenerating fibres but only a sparse inflammatory infiltrate. These findings suggest that cytotoxic T cells and cell-mediated muscle fibre destruction are not involved. The possibility of a humoral mechanism has been proposed but this has not been investigated. In the present study, we utilised an in vitro human myoblast culture system to investigate a possible antibody-mediated cytotoxic mechanism of cell death. Anti-SRP positive sera from NAM patients or anti-SRP negative sera from healthy controls were incubated with myoblasts in the presence or absence of fresh complement. In the absence of complement, there was no difference in cell viability between two groups. In contrast, when complement was added, the survival of myoblasts incubated with anti-SRP positive serum was significantly reduced compared to cultures incubated with anti-SRP negative sera. In anti-SRP positive sera, we also observed complement deposition onto the membrane of normal human myoblast. Complement deposition was also observed on biopsies from three NAM patients who muscle sections were available. We conclude that one of the pathological pathways involved in muscle cell death in anti-SRP positive NAM is antibody-dependent complement mediated cell lysis. However, the possibility that more than one mechanism might be involved cannot be excluded and further studies would be helpful in understanding the pathogenesis of anti-SRP associated NAM.