Molecular mechanisms of complement activation and neuromuscular disruption by combinations of autoantibodies from patients with Myasthenia Gravis

Dr. Nicholas Sanderson, University Hospital Basel


In patients with myasthenia gravis, acetylcholine signaling from motor nerves to muscles is disrupted by autoantibodies against postsynaptic membrane proteins, most commonly the acetylcholine receptor (AChR). Studies of patients' sera, which typically contain complex mixtures of anti-AChR antibodies, have provided support for the existence of several pathomechanisms, of which the most important is complement-mediated destruction of the receptor-bearing postsynaptic membrane. However, there is no correlation between the titers of anti-AChR antibodies and the severity of the disease, or response to treatment, suggesting a large variability in the pathogenicity of individual antibodies. Understanding this variability, however, requires the ability to isolate individual antibodies, which, until recently, was rarely achieved. We therefore developed a suite of techniques to enable isolation of monoclonal AChR-binding antibodies from single B cells. Initial experiments with antibodies from patients with myasthenia gravis have yielded the unexpected finding that their pathogenicity is dependent on synergistic combinations of antibodies targeting disparate subunits of the receptor, and that single antibodies are almost harmless.

The effect appears to be mediated by complement, because complement blockade in vivo prevents the pathogenic effect of the antibody combinations. The objective of this study is to elucidate why combinations of antibodies against different subunits of the AChR are so much more effective in triggering complement activation and tissue destruction than single antibodies. This phenomenon has clear implications not only for the treatment of myasthenia gravis, but for our basic understanding of the interaction between antibodies, complement and cells in health and disease.