The Pathophysiology of MuSK Myasthenia Gravis

The goal of my PhD was to unravel the pathophysiology of MuSK myasthenia gravis (MG) to ultimately facilitate development of better therapies.

Surprisingly, disease severity in MuSK MG correlates with IgG4 antibodies. As IgG4 was previously considered benign and anti-inflammatory, I investigated the pathogenicity of patient IgG4. We passively transferred IgG4 or IgG1-3 fractions from MuSK MG patients to mice. Mice receiving patient IgG4, but not IgG1-3, developed severe muscle weakness. This confirmed the pathogenic nature of patient IgG4. From previous research from colleagues at New York University (NYU) we learned that the main epitope, recognized by patient IgG4 MuSK antibodies, is essential in a signalling cascade that establishes and maintains the neuromuscular synapse. My research at NYU confirmed that the main pathomechanism of disease is physical inhibition of this pathway by patient IgG4. I subsequently recognized that MuSK MG was not the only disease where IgG4 autoantibody-predominance causes severe disease, resulting in the first comprehensive review of a niche of IgG4-mediated autoimmune diseases.