In myasthenia gravis and Lambert-Eaton myasthenic syndrome muscle weakness is a direct consequence of autoantibodies binding to, and interfering with, the function of key neuromuscular junction proteins. A subgroup of patients have antibodies against muscle-specific kinase (MuSK). MuSK is essential for the formation and maintenance of neuromuscular synapses as it propagates a trophic signal to induce acetylcholine receptor clustering and supports presynaptic motor nerve terminal differentiation. We confirmed that MuSK autoantibodies are predominantly of the IgG4 subclass and can induce myasthenia gravis in immune-incompetent mice through blocking the signal of MuSK to maintain the synapse (Klooster & Plomp et al. 2012 Brain, Huijbers et al. 2013 PNAS).

IgG4 antibodies are a subclass of antibodies. In contrast to the other IgG subclass antibodies (IgG1-3), these antibodies are considered anti-inflammatory as they are generally bad at activating the immune system (e.g. via complement, or antibody-dependent cellular cytotoxicity (ADCC). IgG4s therefore mostly acts through antigen binding and blocking. IgG4 furthermore undergoes a unique process called Fab-arm exchange (Figure 1). When IgG4 is produced by plasma cells this molecule looks like other antibodies and has two antigen-binding sites specific for one antigen. When IgG4 reaches the circulation IgG4 molecules undergo Fab-arm exchange and switch with other IgG4 molecules half-antibodies. Due to the large heterogeneity of circulating IgG4 molecules IgG4 rapidly becomes bispecific and functionally monovalent. This only occurs in humans and primates and the role for this in evolution has yet to be elucidated. In MuSK myasthenia gravis Fab-arm exchange turns out to be important as monovalent antibodies are more pathogenic then their bivalent parental equivalents (Vergoossen et al. 2021 PNAS, Huijbers et al. 2019 Neurol, Neuroimmunol & Neuroinflamm).

Interestingly, a niche of other autoimmune diseases has been identified that are associated with predominating IgG4 autoantibodies (Huijbers et al. 2018 Ann N Y Acad Sci, Huijbers et al. 2015 Eur J Neurol.). These include diseases affecting the skin, brain, muscle, peripheral nerve, blood clothing and kidneys. These diseases share many of the disease mechanism characteristics observed in MuSK myasthenia gravis. Why these diseases are hallmarked by IgG4 autoantibodies is not known.