Significance An expanding group of autoimmune diseases is now recognized to be hallmarked by pathogenic IgG4 autoantibodies. IgG4 has the unique ability to exchange Fab-arms, rendering it bispecific and functionally monovalent. Here we show that autoantibody functional monovalency significantly amplifies the pathogenicity of IgG4 autoantibodies using patient-derived monoclonal antibodies in an in vivo model of MuSK myasthenia gravis. Therefore, subclass switching to predominant IgG4 autoantibodies is a critical step in the development of MuSK myasthenia gravis. This new mechanism in autoimmunity is also potentially relevant to 29 other IgG4-mediated autoimmune diseases known to date, allergy and other disease settings where IgG4 antibodies contribute to pathology.