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Immunoglobulin 4 (IgG4) is one of four human IgG subclasses and has several unique functional characteristics. It exhibits low affinity for complement and for most Fc receptors. It furthermore has generally high affinity for its antigen, with binding occurring in a monovalent fashion, as IgG4 can exchange Fab-arms with other IgG4 molecules. Because of these characteristics, IgG4 is believed to block its targets and prevent inflammation, which, depending on the setting, can have a protective or pathogenic effect. One example of IgG4 pathogenicity is muscle-specific kinase (MuSK) myasthenia gravis (MG), in which patients develop IgG4 MuSK autoantibodies, resulting in muscle weakness. As a consequence of the distinct IgG4 characteristics, the pathomechanism of MuSK MG is very different from IgG1-and IgG3-mediated autoimmune diseases, such as acetylcholine receptor MG. In recent years, new autoantibodies in a spectrum of autoimmune diseases have been discovered. Interestingly, some were found to be predominantly IgG4. These IgG4-mediated autoimmune diseases share many pathomechanistic aspects with MuSK MG, suggesting that IgG4-mediated autoimmunity forms a separate niche among the antibody-mediated disorders. In this review, we summarize the group of IgG4-mediated autoimmune diseases, discuss the role of IgG4 in MuSK MG, and highlight interesting future research questions for IgG4-mediated autoimmunity.

Myasthenia gravis (MG) with antibodies to muscle-specific kinase (MuSK) is characterized by fluctuating fatigable weakness. In MuSK MG, involvement of bulbar muscles, neck, and shoulder and respiratory weakness are more prominent than in acetylcholine receptor (AChR) MG. MuSK autoantibodies are mainly of the IgG4 subclass, and as such are unable to activate complement, have low affinity for Fc receptors, and are functionally monovalent. Therefore, the pathogenicity of IgG4 MuSK autoantibodies was initially questioned. A broad collection of in vitro active immunization and passive transfer models has been developed that have shed light on the pathogenicity of MuSK autoantibodies. Passive transfer studies with purified IgG4 from MuSK MG patients confirmed that IgG4 is sufficient to reproduce clear clinical, electrophysiological, and histological signs of myasthenia. In vitro experiments revealed that MuSK IgG4 autoantibodies preferably bind the first Ig-like domain of MuSK, correlate with disease severity, and interfere with the association between MuSK and low-density lipoprotein receptor-related protein 4 and collagen Q. Some patients have additional IgG1 MuSK autoantibodies, but their role in the disease is unclear. Altogether, this provides a rationale for epitope-specific or IgG4-specific treatment strategies for MuSK MG and emphasizes the importance of the development of different experimental models.

The neuromuscular junction (NMJ) forms the synaptic connection between a motor neuron and a skeletal muscle fiber. In order to achieve a sustained muscle contraction, this synapse has to reliably transmit motor neuronal action potentials onto the muscle fiber. To guarantee successful transmission even during intense activation of the NMJ, a safety factor of neuromuscular transmission exists. In the neuromuscular disorder myasthenia gravis (MG), autoantibodies are directed against acetylcholine receptors or, in the rarer variants, against other postsynaptic NMJ proteins. This causes loss of functional acetylcholine receptors, which compromises the safety factor of neuromuscular transmission, leading to the typical fatigable muscle weakness of MG. With intracellular microelectrode measurement of (miniature) endplate potentials at NMJs in ex vivo nerve-muscle preparations from MG animal models, these functional synaptic defects have been determined in much detail. Here, we describe the electrophysiological events at the normal NMJ and the pathoelectrophysiology at NMJs of animal models for MG.

Myasthenia gravis (MG) with antibodies to muscle-specific kinase (MuSK) is characterized by fluctuating fatigable weakness. In MuSK MG, involvement of bulbar muscles, neck, and shoulder and respiratory weakness are more prominent than in acetylcholine receptor (AChR) MG. MuSK autoantibodies are mainly of the IgG4 subclass, and as such are unable to activate complement, have low affinity for Fc receptors, and are functionally monovalent. Therefore, the pathogenicity of IgG4 MuSK autoantibodies was initially questioned. A broad collection of in vitro active immunization and passive transfer models has been developed that have shed light on the pathogenicity of MuSK autoantibodies. Passive transfer studies with purified IgG4 from MuSK MG patients confirmed that IgG4 is sufficient to reproduce clear clinical, electrophysiological, and histological signs of myasthenia. In vitro experiments revealed that MuSK IgG4 autoantibodies preferably bind the first Ig-like domain of MuSK, correlate with disease severity, and interfere with the association between MuSK and low-density lipoprotein receptor-related protein 4 and collagen Q. Some patients have additional IgG1 MuSK autoantibodies, but their role in the disease is unclear. Altogether, this provides a rationale for epitope-specific or IgG4-specific treatment strategies for MuSK MG and emphasizes the importance of the development of different experimental models.

Immunoglobulin 4 (IgG4) is one of four human IgG subclasses and has several unique functional characteristics. It exhibits low affinity for complement and for most Fc receptors. It furthermore has generally high affinity for its antigen, with binding occurring in a monovalent fashion, as IgG4 can exchange Fab-arms with other IgG4 molecules. Because of these characteristics, IgG4 is believed to block its targets and prevent inflammation, which, depending on the setting, can have a protective or pathogenic effect. One example of IgG4 pathogenicity is muscle-specific kinase (MuSK) myasthenia gravis (MG), in which patients develop IgG4 MuSK autoantibodies, resulting in muscle weakness. As a consequence of the distinct IgG4 characteristics, the pathomechanism of MuSK MG is very different from IgG1-and IgG3-mediated autoimmune diseases, such as acetylcholine receptor MG. In recent years, new autoantibodies in a spectrum of autoimmune diseases have been discovered. Interestingly, some were found to be predominantly IgG4. These IgG4-mediated autoimmune diseases share many pathomechanistic aspects with MuSK MG, suggesting that IgG4-mediated autoimmunity forms a separate niche among the antibody-mediated disorders. In this review, we summarize the group of IgG4-mediated autoimmune diseases, discuss the role of IgG4 in MuSK MG, and highlight interesting future research questions for IgG4-mediated autoimmunity.

Autoantibodies against muscle-specific kinase (MuSK), a protein essential for clustering of acetylcholine receptors at the neuromuscular junction (NMJ), are detected in the serum of a proportion of myasthenia gravis (MG) patients. In most MuSK MG patients the anti-MuSK activity resides in the IgG4 subclass, a minor IgG component without very well-defined, but presumably anti-inflammatory, roles in immunity. In recent years, several animal model studies showed that anti-MuSK autoantibodies can cause muscle weakness by directly affecting NMJ function and, therefore, are likely not simply bystander disease markers in MuSK MG patients. In passive transfer mice, we recently provided proof that MuSK MG patient IgG4 is severely myasthenogenic, causing functional defects at NMJs. Against the clinical, serological, and pharmacological background of MuSK MG, here we discuss the MuSK MG animal models generated by our laboratory and others that have been instrumental in elucidating the etiological and pathophysiological roles of anti-MuSK antibodies.

Autoantibodies against muscle-specific kinase (MuSK), a protein essential for clustering of acetylcholine receptors at the neuromuscular junction (NMJ), are detected in the serum of a proportion of myasthenia gravis (MG) patients. In most MuSK MG patients the anti-MuSK activity resides in the IgG4 subclass, a minor IgG component without very well-defined, but presumably anti-inflammatory, roles in immunity. In recent years, several animal model studies showed that anti-MuSK autoantibodies can cause muscle weakness by directly affecting NMJ function and, therefore, are likely not simply bystander disease markers in MuSK MG patients. In passive transfer mice, we recently provided proof that MuSK MG patient IgG4 is severely myasthenogenic, causing functional defects at NMJs. Against the clinical, serological, and pharmacological background of MuSK MG, here we discuss the MuSK MG animal models generated by our laboratory and others that have been instrumental in elucidating the etiological and pathophysiological roles of anti-MuSK antibodies.