Muscle-specific kinase (MuSK) myasthenia gravis (MG) is a neuromuscular autoimmune disorder caused by predominantly IgG4 antibodies targeting the MuSK protein. IgG4 has the unique ability to... Show moreMuscle-specific kinase (MuSK) myasthenia gravis (MG) is a neuromuscular autoimmune disorder caused by predominantly IgG4 antibodies targeting the MuSK protein. IgG4 has the unique ability to exchange half-molecules with other IgG4s, resulting in monovalent binding to their antigen. To investigate if MuSK-antibody valency influences its pathogenicity, recombinant bivalent and functionally monovalent MuSK antibodies were generated from B-cell receptor sequences isolated from MuSK MG patients. Passive transfer studies revealed that monovalency amplifies MuSK antibody pathogenicity in vivo. This may be because monovalent MuSK antibodies inhibit MuSK signaling (antagonist), while bivalent MuSK antibodies activate MuSK signaling (agonist) in vitro. The binding epitope on MuSK further influences the consequences and pathogenicity of MuSK antibodies. Collectively, these results suggest that the pathophysiology in individual patients depends on their unique antibody composition and that class-switching to IgG4 is a critical step in developing MuSK MG. Furthermore, the IgG4 response against MuSK does not appear to result from a global increase in IgG4 responses, as MuSK MG patients only had mildly elevated serum IgG4. Instead, it is thought to be driven by the antigen itself. Importantly, MUSK and other MG associated genes are also expressed outside skeletal muscle. These locations are at risk for non-motor symptoms caused by autoantibodies or mutations, or for side-effects of targeted therapeutic strategies. Show less
Muscle-specific kinase (MuSK) myasthenia gravis (MG) is a neuromuscular autoimmune disease belonging to a growing group of IgG4 autoimmune diseases (IgG4-AIDs), in which the majority of pathogenic... Show moreMuscle-specific kinase (MuSK) myasthenia gravis (MG) is a neuromuscular autoimmune disease belonging to a growing group of IgG4 autoimmune diseases (IgG4-AIDs), in which the majority of pathogenic autoantibodies are of the IgG4 subclass. The more prevalent form of MG with acetylcholine receptor (AChR) antibodies is caused by IgG1-3 autoantibodies. A dominant role for IgG4 in autoimmune disease is intriguing due to its antiinflammatory characteristics. It is unclear why MuSK autoantibodies are predominantly IgG4. We hypothesized that MuSK MG patients have a general predisposition to generate IgG4 responses, therefore resulting in high levels of circulating IgG4. To investigate this, we quantified serum Ig isotypes and IgG subclasses using nephelometric and turbidimetric assays in MuSK MG and AChR MG patients not under influence of immunosuppressive treatment. Absolute serum IgG1 was increased in both MuSK and AChR MG patients compared to healthy donors. In addition, only MuSK MG patients on average had significantly increased and enriched serum IgG4. Although more MuSK MG patients had elevated serum IgG4, for most the IgG4 serum levels fell within the normal range. Correlation analyses suggest MuSK-specific antibodies do not solely explain the variation in IgG4 levels. In conclusion, although serum IgG4 levels are slightly increased, the levels do not support ubiquitous IgG4 responses in MuSK MG patients as the underlying cause of dominant IgG4 MuSK antibodies. Show less
