Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis

Abstract

Human IgG4 usually displays anti-inflammatory activity, and observations of IgG4 autoantibodies causing severe autoimmune disorders are therefore poorly understood. In blood, IgG4 antibodies naturally engage in a stochastic process termed Fab-arm exchange in which unrelated IgG4s exchange half-molecules continuously. The resulting IgG4 antibodies are composed of two different binding sites, thereby acquiring monovalent binding and inability to cross-link for each antigen recognized. Here, we demonstrate this process amplifies autoantibody pathogenicity in a classic IgG4-mediated autoimmune disease: muscle-specific kinase (MuSK) myasthenia gravis (MG). In mice, monovalent anti-MuSK IgG4s caused rapid and severe myasthenic muscle weakness, whereas the same antibodies in their parental bivalent form were less potent or did not induce a phenotype. Mechanistically this could be explained by opposing effects on MuSK signaling. Isotype switching to IgG4 in an autoimmune response thereby may be a critical step in the development of disease. Our study establishes functional monovalency as a novel pathogenic mechanism in IgG4-mediated autoimmune disease and potentially other disorders.Graphical abstract

The MuSK-BMP pathway maintains myofiber size in slow muscle through regulation of Akt-mTOR signaling

“…This form of MG is distinct from the more common anti-AChR MG, can be more severe and does not respond to cholinesterase inhibitors. The pathogenesis of MuSK-MG is mediated at least in part by IgG4 antibodies directed against the MuSK Ig1 domain that disrupt agrin-LRP4 binding and signaling 15,[34][35][36][37] . However, some clinical features of MuSK-MG suggest that non-synaptic pathology mediated by the MuSK autoantibodies may also contribute to the disease.…”

“…This form of MG is distinct from the more common anti-AChR MG, can be more severe and does not respond to cholinesterase inhibitors. The pathogenesis of MuSK-MG is mediated at least in part by IgG4 antibodies directed against the MuSK Ig1 domain that disrupt agrin-LRP4 binding and signaling 15,34–37 .…”

The MuSK-BMP pathway maintains myofiber size in slow muscle through regulation of Akt- mTOR signaling

“…This form of MG is distinct from the more common anti-AChR MG, can be more severe and does not respond to cholinesterase inhibitors. The pathogenesis of MuSK-MG is mediated at least in part by IgG4 antibodies directed against the MuSK Ig1 domain that disrupt agrin-LRP4 binding and signaling 15,[34][35][36][37] . However, some clinical features of MuSK-MG suggest that non-synaptic pathology mediated by the MuSK autoantibodies may also contribute to the disease.…”

Novel pathophysiological insights in autoimmune myasthenia gravis

“…The resulting monovalency is directly responsible for augmented pathogenicity in vivo . Indeed, passive transfer of MuSK monovalent Abs into mice induced severe and rapid myasthenic symptoms, while injection of bivalent MuSK Abs resulted in delayed, milder effects [20 ▪▪ ]. Another critical factor that dictates pathogenicity is the affinity of MuSK Abs for the cognate self-antigen.…”