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

Abstract

Human immunoglobulin (Ig) G4 usually displays antiinflammatory activity, and observations of IgG4 autoantibodies causing severe autoimmune disorders are therefore poorly understood. In blood, IgG4 naturally engages 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 that this process amplifies autoantibody pathogenicity in a classic IgG4-mediated autoimmune disease: muscle-specific kinase (MuSK) myasthenia gravis. 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 pathogenic mechanism in IgG4-mediated autoimmune disease and potentially other disorders.

Laboratory Investigation of Hybrid IgG4 k/λ in MuSK Positive Myasthenia Gravis

“…A more pronounced and longstanding response to RTX-induced B-cell depletion was observed in MuSK-MG, refractory to traditional therapies: it involves the circuit of specific anti-MuSK IgG4 as we previously demonstrated by the paralleled prolonged reduction of specific IgG4 MuSK antibodies [9]. Since most of pathogenetic MuSK IgG4 consists in hybrid molecules, our results could be very useful for a better selection of MuSK-MG pts to be treated with RTX [11][12][13].…”

“…However, MuSK-MG does not fulfill IgG4-RD criteria, even if a recent case report opens a new scenario on a putative link between the two diseases [16]. In recent years, it has been well demonstrated that a considerable proportion of MuSK IgG4 is Fab-arm exchanged without affecting pathogenetic mechanisms of disease [11][12][13].…”

“…Considered as an emerging direct biomarker of B cell activity in AD, FLC has been confirmed as a challenging biomarker for MG in suspected pts who are double seronegative [23]. Since the demonstration that hybrid IgG4 mediates pathogenesis in MuSK-MG [11][12][13], our interest was focused on understanding the clinical relevance of such molecules.…”

“…To verify if hybrid IgG4 plays a pathogenic role as already reported [11][12][13], we analyzed the correlation between hybrid/total IgG4 ratio and disease severity. In Figure 4, we visualized the distribution of Hybrid/Total IgG4 ratios at different MGFA scores for 13 out of 14 MuSK-MG pts who were evaluated for the MGFA at the time of withdrawal.…”

“…The resulting impairment of neuromuscular transmission underlies the clinically severe and fatigable weakness of skeletal muscles. It has been demonstrated that MuSK IgG4s undergo FAE in vitro and in vivo, but without affecting their pathogenicity: while monospecific bivalent anti-MuSK Abs would have a protective effect by enhancing MuSK phosphorylation, functional monovalency following FAE increases their interfering effect on AChR clustering and therefore their pathogenicity [11][12][13]. Starting from the proven pathogenicity of hybrid MuSK IgG4s, the open question is to define if their characterization in diagnostics may add a plus value in the management of disease.…”