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

Dana L.E. Vergoossen, Jaap J. Plomp, Christöph Gstottner, Yvonne E. Fillié-Grijpma, Roy Augustinus, Robyn Verpalen, Manfred Wuhrer, Paul W.H.I. Parren, Elena Dominguez-Vega, Silvère M. van der Maarel, Jan J. Verschuuren, Maartje G. Huijbers
2020 bioRxiv   pre-print
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
more » ... onstrate 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.
doi:10.1101/2020.09.24.296293 fatcat:pqnbigtptnfmvpq3zct2wvq23y