TY - JOUR
T1 - MuSK myasthenia gravis monoclonal antibodies: Valency dictates pathogenicity
AU - Huijbers, Maartje G.
AU - Vergoossen, Dana L.
AU - Fillié-Grijpma, Yvonne E.
AU - van Es, Inge E.
AU - Koning, Marvyn T.
AU - Slot, Linda M.
AU - Veelken, Hendrik
AU - Plomp, Jaap J.
AU - van der Maarel, Silvère M.
AU - Verschuuren, Jan J.
PY - 2019
Y1 - 2019
N2 - ObjectiveTo isolate and characterize muscle-specific kinase (MuSK) monoclonal antibodies from patients with MuSK myasthenia gravis (MG) on a genetic and functional level.MethodsWe generated recombinant MuSK antibodies from patient-derived clonal MuSK-specific B cells and produced monovalent Fab fragments from them. Both the antibodies and Fab fragments were tested for their effects on neural agrin-induced MuSK phosphorylation and acetylcholine receptor (AChR) clustering in myotube cultures.ResultsThe isolated MuSK monoclonal antibody sequences included IgG1, IgG3, and IgG4 that had undergone high levels of affinity maturation, consistent with antigenic selection. We confirmed their specificity for the MuSK Ig-like 1 domain and binding to neuromuscular junctions. Monovalent MuSK Fab, mimicking functionally monovalent MuSK MG patient Fab-arm exchanged serum IgG4, abolished agrin-induced MuSK phosphorylation and AChR clustering. Surprisingly, bivalent monospecific MuSK antibodies instead activated MuSK phosphorylation and partially induced AChR clustering, independent of agrin.ConclusionsPatient-derived MuSK antibodies can act either as MuSK agonist or MuSK antagonist, depending on the number of MuSK binding sites. Functional monovalency, induced by Fab-arm exchange in patient serum, makes MuSK IgG4 antibodies pathogenic.
AB - ObjectiveTo isolate and characterize muscle-specific kinase (MuSK) monoclonal antibodies from patients with MuSK myasthenia gravis (MG) on a genetic and functional level.MethodsWe generated recombinant MuSK antibodies from patient-derived clonal MuSK-specific B cells and produced monovalent Fab fragments from them. Both the antibodies and Fab fragments were tested for their effects on neural agrin-induced MuSK phosphorylation and acetylcholine receptor (AChR) clustering in myotube cultures.ResultsThe isolated MuSK monoclonal antibody sequences included IgG1, IgG3, and IgG4 that had undergone high levels of affinity maturation, consistent with antigenic selection. We confirmed their specificity for the MuSK Ig-like 1 domain and binding to neuromuscular junctions. Monovalent MuSK Fab, mimicking functionally monovalent MuSK MG patient Fab-arm exchanged serum IgG4, abolished agrin-induced MuSK phosphorylation and AChR clustering. Surprisingly, bivalent monospecific MuSK antibodies instead activated MuSK phosphorylation and partially induced AChR clustering, independent of agrin.ConclusionsPatient-derived MuSK antibodies can act either as MuSK agonist or MuSK antagonist, depending on the number of MuSK binding sites. Functional monovalency, induced by Fab-arm exchange in patient serum, makes MuSK IgG4 antibodies pathogenic.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85065043346&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30882021
U2 - https://doi.org/10.1212/NXI.0000000000000547
DO - https://doi.org/10.1212/NXI.0000000000000547
M3 - Article
C2 - 30882021
SN - 2332-7812
VL - 6
JO - Neurology® neuroimmunology & neuroinflammation
JF - Neurology® neuroimmunology & neuroinflammation
IS - 3
M1 - e547
ER -