RT Journal Article
SR Electronic
T1 MuSK myasthenia gravis monoclonal antibodies
JF Neurology - Neuroimmunology Neuroinflammation
JO Neurol Neuroimmunol Neuroinflamm
FD Lippincott Williams & Wilkins
SP e547
DO 10.1212/NXI.0000000000000547
VO 6
IS 3
A1 Huijbers, Maartje G.
A1 Vergoossen, Dana L.
A1 Fillié-Grijpma, Yvonne E.
A1 van Es, Inge E.
A1 Koning, Marvyn T.
A1 Slot, Linda M.
A1 Veelken, Hendrik
A1 Plomp, Jaap J.
A1 van der Maarel, Silvère M.
A1 Verschuuren, Jan J.
YR 2019
UL http://nn.neurology.org/content/6/3/e547.abstract
AB Objective To isolate and characterize muscle-specific kinase (MuSK) monoclonal antibodies from patients with MuSK myasthenia gravis (MG) on a genetic and functional level.Methods We 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.Results The 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.Conclusions Patient-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.AChR=acetylcholine receptor; Lrp4=LDL receptor–related protein 4; MG=myasthenia gravis; MIR=main immunogenic region; MuSK=muscle-specific kinase; NMJ=neuromuscular junction; PBMC=peripheral blood mononuclear cell; VH=heavy chain; VL=light chain