PMID- 30882021
OWN - NLM
STAT- MEDLINE
DCOM- 20200924
LR  - 20200924
IS  - 2332-7812 (Print)
IS  - 2332-7812 (Electronic)
IS  - 2332-7812 (Linking)
VI  - 6
IP  - 3
DP  - 2019 May
TI  - MuSK myasthenia gravis monoclonal antibodies: Valency dictates pathogenicity.
PG  - e547
LID - 10.1212/NXI.0000000000000547 [doi]
LID - e547
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.
FAU - Huijbers, Maartje G
AU  - Huijbers MG
AD  - Department of Neurology (M.G.H., Y.E.F.-G., I.E.v.E., J.J.P., J.J.V.), Department 
      of Human Genetics (M.G.H., D.L.V., Y.F.-G., I.E.v.E., S.M.v.d.M.), Department of 
      Hematology (M.T.K., H.V.), and Department of Rheumatology (L.M.S.), Leiden 
      University Medical Center, The Netherlands.
FAU - Vergoossen, Dana L
AU  - Vergoossen DL
AD  - Department of Neurology (M.G.H., Y.E.F.-G., I.E.v.E., J.J.P., J.J.V.), Department 
      of Human Genetics (M.G.H., D.L.V., Y.F.-G., I.E.v.E., S.M.v.d.M.), Department of 
      Hematology (M.T.K., H.V.), and Department of Rheumatology (L.M.S.), Leiden 
      University Medical Center, The Netherlands.
FAU - Fillie-Grijpma, Yvonne E
AU  - Fillie-Grijpma YE
AD  - Department of Neurology (M.G.H., Y.E.F.-G., I.E.v.E., J.J.P., J.J.V.), Department 
      of Human Genetics (M.G.H., D.L.V., Y.F.-G., I.E.v.E., S.M.v.d.M.), Department of 
      Hematology (M.T.K., H.V.), and Department of Rheumatology (L.M.S.), Leiden 
      University Medical Center, The Netherlands.
FAU - van Es, Inge E
AU  - van Es IE
AD  - Department of Neurology (M.G.H., Y.E.F.-G., I.E.v.E., J.J.P., J.J.V.), Department 
      of Human Genetics (M.G.H., D.L.V., Y.F.-G., I.E.v.E., S.M.v.d.M.), Department of 
      Hematology (M.T.K., H.V.), and Department of Rheumatology (L.M.S.), Leiden 
      University Medical Center, The Netherlands.
FAU - Koning, Marvyn T
AU  - Koning MT
AD  - Department of Neurology (M.G.H., Y.E.F.-G., I.E.v.E., J.J.P., J.J.V.), Department 
      of Human Genetics (M.G.H., D.L.V., Y.F.-G., I.E.v.E., S.M.v.d.M.), Department of 
      Hematology (M.T.K., H.V.), and Department of Rheumatology (L.M.S.), Leiden 
      University Medical Center, The Netherlands.
FAU - Slot, Linda M
AU  - Slot LM
AD  - Department of Neurology (M.G.H., Y.E.F.-G., I.E.v.E., J.J.P., J.J.V.), Department 
      of Human Genetics (M.G.H., D.L.V., Y.F.-G., I.E.v.E., S.M.v.d.M.), Department of 
      Hematology (M.T.K., H.V.), and Department of Rheumatology (L.M.S.), Leiden 
      University Medical Center, The Netherlands.
FAU - Veelken, Hendrik
AU  - Veelken H
AD  - Department of Neurology (M.G.H., Y.E.F.-G., I.E.v.E., J.J.P., J.J.V.), Department 
      of Human Genetics (M.G.H., D.L.V., Y.F.-G., I.E.v.E., S.M.v.d.M.), Department of 
      Hematology (M.T.K., H.V.), and Department of Rheumatology (L.M.S.), Leiden 
      University Medical Center, The Netherlands.
FAU - Plomp, Jaap J
AU  - Plomp JJ
AD  - Department of Neurology (M.G.H., Y.E.F.-G., I.E.v.E., J.J.P., J.J.V.), Department 
      of Human Genetics (M.G.H., D.L.V., Y.F.-G., I.E.v.E., S.M.v.d.M.), Department of 
      Hematology (M.T.K., H.V.), and Department of Rheumatology (L.M.S.), Leiden 
      University Medical Center, The Netherlands.
FAU - van der Maarel, Silvere M
AU  - van der Maarel SM
AD  - Department of Neurology (M.G.H., Y.E.F.-G., I.E.v.E., J.J.P., J.J.V.), Department 
      of Human Genetics (M.G.H., D.L.V., Y.F.-G., I.E.v.E., S.M.v.d.M.), Department of 
      Hematology (M.T.K., H.V.), and Department of Rheumatology (L.M.S.), Leiden 
      University Medical Center, The Netherlands.
FAU - Verschuuren, Jan J
AU  - Verschuuren JJ
AD  - Department of Neurology (M.G.H., Y.E.F.-G., I.E.v.E., J.J.P., J.J.V.), Department 
      of Human Genetics (M.G.H., D.L.V., Y.F.-G., I.E.v.E., S.M.v.d.M.), Department of 
      Hematology (M.T.K., H.V.), and Department of Rheumatology (L.M.S.), Leiden 
      University Medical Center, The Netherlands.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190221
PL  - United States
TA  - Neurol Neuroimmunol Neuroinflamm
JT  - Neurology(R) neuroimmunology & neuroinflammation
JID - 101636388
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Autoantibodies)
RN  - 0 (Receptors, Cholinergic)
RN  - 0 (Recombinant Proteins)
RN  - EC 2.7.10.1 (MUSK protein, human)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
SB  - IM
MH  - Adult
MH  - Antibodies, Monoclonal/*immunology/isolation & purification
MH  - Autoantibodies/*immunology/isolation & purification
MH  - Cells, Cultured
MH  - Humans
MH  - Muscle Fibers, Skeletal
MH  - Myasthenia Gravis/*immunology
MH  - Receptor Protein-Tyrosine Kinases/agonists/antagonists & inhibitors/*immunology
MH  - Receptors, Cholinergic/*immunology
MH  - Recombinant Proteins
PMC - PMC6410930
EDAT- 2019/03/19 06:00
MHDA- 2019/03/19 06:01
PMCR- 2019/02/21
CRDT- 2019/03/19 06:00
PHST- 2018/12/03 00:00 [received]
PHST- 2019/01/14 00:00 [accepted]
PHST- 2019/03/19 06:00 [entrez]
PHST- 2019/03/19 06:00 [pubmed]
PHST- 2019/03/19 06:01 [medline]
PHST- 2019/02/21 00:00 [pmc-release]
AID - NEURIMMINFL2018019430 [pii]
AID - 10.1212/NXI.0000000000000547 [doi]
PST - epublish
SO  - Neurol Neuroimmunol Neuroinflamm. 2019 Feb 21;6(3):e547. doi: 
      10.1212/NXI.0000000000000547. eCollection 2019 May.