MuSK myasthenia gravis monoclonal antibodies

被引：72

作者：

Huijbers, Maartje G. ^{[1
,2
]}

Vergoossen, Dana L. ^{[2
]}

Fillie-Grijpma, Yvonne E. ^{[1
,2
]}

van Es, Inge E. ^{[1
,2
]}

Koning, Marvyn T. ^{[3
]}

Slot, Linda M. ^{[4
]}

Veelken, Hendrik ^{[3
]}

Plomp, Jaap J. ^{[1
]}

van der Maarel, Silvere M. ^{[2
]}

Verschuuren, Jan J. ^{[1
]}

机构：

[1] Leiden Univ, Med Ctr, Dept Neurol, Leiden, Netherlands

[2] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands

[3] Leiden Univ, Med Ctr, Dept Hematol, Leiden, Netherlands

[4] Leiden Univ, Med Ctr, Dept Rheumatol, Leiden, Netherlands

来源：

NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION | 2019年 / 6卷 / 03期

关键词：

IGG4; AUTOANTIBODIES; ACETYLCHOLINE-RECEPTORS; TYROSINE KINASE; COLLAGEN Q; BINDING; IDENTIFICATION; DYSFUNCTION;

D O I：

10.1212/NXI.0000000000000547

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

100204 [神经病学];

摘要：

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 Fabarm exchange in patient serum, makes MuSK IgG4 antibodies pathogenic.

引用

页数：9

共 32 条

[1]

Anti-MuSK antibodies: Correlation with myasthenia gravis severity [J].

Bartoccioni, E. ;

Scuderi, F. ;

Minicuci, G. M. ;

Marino, M. ;

Ciaraffa, F. ;

Evoli, A. .

NEUROLOGY, 2006, 67 (03) :505-507

[2]

Fundamental Molecules and Mechanisms for Forming and Maintaining Neuromuscular Synapses [J].

Burden, Steven J. ;

Huijbers, Maartje G. ;

Remedio, Leonor .

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2018, 19 (02)

[3]

Preserving neuromuscular synapses in ALS by stimulating MuSK with a therapeutic agonist antibody [J].

Cantor, Sarah ;

Zhang, Wei ;

Delestree, Nicolas ;

Remedio, Leonor ;

Mentis, George Z. ;

Burden, Steven J. .

ELIFE, 2018, 7

[4]

Patient autoantibodies deplete postsynaptic muscle-specific kinase leading to disassembly of the ACh receptor scaffold and myasthenia gravis in mice [J].

Cole, R. N. ;

Ghazanfari, N. ;

Ngo, S. T. ;

Gervasio, O. L. ;

Reddel, S. W. ;

Phillips, W. D. .

JOURNAL OF PHYSIOLOGY-LONDON, 2010, 588 (17) :3217-3229

[5]

Pemphigus autoantibodies generated through somatic mutations target the desmoglein-3 cis-interface [J].

Di Zenzo, Giovanni ;

Di Lullo, Giulia ;

Corti, Davide ;

Calabresi, Valentina ;

Sinistro, Anna ;

Vanzetta, Fabrizia ;

Didona, Biagio ;

Cianchini, Giuseppe ;

Hertl, Michael ;

Eming, Rudiger ;

Amagai, Masayuki ;

Ohyama, Bungo ;

Hashimoto, Takashi ;

Sloostra, Jerry ;

Sallusto, Federica ;

Zambruno, Giovanna ;

Lanzavecchia, Antonio .

JOURNAL OF CLINICAL INVESTIGATION, 2012, 122 (10) :3781-3790

[6]

The juxtamembrane region of MuSK has a critical role in agrin-mediated signaling (vol 19, pg 67, 2000) [J].

Herbst, R ;

Burden, SJ .

EMBO JOURNAL, 2000, 19 (05) :1167-1167

[7]

Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies [J].

Hoch, W ;

McConville, J ;

Helms, S ;

Newsom-Davis, J ;

Melms, A ;

Vincent, A .

NATURE MEDICINE, 2001, 7 (03) :365-368

[8]

Dimerization of the muscle-specific kinase induces tyrosine phosphorylation of acetylcholine receptors and their aggregation on the surface of myotubes [J].

Hopf, C ;

Hoch, W .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (11) :6467-6473

[9]

The expanding field of IgG4-mediated neurological autoimmune disorders [J].

Huijbers, M. G. ;

Querol, L. A. ;

Niks, E. H. ;

Plomp, J. J. ;

van der Maarel, S. M. ;

Graus, F. ;

Dalmau, J. ;

Illa, I. ;

Verschuuren, J. J. .

EUROPEAN JOURNAL OF NEUROLOGY, 2015, 22 (08) :1151-1161

[10]

IgG4-mediated autoimmune diseases: a niche of antibody-mediated disorders [J].

Huijbers, Maartje G. ;

Plomp, Jaap J. ;

van der Maarel, Silvere M. ;

Verschuuren, Jan J. .

ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, 2018, 1413 (01) :92-103

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