Autoantibody pathogenicity in a multifocal motor neuropathy induced pluripotent stem cell-derived model

Oliver Harschnitz; Leonard H van den Berg; Lill Eva Johansen; Marc D Jansen; Sandra Kling; Renata Vieira de Sá; Lotte Vlam; Wouter van Rheenen; Henk Karst; Corette J Wierenga; R Jeroen Pasterkamp; W Ludo van der Pol

doi:10.1002/ana.24680

Autoantibody pathogenicity in a multifocal motor neuropathy induced pluripotent stem cell-derived model

Oliver Harschnitz, Leonard H van den Berg^*, Lill Eva Johansen, Marc D Jansen, Sandra Kling, Renata Vieira de Sá, Lotte Vlam, Wouter van Rheenen, Henk Karst, Corette J Wierenga, R Jeroen Pasterkamp, W Ludo van der Pol

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

OBJECTIVE: We investigated the pathogenicity of immunoglobulin M (IgM) anti-GM1 antibodies in serum from patients with multifocal motor neuropathy (MMN) using human induced pluripotent stem cell (iPSC)-derived motor neurons (MNs).

METHODS: iPSCs were generated from fibroblasts and differentiated into MNs. We studied the binding of IgM to MNs, their complement-activating properties, and effects on structural integrity using fluorescence and electron microscopy. Live cell imaging was used to study effects of antibody binding on MNs in the presence and absence of complement.

RESULTS: IgM antibody binding to MNs was detected using sera from MMN patients with and without detectable anti-GM1 IgM antibody titers in enzyme-linked immunosorbent assay, but not with sera from (disease) controls. Competition and depletion experiments showed that antibodies specifically bound to GM1 on iPSC-derived MNs. Binding of these antibodies disrupted calcium homeostasis by both complement-dependent and complement-independent pathways. MNs showed marked axonal damage after complement activation, and reduced antibody pathogenicity following treatment with immunoglobulin preparations.

INTERPRETATION: Our data provide evidence for the pathogenicity of anti-GM1 IgM antibodies in MMN patients and link their presence to the clinical characteristics of axonal damage and immunoglobulin responsiveness. This iPSC-derived disease model will facilitate diagnosis, studies on autoantibody pathogenicity, drug development, and screening in immune-mediated neuropathies. Ann Neurol 2016;80:71-88.

Original language	English
Pages (from-to)	71-88
Number of pages	18
Journal	Annals of Neurology
Volume	80
Issue number	1
DOIs	https://doi.org/10.1002/ana.24680
Publication status	Published - Jul 2016

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AutoantibodyFinal published version, 1.32 MBLicence: Taverne

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Harschnitz, O., van den Berg, L. H., Johansen, L. E., Jansen, M. D., Kling, S., Vieira de Sá, R., Vlam, L., van Rheenen, W., Karst, H., Wierenga, C. J., Pasterkamp, R. J., & van der Pol, W. L. (2016). Autoantibody pathogenicity in a multifocal motor neuropathy induced pluripotent stem cell-derived model. Annals of Neurology, 80(1), 71-88. https://doi.org/10.1002/ana.24680

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title = "Autoantibody pathogenicity in a multifocal motor neuropathy induced pluripotent stem cell-derived model",

abstract = "OBJECTIVE: We investigated the pathogenicity of immunoglobulin M (IgM) anti-GM1 antibodies in serum from patients with multifocal motor neuropathy (MMN) using human induced pluripotent stem cell (iPSC)-derived motor neurons (MNs).METHODS: iPSCs were generated from fibroblasts and differentiated into MNs. We studied the binding of IgM to MNs, their complement-activating properties, and effects on structural integrity using fluorescence and electron microscopy. Live cell imaging was used to study effects of antibody binding on MNs in the presence and absence of complement.RESULTS: IgM antibody binding to MNs was detected using sera from MMN patients with and without detectable anti-GM1 IgM antibody titers in enzyme-linked immunosorbent assay, but not with sera from (disease) controls. Competition and depletion experiments showed that antibodies specifically bound to GM1 on iPSC-derived MNs. Binding of these antibodies disrupted calcium homeostasis by both complement-dependent and complement-independent pathways. MNs showed marked axonal damage after complement activation, and reduced antibody pathogenicity following treatment with immunoglobulin preparations.INTERPRETATION: Our data provide evidence for the pathogenicity of anti-GM1 IgM antibodies in MMN patients and link their presence to the clinical characteristics of axonal damage and immunoglobulin responsiveness. This iPSC-derived disease model will facilitate diagnosis, studies on autoantibody pathogenicity, drug development, and screening in immune-mediated neuropathies. Ann Neurol 2016;80:71-88.",

author = "Oliver Harschnitz and {van den Berg}, {Leonard H} and Johansen, {Lill Eva} and Jansen, {Marc D} and Sandra Kling and {Vieira de S{\'a}}, Renata and Lotte Vlam and {van Rheenen}, Wouter and Henk Karst and Wierenga, {Corette J} and Pasterkamp, {R Jeroen} and {van der Pol}, {W Ludo}",

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year = "2016",

month = jul,

doi = "10.1002/ana.24680",

language = "English",

volume = "80",

pages = "71--88",

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T1 - Autoantibody pathogenicity in a multifocal motor neuropathy induced pluripotent stem cell-derived model

AU - Harschnitz, Oliver

AU - van den Berg, Leonard H

AU - Johansen, Lill Eva

AU - Jansen, Marc D

AU - Kling, Sandra

AU - Vieira de Sá, Renata

AU - Vlam, Lotte

AU - van Rheenen, Wouter

AU - Karst, Henk

AU - Wierenga, Corette J

AU - Pasterkamp, R Jeroen

AU - van der Pol, W Ludo

PY - 2016/7

Y1 - 2016/7

N2 - OBJECTIVE: We investigated the pathogenicity of immunoglobulin M (IgM) anti-GM1 antibodies in serum from patients with multifocal motor neuropathy (MMN) using human induced pluripotent stem cell (iPSC)-derived motor neurons (MNs).METHODS: iPSCs were generated from fibroblasts and differentiated into MNs. We studied the binding of IgM to MNs, their complement-activating properties, and effects on structural integrity using fluorescence and electron microscopy. Live cell imaging was used to study effects of antibody binding on MNs in the presence and absence of complement.RESULTS: IgM antibody binding to MNs was detected using sera from MMN patients with and without detectable anti-GM1 IgM antibody titers in enzyme-linked immunosorbent assay, but not with sera from (disease) controls. Competition and depletion experiments showed that antibodies specifically bound to GM1 on iPSC-derived MNs. Binding of these antibodies disrupted calcium homeostasis by both complement-dependent and complement-independent pathways. MNs showed marked axonal damage after complement activation, and reduced antibody pathogenicity following treatment with immunoglobulin preparations.INTERPRETATION: Our data provide evidence for the pathogenicity of anti-GM1 IgM antibodies in MMN patients and link their presence to the clinical characteristics of axonal damage and immunoglobulin responsiveness. This iPSC-derived disease model will facilitate diagnosis, studies on autoantibody pathogenicity, drug development, and screening in immune-mediated neuropathies. Ann Neurol 2016;80:71-88.

AB - OBJECTIVE: We investigated the pathogenicity of immunoglobulin M (IgM) anti-GM1 antibodies in serum from patients with multifocal motor neuropathy (MMN) using human induced pluripotent stem cell (iPSC)-derived motor neurons (MNs).METHODS: iPSCs were generated from fibroblasts and differentiated into MNs. We studied the binding of IgM to MNs, their complement-activating properties, and effects on structural integrity using fluorescence and electron microscopy. Live cell imaging was used to study effects of antibody binding on MNs in the presence and absence of complement.RESULTS: IgM antibody binding to MNs was detected using sera from MMN patients with and without detectable anti-GM1 IgM antibody titers in enzyme-linked immunosorbent assay, but not with sera from (disease) controls. Competition and depletion experiments showed that antibodies specifically bound to GM1 on iPSC-derived MNs. Binding of these antibodies disrupted calcium homeostasis by both complement-dependent and complement-independent pathways. MNs showed marked axonal damage after complement activation, and reduced antibody pathogenicity following treatment with immunoglobulin preparations.INTERPRETATION: Our data provide evidence for the pathogenicity of anti-GM1 IgM antibodies in MMN patients and link their presence to the clinical characteristics of axonal damage and immunoglobulin responsiveness. This iPSC-derived disease model will facilitate diagnosis, studies on autoantibody pathogenicity, drug development, and screening in immune-mediated neuropathies. Ann Neurol 2016;80:71-88.

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DO - 10.1002/ana.24680

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JO - Annals of Neurology

JF - Annals of Neurology

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Autoantibody pathogenicity in a multifocal motor neuropathy induced pluripotent stem cell-derived model

Abstract

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