Antibodies Against Glutamic Acid Decarboxylase 65 Are Locally Produced in the CSF and Arise During Affinity Maturation.

Humans Autoantibodies Glutamate Decarboxylase Antibodies, Monoclonal Syndrome Immunoglobulin G

Journal

Neurology(R) neuroimmunology & neuroinflammation
ISSN: 2332-7812
Titre abrégé: Neurol Neuroimmunol Neuroinflamm
Pays: United States
ID NLM: 101636388

Informations de publication

Date de publication:
05 2023
Historique:
received: 02 08 2022
accepted: 12 12 2022
entrez: 23 2 2023
pubmed: 24 2 2023
medline: 3 3 2023
Statut: epublish

Résumé

Antibodies (Abs) against the cytoplasmic protein glutamic acid decarboxylase 65 (GAD65) are detected in patients with neurologic syndromes together referred to as GAD65-Ab spectrum disorders. The response of some of these patients to plasma exchange or immunoglobulins indicates that GAD65-Abs could contribute to disease pathogenesis at least at some stages of disease. However, the involvement of GAD65-reactive B cells in the CNS is incompletely understood. We studied 7 patients with high levels of GAD65-Abs and generated monoclonal Abs (mAbs) derived from single cells in the CSF. Sequence characteristics, reactivity to GAD65, and the role of somatic hypermutations of the mAbs were analyzed. Twelve CSF-derived mAbs were generated originating from 3 patients with short disease duration, and 7/12 of these mAbs (58%) were GAD65 reactive in at least 1 detection assay. Four of 12 (33%) were definitely positive in all 3 detection assays. The intrathecal anti-GAD65 response was polyclonal. GAD65-Abs were mostly of the IgG1 subtype and had undergone affinity maturation. Reversion of 2 GAD65-reactive mAbs to their corresponding germline-encoded unmutated common ancestors abolished GAD65 reactivity. GAD65-specific B cells are present in the CNS and represent a sizable fraction of CSF B cells early in the disease course. The anti-GAD65 response in the CSF is polyclonal and shows evidence of antigen-driven affinity maturation required for GAD65 recognition. Our data support the hypothesis that the accumulation of GAD65-specific B cells and plasma cells in the CSF is an important feature of early disease stages.

Sections du résumé

BACKGROUND AND OBJECTIVES
Antibodies (Abs) against the cytoplasmic protein glutamic acid decarboxylase 65 (GAD65) are detected in patients with neurologic syndromes together referred to as GAD65-Ab spectrum disorders. The response of some of these patients to plasma exchange or immunoglobulins indicates that GAD65-Abs could contribute to disease pathogenesis at least at some stages of disease. However, the involvement of GAD65-reactive B cells in the CNS is incompletely understood.
METHODS
We studied 7 patients with high levels of GAD65-Abs and generated monoclonal Abs (mAbs) derived from single cells in the CSF. Sequence characteristics, reactivity to GAD65, and the role of somatic hypermutations of the mAbs were analyzed.
RESULTS
Twelve CSF-derived mAbs were generated originating from 3 patients with short disease duration, and 7/12 of these mAbs (58%) were GAD65 reactive in at least 1 detection assay. Four of 12 (33%) were definitely positive in all 3 detection assays. The intrathecal anti-GAD65 response was polyclonal. GAD65-Abs were mostly of the IgG1 subtype and had undergone affinity maturation. Reversion of 2 GAD65-reactive mAbs to their corresponding germline-encoded unmutated common ancestors abolished GAD65 reactivity.
DISCUSSION
GAD65-specific B cells are present in the CNS and represent a sizable fraction of CSF B cells early in the disease course. The anti-GAD65 response in the CSF is polyclonal and shows evidence of antigen-driven affinity maturation required for GAD65 recognition. Our data support the hypothesis that the accumulation of GAD65-specific B cells and plasma cells in the CSF is an important feature of early disease stages.

Identifiants

DOI: 10.1212/NXI.0000000000200090 PMID: 36823135 PMC: PMC9969496
pubmed: 36823135
pii: 10/3/e200090
doi: 10.1212/NXI.0000000000200090
pmc: PMC9969496
pii:
doi:

Substances chimiques

Autoantibodies 0
Glutamate Decarboxylase EC 4.1.1.15
Antibodies, Monoclonal 0
Immunoglobulin G 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

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Auteurs

Michelle Biljecki (M)

From the Institute of Clinical Neuroimmunology (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), University Hospital, Ludwig-Maximilians-Universität Munich; Biomedical Center (BMC) (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), Medical Faculty, Ludwig-Maximilians-Universität Munich, Martinsried; Graduate School of Systemic Neurosciences Ludwig-Maximilians-Universität Munich (M.B., K.E.); Munich Cluster for Systems Neurology (SyNergy) (E.B., M.K., F.S.T.); Innate Immunity Unit (A.T.), Institut Pasteur, Inserm U1223, Paris, France; Université de Paris (A.T.), Sorbonne Paris Cité, France; Institute of Laboratory Medicine (P.E.), University Hospital, LMU Munich; Institute of Clinical and Molecular Virology (P.S.), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg; and Department of Neurology (J.L.), University Hospital Ulm, Germany.

Katharina Eisenhut (K)

From the Institute of Clinical Neuroimmunology (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), University Hospital, Ludwig-Maximilians-Universität Munich; Biomedical Center (BMC) (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), Medical Faculty, Ludwig-Maximilians-Universität Munich, Martinsried; Graduate School of Systemic Neurosciences Ludwig-Maximilians-Universität Munich (M.B., K.E.); Munich Cluster for Systems Neurology (SyNergy) (E.B., M.K., F.S.T.); Innate Immunity Unit (A.T.), Institut Pasteur, Inserm U1223, Paris, France; Université de Paris (A.T.), Sorbonne Paris Cité, France; Institute of Laboratory Medicine (P.E.), University Hospital, LMU Munich; Institute of Clinical and Molecular Virology (P.S.), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg; and Department of Neurology (J.L.), University Hospital Ulm, Germany.
ORCID: 0000-0001-6448-3126

Eduardo Beltrán (E)

From the Institute of Clinical Neuroimmunology (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), University Hospital, Ludwig-Maximilians-Universität Munich; Biomedical Center (BMC) (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), Medical Faculty, Ludwig-Maximilians-Universität Munich, Martinsried; Graduate School of Systemic Neurosciences Ludwig-Maximilians-Universität Munich (M.B., K.E.); Munich Cluster for Systems Neurology (SyNergy) (E.B., M.K., F.S.T.); Innate Immunity Unit (A.T.), Institut Pasteur, Inserm U1223, Paris, France; Université de Paris (A.T.), Sorbonne Paris Cité, France; Institute of Laboratory Medicine (P.E.), University Hospital, LMU Munich; Institute of Clinical and Molecular Virology (P.S.), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg; and Department of Neurology (J.L.), University Hospital Ulm, Germany.

Stephan Winklmeier (S)

From the Institute of Clinical Neuroimmunology (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), University Hospital, Ludwig-Maximilians-Universität Munich; Biomedical Center (BMC) (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), Medical Faculty, Ludwig-Maximilians-Universität Munich, Martinsried; Graduate School of Systemic Neurosciences Ludwig-Maximilians-Universität Munich (M.B., K.E.); Munich Cluster for Systems Neurology (SyNergy) (E.B., M.K., F.S.T.); Innate Immunity Unit (A.T.), Institut Pasteur, Inserm U1223, Paris, France; Université de Paris (A.T.), Sorbonne Paris Cité, France; Institute of Laboratory Medicine (P.E.), University Hospital, LMU Munich; Institute of Clinical and Molecular Virology (P.S.), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg; and Department of Neurology (J.L.), University Hospital Ulm, Germany.
ORCID: 0000-0001-8675-0387

Simone Mader (S)

From the Institute of Clinical Neuroimmunology (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), University Hospital, Ludwig-Maximilians-Universität Munich; Biomedical Center (BMC) (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), Medical Faculty, Ludwig-Maximilians-Universität Munich, Martinsried; Graduate School of Systemic Neurosciences Ludwig-Maximilians-Universität Munich (M.B., K.E.); Munich Cluster for Systems Neurology (SyNergy) (E.B., M.K., F.S.T.); Innate Immunity Unit (A.T.), Institut Pasteur, Inserm U1223, Paris, France; Université de Paris (A.T.), Sorbonne Paris Cité, France; Institute of Laboratory Medicine (P.E.), University Hospital, LMU Munich; Institute of Clinical and Molecular Virology (P.S.), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg; and Department of Neurology (J.L.), University Hospital Ulm, Germany.

Anna Thaller (A)

From the Institute of Clinical Neuroimmunology (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), University Hospital, Ludwig-Maximilians-Universität Munich; Biomedical Center (BMC) (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), Medical Faculty, Ludwig-Maximilians-Universität Munich, Martinsried; Graduate School of Systemic Neurosciences Ludwig-Maximilians-Universität Munich (M.B., K.E.); Munich Cluster for Systems Neurology (SyNergy) (E.B., M.K., F.S.T.); Innate Immunity Unit (A.T.), Institut Pasteur, Inserm U1223, Paris, France; Université de Paris (A.T.), Sorbonne Paris Cité, France; Institute of Laboratory Medicine (P.E.), University Hospital, LMU Munich; Institute of Clinical and Molecular Virology (P.S.), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg; and Department of Neurology (J.L.), University Hospital Ulm, Germany.

Peter Eichhorn (P)

From the Institute of Clinical Neuroimmunology (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), University Hospital, Ludwig-Maximilians-Universität Munich; Biomedical Center (BMC) (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), Medical Faculty, Ludwig-Maximilians-Universität Munich, Martinsried; Graduate School of Systemic Neurosciences Ludwig-Maximilians-Universität Munich (M.B., K.E.); Munich Cluster for Systems Neurology (SyNergy) (E.B., M.K., F.S.T.); Innate Immunity Unit (A.T.), Institut Pasteur, Inserm U1223, Paris, France; Université de Paris (A.T.), Sorbonne Paris Cité, France; Institute of Laboratory Medicine (P.E.), University Hospital, LMU Munich; Institute of Clinical and Molecular Virology (P.S.), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg; and Department of Neurology (J.L.), University Hospital Ulm, Germany.

Philipp Steininger (P)

From the Institute of Clinical Neuroimmunology (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), University Hospital, Ludwig-Maximilians-Universität Munich; Biomedical Center (BMC) (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), Medical Faculty, Ludwig-Maximilians-Universität Munich, Martinsried; Graduate School of Systemic Neurosciences Ludwig-Maximilians-Universität Munich (M.B., K.E.); Munich Cluster for Systems Neurology (SyNergy) (E.B., M.K., F.S.T.); Innate Immunity Unit (A.T.), Institut Pasteur, Inserm U1223, Paris, France; Université de Paris (A.T.), Sorbonne Paris Cité, France; Institute of Laboratory Medicine (P.E.), University Hospital, LMU Munich; Institute of Clinical and Molecular Virology (P.S.), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg; and Department of Neurology (J.L.), University Hospital Ulm, Germany.

Andrea Flierl-Hecht (A)

From the Institute of Clinical Neuroimmunology (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), University Hospital, Ludwig-Maximilians-Universität Munich; Biomedical Center (BMC) (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), Medical Faculty, Ludwig-Maximilians-Universität Munich, Martinsried; Graduate School of Systemic Neurosciences Ludwig-Maximilians-Universität Munich (M.B., K.E.); Munich Cluster for Systems Neurology (SyNergy) (E.B., M.K., F.S.T.); Innate Immunity Unit (A.T.), Institut Pasteur, Inserm U1223, Paris, France; Université de Paris (A.T.), Sorbonne Paris Cité, France; Institute of Laboratory Medicine (P.E.), University Hospital, LMU Munich; Institute of Clinical and Molecular Virology (P.S.), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg; and Department of Neurology (J.L.), University Hospital Ulm, Germany.

Jan Lewerenz (J)

From the Institute of Clinical Neuroimmunology (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), University Hospital, Ludwig-Maximilians-Universität Munich; Biomedical Center (BMC) (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), Medical Faculty, Ludwig-Maximilians-Universität Munich, Martinsried; Graduate School of Systemic Neurosciences Ludwig-Maximilians-Universität Munich (M.B., K.E.); Munich Cluster for Systems Neurology (SyNergy) (E.B., M.K., F.S.T.); Innate Immunity Unit (A.T.), Institut Pasteur, Inserm U1223, Paris, France; Université de Paris (A.T.), Sorbonne Paris Cité, France; Institute of Laboratory Medicine (P.E.), University Hospital, LMU Munich; Institute of Clinical and Molecular Virology (P.S.), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg; and Department of Neurology (J.L.), University Hospital Ulm, Germany.

Tania Kümpfel (T)

From the Institute of Clinical Neuroimmunology (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), University Hospital, Ludwig-Maximilians-Universität Munich; Biomedical Center (BMC) (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), Medical Faculty, Ludwig-Maximilians-Universität Munich, Martinsried; Graduate School of Systemic Neurosciences Ludwig-Maximilians-Universität Munich (M.B., K.E.); Munich Cluster for Systems Neurology (SyNergy) (E.B., M.K., F.S.T.); Innate Immunity Unit (A.T.), Institut Pasteur, Inserm U1223, Paris, France; Université de Paris (A.T.), Sorbonne Paris Cité, France; Institute of Laboratory Medicine (P.E.), University Hospital, LMU Munich; Institute of Clinical and Molecular Virology (P.S.), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg; and Department of Neurology (J.L.), University Hospital Ulm, Germany.

Martin Kerschensteiner (M)

From the Institute of Clinical Neuroimmunology (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), University Hospital, Ludwig-Maximilians-Universität Munich; Biomedical Center (BMC) (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), Medical Faculty, Ludwig-Maximilians-Universität Munich, Martinsried; Graduate School of Systemic Neurosciences Ludwig-Maximilians-Universität Munich (M.B., K.E.); Munich Cluster for Systems Neurology (SyNergy) (E.B., M.K., F.S.T.); Innate Immunity Unit (A.T.), Institut Pasteur, Inserm U1223, Paris, France; Université de Paris (A.T.), Sorbonne Paris Cité, France; Institute of Laboratory Medicine (P.E.), University Hospital, LMU Munich; Institute of Clinical and Molecular Virology (P.S.), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg; and Department of Neurology (J.L.), University Hospital Ulm, Germany.

Edgar Meinl (E)

From the Institute of Clinical Neuroimmunology (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), University Hospital, Ludwig-Maximilians-Universität Munich; Biomedical Center (BMC) (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), Medical Faculty, Ludwig-Maximilians-Universität Munich, Martinsried; Graduate School of Systemic Neurosciences Ludwig-Maximilians-Universität Munich (M.B., K.E.); Munich Cluster for Systems Neurology (SyNergy) (E.B., M.K., F.S.T.); Innate Immunity Unit (A.T.), Institut Pasteur, Inserm U1223, Paris, France; Université de Paris (A.T.), Sorbonne Paris Cité, France; Institute of Laboratory Medicine (P.E.), University Hospital, LMU Munich; Institute of Clinical and Molecular Virology (P.S.), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg; and Department of Neurology (J.L.), University Hospital Ulm, Germany.
ORCID: 0000-0002-2570-6785

Franziska S Thaler (FS)

From the Institute of Clinical Neuroimmunology (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), University Hospital, Ludwig-Maximilians-Universität Munich; Biomedical Center (BMC) (M.B., K.E., E.B., S.W., S.M., A.T., A.F.-H., T.K., M.K., E.M., F.S.T.), Medical Faculty, Ludwig-Maximilians-Universität Munich, Martinsried; Graduate School of Systemic Neurosciences Ludwig-Maximilians-Universität Munich (M.B., K.E.); Munich Cluster for Systems Neurology (SyNergy) (E.B., M.K., F.S.T.); Innate Immunity Unit (A.T.), Institut Pasteur, Inserm U1223, Paris, France; Université de Paris (A.T.), Sorbonne Paris Cité, France; Institute of Laboratory Medicine (P.E.), University Hospital, LMU Munich; Institute of Clinical and Molecular Virology (P.S.), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg; and Department of Neurology (J.L.), University Hospital Ulm, Germany. franziska.thaler@med.uni-muenchen.de.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Antibodies Against Glutamic Acid Decarboxylase...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Autoanticorps › Antibodies Against Glutamic Acid Decarboxylase...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Lyases › Carbon-carbon lyases › Carboxy-lyases › Glutamate decarboxylase › Antibodies Against Glutamic Acid Decarboxylase...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Anticorps monoclonaux › Antibodies Against Glutamic Acid Decarboxylase...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Maladie › Syndrome › Antibodies Against Glutamic Acid Decarboxylase...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Isotypes des immunoglobulines › Immunoglobuline G › Antibodies Against Glutamic Acid Decarboxylase...