Table of Contents Author Guidelines Submit a Manuscript
Journal of Immunology Research
Volume 2017 (2017), Article ID 2913297, 12 pages
Review Article

Pathogenic Roles of Glutamic Acid Decarboxylase 65 Autoantibodies in Cerebellar Ataxias

1Medical Education Promotion Center, Tokyo Medical University, Tokyo, Japan
2Unité d’Etude du Mouvement (UEM), GRIM, FNRS, ULB Erasme, 1070 Bruxelles, Belgium
3School of Medicine, University of Washington, Seattle, WA 98109, USA

Correspondence should be addressed to Hiroshi Mitoma

Received 22 September 2016; Revised 5 December 2016; Accepted 10 January 2017; Published 12 March 2017

Academic Editor: Alessandra Santos

Copyright © 2017 Hiroshi Mitoma et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Reports suggesting a pathogenic role of autoantibodies directed against glutamic acid decarboxylase 65 (GAD65Abs) in cerebellar ataxias (CAs) are reviewed, and debatable issues such as internalization of antibodies by neurons and roles of epitopes are discussed. GAD65 is one of two enzymes that catalyze the conversion of glutamate to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). A pathogenic role of GAD65Ab in CAs is suggested by in vivo and in vitro studies. (1) Intracerebellar administration of cerebrospinal fluid (CSF) immunoglobulins (IgGs) obtained from GAD65Ab-positive CA patients impairs cerebellar modulation of motor control in rats. (2) CSF IgGs act on terminals of GABAergic neurons and decrease the release of GABA in cerebellar slices from rats and mice. (3) Absorption of GAD65Ab by recombinant GAD65 diminishes the above effects, and monoclonal human GAD65Ab (b78) mimic the effects of CSF IgGs in vivo and in vitro. Studies using GAD65-KO mice confirm that the target molecule is GAD65. (4) Notably, the effects of GAD65Ab depend on the epitope specificity of the monoclonal GAD65Ab. Taken together, these results indicate that epitope-specific GAD65Ab-induced impairment of GABA release is involved in the pathogenesis of GAD65Ab-positive CA and support the early detection of GAD65Ab-associated CA to initiate immunotherapy before irreversible neuronal death in the cerebellum.