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Journal of Immunology Research
Volume 2017 (2017), Article ID 2913297, 12 pages
https://doi.org/10.1155/2017/2913297
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.

Linked References

  1. M. Manto, J. M. Bower, A. B. Conforto et al., “Consensus paper: roles of the cerebellum in motor control-the diversity of ideas on cerebellar involvement in movement,” Cerebellum, vol. 11, no. 2, pp. 457–487, 2012. View at Publisher · View at Google Scholar · View at Scopus
  2. H. Mitoma, K. Adhikari, D. Aeschlimann et al., “Consensus paper: neuroimmune mechanisms of cerebellar ataxias,” Cerebellum, vol. 15, no. 2, pp. 213–232, 2016. View at Publisher · View at Google Scholar · View at Scopus
  3. H. Mitoma, M. Hadjivassiliou, and J. Honnorat, “Guidelines for treatment of immune-mediated cerebellar ataxias,” Cerebellum & Ataxias, vol. 2, no. 1, 2015. View at Publisher · View at Google Scholar
  4. M. Hadjivassiliou, S. Boscolo, E. Tongiorgi et al., “Cerebellar ataxia as a possible organ-specific autoimmune disease,” Movement Disorders, vol. 23, no. 10, pp. 1370–1377, 2008. View at Publisher · View at Google Scholar · View at Scopus
  5. I. Rouco, P. Hurtado, L. Castaño, and J. J. Zarranz, “Experience with immunotherapy in 3 patients with cerebellar ataxia associated with anti-glutamic acid decarboxylase antibodies,” Neurologia, vol. 30, no. 4, pp. 247–249, 2015. View at Publisher · View at Google Scholar · View at Scopus
  6. H. Mitoma and M. Manto, “The physiological basis of therapies for cerebellar ataxias,” Therapeutic Advances in Neurological Disorders, vol. 9, no. 5, pp. 396–413, 2016. View at Publisher · View at Google Scholar · View at Scopus
  7. M. Manto, J. Honnorat, C. S. Hampe et al., “Disease-specific monoclonal antibodies targeting glutamate decarboxylase impair GABAergic neurotransmission and affect motor learning and behavioral functions,” Frontiers in Behavioral Neuroscience, vol. 9, article 78, 2015. View at Publisher · View at Google Scholar · View at Scopus
  8. E. Lancaster and J. Dalmau, “Neuronal autoantigens-pathogenesis, associated disorders and antibody testing,” Nature Reviews Neurology, vol. 8, no. 7, pp. 380–390, 2012. View at Publisher · View at Google Scholar · View at Scopus
  9. M. Abele, M. Weller, S. Mescheriakov, K. Bürk, J. Dichgans, and T. Klockgether, “Cerebellar ataxia with glutamic acid decarboxylase autoantibodies,” Neurology, vol. 52, no. 4, pp. 857–859, 1999. View at Publisher · View at Google Scholar · View at Scopus
  10. A. Saiz, J. Arpa, A. Sagasta et al., “Autoantibodies to glutamic acid decarboxylase in three patients with cerebellar ataxia, late-onset insulin-dependent diabetes mellitus, and polyendocrine autoimmunity,” Neurology, vol. 49, no. 4, pp. 1026–1030, 1997. View at Publisher · View at Google Scholar · View at Scopus
  11. J. Honnorat, A. Saiz, B. Giometto et al., “Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients,” Archives of Neurology, vol. 58, no. 2, pp. 225–230, 2001. View at Publisher · View at Google Scholar · View at Scopus
  12. H. Iwasaki, R. Sato, M. Shichiri, and Y. Hirata, “A patient with type 1 diabetes mellitus and cerebellar ataxia associated with high titer of circulating anti-glutamic acid decarboxylase antibodies,” Endocrine Journal, vol. 48, no. 2, pp. 261–268, 2001. View at Publisher · View at Google Scholar · View at Scopus
  13. C. Bayreuther, S. Hieronimus, P. Ferrari, P. Thomas, and C. Lebrun, “Auto-immune cerebellar ataxia with anti-GAD antibodies accompanied by de novo late-onset type 1 diabetes mellitus,” Diabetes and Metabolism, vol. 34, no. 4, pp. 386–388, 2008. View at Publisher · View at Google Scholar · View at Scopus
  14. M.-F. Kong, G. Glibert, F. Baleanu, and R. Karmali, “Progressive cerebellar ataxia and new-onset diabetes,” The Lancet, vol. 383, no. 9912, p. 186, 2014. View at Publisher · View at Google Scholar · View at Scopus
  15. V. Planche, A. Marques, M. Ulla, M. Ruivard, and F. Durif, “Intravenous immunoglobulin and rituximab for cerebellar ataxia with glutamic acid decarboxylase autoantibodies,” Cerebellum, vol. 13, no. 3, pp. 318–322, 2014. View at Publisher · View at Google Scholar · View at Scopus
  16. H. Ariño, N. Gresa-Arribas, Y. Blanco et al., “Cerebellar ataxia and glutamic acid decarboxylase antibodies: immunologic profile and long-term effect of immunotherapy,” JAMA Neurology, vol. 71, no. 8, pp. 1009–1016, 2014. View at Publisher · View at Google Scholar · View at Scopus
  17. V. Nociti, G. Frisullo, T. Tartaglione et al., “Refractory generalized seizures and cerebellar ataxia associated with anti-GAD antibodies responsive to immunosuppressive treatment,” European Journal of Neurology, vol. 17, no. 1, p. e5, 2010. View at Publisher · View at Google Scholar · View at Scopus
  18. H. Ariño, R. Höftberger, N. Gresa-Arribas et al., “Paraneoplastic neurological syndromes and glutamic acid decarboxylase antibodies,” JAMA Neurology, vol. 72, no. 8, pp. 874–881, 2015. View at Publisher · View at Google Scholar · View at Scopus
  19. R. Raju, J. Foote, J. P. Banga et al., “Analysis of GAD65 autoantibodies in Stiff-Person syndrome patients,” Journal of Immunology, vol. 175, no. 11, pp. 7755–7762, 2005. View at Publisher · View at Google Scholar · View at Scopus
  20. A. Reetz, M. Solimena, M. Matteoli, F. Folli, K. Takei, and P. De Camilli, “GABA and pancreatic β-cells: colocalization of glutamic acid decarboxylase (GAD) and GABA with synaptic-like microvesicles suggests their role in GABA storage and secretion,” EMBO Journal, vol. 10, no. 5, pp. 1275–1284, 1991. View at Google Scholar · View at Scopus
  21. S. Christgau, H.-J. Annstoot, H. Schierbeck et al., “Membrane anchoring of the autoantigen GAD65 to microvesicles in pancreatic β-cells by palmitoylation in the NH2-terminal domain,” The Journal of Cell Biology, vol. 118, no. 2, pp. 309–320, 1992. View at Publisher · View at Google Scholar · View at Scopus
  22. J. Kanaani, M. J. Diacovo, El-Husseini Ael-D et al., “Palmitoylation controls trafficking of GAD65 from Golgi membranes to axon-specific endosomes and a Rab5a-dependent pathway to presynaptic clusters,” Journal of Cell Science, vol. 117, part 10, pp. 2001–2013, 2004. View at Publisher · View at Google Scholar
  23. T. Ishikawa, S. Kakei, and H. Mitoma, “Overlooked Holmes’ clinical signs: reevaluation by recent physiological findings,” Cerebellum & Ataxias, vol. 2, article 13, 2015. View at Publisher · View at Google Scholar
  24. T. Ishikawa, S. Tomatsu, Y. Tsunoda, J. Lee, D. S. Hoffman, and S. Kakei, “Releasing dentate nucleus cells from Purkinje cell inhibition generates output from the cerebrocerebellum,” PLoS ONE, vol. 9, no. 10, Article ID e108774, 2014. View at Publisher · View at Google Scholar · View at Scopus
  25. M.-U. Manto, M.-A. Laute, M. Aguera, V. Rogemond, M. Pandolfo, and J. Honnorat, “Effects of anti-glutamic acid decarboxylase antibodies associated with neurological diseases,” Annals of Neurology, vol. 61, no. 6, pp. 544–551, 2007. View at Publisher · View at Google Scholar · View at Scopus
  26. M. U. Manto, C. S. Hampe, V. Rogemond, and J. Honnorat, “Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia,” Orphanet Journal of Rare Diseases, vol. 6, no. 3, 2011. View at Publisher · View at Google Scholar · View at Scopus
  27. N. Ouland Ben Taib, M. Manto, M. Pandolfo, and J. Brotchi, “Hemicerebellectomy blocks the enhancement of cortical motor output associated with repetitive somatosensory stimulation in the rat,” Journal of Physiology, vol. 567, no. 1, pp. 293–300, 2005. View at Publisher · View at Google Scholar · View at Scopus
  28. E. Ciani, M. Virgili, and A. Contestabile, “Akt pathway mediates a cGMP-dependent survival role of nitric oxide in cerebellar granule neurones,” Journal of Neurochemistry, vol. 81, no. 2, pp. 218–228, 2002. View at Publisher · View at Google Scholar · View at Scopus
  29. S. M. Sequeira, J. O. Malva, A. P. Carvalho, and C. M. Carvalho, “Presynaptic N-methyl-D-aspartate receptor activation inhibits neurotransmitter release through nitric oxide formation in rat hippocampal nerve terminals,” Molecular Brain Research, vol. 89, no. 1-2, pp. 111–118, 2001. View at Publisher · View at Google Scholar · View at Scopus
  30. K. Ishida, H. Mitoma, S.-Y. Song et al., “Selective suppression of cerebellar GABAergic transmission by an autoantibody to glutamic acid decarboxylase,” Annals of Neurology, vol. 46, no. 2, pp. 263–267, 1999. View at Publisher · View at Google Scholar · View at Scopus
  31. H. Mitoma, S.-Y. Song, K. Ishida, T. Yamakuni, T. Kobayashi, and H. Mizusawa, “Presynaptic impairment of cerebellar inhibitory synapses by an autoantibody to glutamate decarboxylase,” Journal of the Neurological Sciences, vol. 175, no. 1, pp. 40–44, 2000. View at Publisher · View at Google Scholar · View at Scopus
  32. H. Takenoshita, M. Shizuka-Ikeda, H. Mitoma et al., “Presynaptic inhibition of cerebellar GABAergic transmission by glutamate decarboxylase autoantibodies in progressive cerebellar ataxia,” Journal of Neurology Neurosurgery and Psychiatry, vol. 70, no. 3, pp. 386–389, 2001. View at Publisher · View at Google Scholar · View at Scopus
  33. H. Mitoma, K. Ishida, M. Shizuka-Ikeda, and H. Mizusawa, “Dual impairment of GABAA- and GABAB-receptor-mediated synaptic responses by autoantibodies to glutamic acid decarboxylase,” Journal of the Neurological Sciences, vol. 208, no. 1-2, pp. 51–56, 2003. View at Publisher · View at Google Scholar · View at Scopus
  34. K. Ishida, H. Mitoma, and H. Mizusawa, “Reversibility of cerebellar GABAergic synapse impairment induced by anti-glutamic acid decarboxylase autoantibodies,” Journal of the Neurological Sciences, vol. 271, no. 1-2, pp. 186–190, 2008. View at Publisher · View at Google Scholar · View at Scopus
  35. C. S. Hampe, L. Petrosini, P. De Bartolo et al., “Monoclonal antibodies to 65kDa glutamate decarboxylase induce epitope specific effects on motor and cognitive functions in rats,” Orphanet Journal of Rare Diseases, vol. 8, article 82, 2013. View at Publisher · View at Google Scholar · View at Scopus
  36. M. Solimena and P. De Camilli, “Autoimmunity to glutamic acid decarboxylase (GAD) in stiffman syndrome and insulin-dependent diabetes mellitus,” Trends in Neurosciences, vol. 14, no. 10, pp. 452–457, 1991. View at Publisher · View at Google Scholar · View at Scopus
  37. S. Baekkeskov, H. J. Aanstoot, S. Christgau et al., “Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase,” Nature, vol. 340, no. 6289, pp. 151–156, 1990. View at Google Scholar
  38. J. Kim, M. Namchuk, T. Bugawan et al., “Higher autoantibody levels and recognition of a linear NH2-terminal epitope in the autoantigen GAD65, distinguish Stiff-Man syndrome from insulin-dependent diabetes mellitus,” The Journal of Experimental Medicine, vol. 180, no. 2, pp. 595–606, 1994. View at Publisher · View at Google Scholar · View at Scopus
  39. E. Bjork, L. A. Velloso, O. Kampe, and F. A. Karlsson, “GAD autoantibodies in IDDM, stiff-man syndrome, and autoimmune polyendocrine syndrome type I recognize different epitopes,” Diabetes, vol. 43, no. 1, pp. 161–165, 1994. View at Publisher · View at Google Scholar · View at Scopus
  40. K. Daw, N. Ujihara, M. Atkinson, and A. C. Powers, “Glutamic acid decarboxylase autoantibodies in stiff-man syndrome and insulin-dependent diabetes mellitus exhibit similarities and differences in epitope recognition,” Journal of Immunology, vol. 156, no. 2, pp. 818–825, 1996. View at Google Scholar · View at Scopus
  41. K. Dinkel, H.-M. Meinck, K. M. Jury, W. Karges, and W. Richter, “Inhibition of γ-aminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff-man syndrome,” Annals of Neurology, vol. 44, no. 2, pp. 194–201, 1998. View at Publisher · View at Google Scholar · View at Scopus
  42. M. H. Butler, M. Solimena, R. Dirkx Jr., A. Hayday, and P. De Camilli, “Identification of a dominant epitope of glutamic acid decarboxylase (GAD-65) recognized by autoantibodies in Stiff-Man syndrome,” Journal of Experimental Medicine, vol. 178, no. 6, pp. 2097–2106, 1993. View at Publisher · View at Google Scholar · View at Scopus
  43. C. J. Padoa, J. P. Banga, A.-M. Madec et al., “Recombinant Fabs of human monoclonal antibodies specific to the middle epitope of GAD65 inhibit type 1 diabetes-specific GAD65Abs,” Diabetes, vol. 52, no. 11, pp. 2689–2695, 2003. View at Publisher · View at Google Scholar · View at Scopus
  44. G. Fenalti, C. S. Hampe, Y. Arafat et al., “COOH-terminal clustering of autoantibody and T-cell determinants on the structure of GAD65 provide insights into the molecular basis of autoreactivity,” Diabetes, vol. 57, no. 5, pp. 1293–1301, 2008. View at Publisher · View at Google Scholar · View at Scopus
  45. N. Gresa-Arribas, H. Ariño, E. Martínez-Hernández et al., “Antibodies to inhibitory synaptic proteins in neurological syndromes associated with glutamic acid decarboxylase autoimmunity,” PLOS ONE, vol. 10, no. 3, Article ID e0121364, 2015. View at Publisher · View at Google Scholar · View at Scopus
  46. K. E. Hill, S. A. Clawson, J. W. Rose, N. G. Carlson, and J. E. Greenlee, “Cerebellar Purkinje cells incorporate immunoglobulins and immunotoxins in vitro: implications for human neurological disease and immunotherapeutics,” Journal of Neuroinflammation, vol. 6, no. 31, 2009. View at Publisher · View at Google Scholar · View at Scopus
  47. L. F. Borges and N. A. Busis, “Intraneuronal accumulation of myeloma proteins,” Archives of Neurology, vol. 42, no. 7, pp. 690–694, 1985. View at Publisher · View at Google Scholar · View at Scopus
  48. R. H. Fabian and T. C. Ritchie, “Intraneuronal IgG in the central nervous system,” Journal of the Neurological Sciences, vol. 73, no. 3, pp. 257–267, 1986. View at Publisher · View at Google Scholar · View at Scopus
  49. P. S. Fishman, D. A. Farrand, and D. A. Kristt, “Internalization of plasma proteins by cerebellar Purkinje cells,” Journal of the Neurological Sciences, vol. 100, no. 1-2, pp. 43–49, 1990. View at Publisher · View at Google Scholar · View at Scopus
  50. F. Graus, I. Illa, M. Agusti, T. Ribalta, F. Cruz-Sanchez, and C. Juarez, “Effect of intraventricular injection of an anti-Purkinje cell antibody (anti-Yo) in a guinea pig model,” Journal of the Neurological Sciences, vol. 106, no. 1, pp. 82–87, 1991. View at Publisher · View at Google Scholar · View at Scopus
  51. J. E. Greenlee, J. B. Burns, J. W. Rose, K. A. Jaeckle, and S. Clawson, “Uptake of systemically administered human anticerebellar antibody by rat Purkinje cells following blood-brain barrier disruption,” Acta Neuropathologica, vol. 89, no. 4, pp. 341–345, 1995. View at Publisher · View at Google Scholar · View at Scopus
  52. G. Vega-Flores, S. E. Rubio, M. T. Jurado-Parras et al., “The GABAergic septohippocampal pathway is directly involved in internal processes related to operant reward learning,” Cerebral Cortex, vol. 24, no. 8, pp. 2093–2107, 2014. View at Publisher · View at Google Scholar · View at Scopus
  53. C. Geis, A. Weishaupt, S. Hallermann et al., “Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition,” Brain, vol. 133, no. 11, pp. 3166–3180, 2010. View at Publisher · View at Google Scholar · View at Scopus
  54. P. Fouka, H. Alexopoulos, S. Akrivou, O. Trohatou, P. K. Politis, and M. C. Dalakas, “GAD65 epitope mapping and search for novel autoantibodies in GAD-associated neurological disorders,” Journal of Neuroimmunology, vol. 281, pp. 73–77, 2015. View at Publisher · View at Google Scholar · View at Scopus
  55. K. A. Binder, J. P. Banga, A.-M. Madec, E. Ortqvist, D. Luo, and C. S. Hampe, “Epitope analysis of GAD65Ab using fusion proteins and rFab,” Journal of Immunological Methods, vol. 295, no. 1-2, pp. 101–109, 2004. View at Publisher · View at Google Scholar · View at Scopus
  56. M. Vianello, G. Bisson, M. D. Maschio et al., “Increased spontaneous activity of a network of hippocampal neurons in culture caused by suppression of inhibitory potentials mediated by anti-gad antibodies,” Autoimmunity, vol. 41, no. 1, pp. 66–73, 2008. View at Publisher · View at Google Scholar · View at Scopus
  57. K. Ishida, H. Mitoma, Y. Wada et al., “Selective loss of Purkinje cells in a patient with anti-glutamic acid decarboxylase antibody-associated cerebellar ataxia,” Journal of Neurology, Neurosurgery & Psychiatry, vol. 78, no. 2, pp. 190–192, 2007. View at Publisher · View at Google Scholar · View at Scopus
  58. G. Piccolo, E. Tavazzi, T. Cavallaro, A. Romani, R. Scelsi, and G. Martino, “Clinico-pathological findings in a patient with progressive cerebellar ataxia, autoimmune polyendocrine syndrome, hepatocellular carcinoma and anti-GAD autoantibodies,” Journal of the Neurological Sciences, vol. 290, no. 1-2, pp. 148–149, 2010. View at Publisher · View at Google Scholar · View at Scopus
  59. W.-K. Kim and K. H. Ko, “Potentiation of N-methyl-D-aspartate-mediated neurotoxicity by immunostimulated murine microglia,” Journal of Neuroscience Research, vol. 54, no. 1, pp. 17–26, 1998. View at Publisher · View at Google Scholar · View at Scopus
  60. D. G. Fujikawa, “The role of excitotoxic programmed necrosis in acute brain injury,” Computational and Structural Biotechnology Journal, vol. 13, pp. 212–221, 2015. View at Publisher · View at Google Scholar · View at Scopus
  61. G. E. Hardingham and H. Bading, “Coupling of extrasynaptic NMDA receptors to a CREB shut-off pathway is developmentally regulated,” Biochimica et Biophysica Acta—Proteins and Proteomics, vol. 1600, no. 1-2, pp. 148–153, 2002. View at Publisher · View at Google Scholar · View at Scopus
  62. D. Watanabe, H. Inokawa, K. Hashimoto et al., “Ablation of cerebellar Golgi cells disrupts synaptic integration involving GABA inhibition and NMDA receptor activation in motor coordination,” Cell, vol. 95, no. 1, pp. 17–27, 1998. View at Publisher · View at Google Scholar · View at Scopus
  63. W. T. Wong, M. Wang, and W. Li, “Regulation of microglia by ionotropic glutamatergic and GABAergic neurotransmission,” Neuron Glia Biology, vol. 7, no. 1, pp. 41–46, 2012. View at Publisher · View at Google Scholar · View at Scopus
  64. A. Suzumura, “Neuron-microglia interaction in neuroinflammation,” Current Protein and Peptide Science, vol. 14, no. 1, pp. 16–20, 2013. View at Publisher · View at Google Scholar · View at Scopus
  65. G. Mandolesi, A. Musella, A. Gentile et al., “Interleukin-1β alters glutamate transmission at Purkinje cell synapses in a mouse model of multiple sclerosis,” Journal of Neuroscience, vol. 33, no. 29, pp. 12105–12121, 2013. View at Publisher · View at Google Scholar · View at Scopus
  66. G. Olmos and J. Lladó, “Tumor necrosis factor alpha: a link between neuroinflammation and excitotoxicity,” Mediators of Inflammation, vol. 2014, Article ID 861231, 12 pages, 2014. View at Publisher · View at Google Scholar · View at Scopus
  67. J. E. Yuste, E. Tarragon, C. M. Campuzano, and F. Ros-Bernal, “Implications of glial nitric oxide in neurodegenerative diseases,” Frontiers in Cellular Neuroscience, vol. 9, article 322, 2015. View at Publisher · View at Google Scholar · View at Scopus
  68. C. M. Anderson and R. A. Swanson, “Astrocyte glutamate transport: review of properties, regulation, and physiological functions,” Glia, vol. 32, no. 1, pp. 1–14, 2000. View at Publisher · View at Google Scholar · View at Scopus
  69. M. Manto, J. Dalmau, A. Didelot, V. Rogemond, and J. Honnorat, “In vivo effects of antibodies from patients with anti-NMDA receptor encephalitis: further evidence of synaptic glutamatergic dysfunction,” Orphanet Journal of Rare Diseases, vol. 5, no. 1, article 31, 2010. View at Publisher · View at Google Scholar · View at Scopus
  70. A. Massie, S. Boillėe, S. Hewett, L. Knackstedt, and J. Lewerenz, “Main path and byways: non-vesicular glutamate release by system xc- as an important modifier glutamatergic neurotransmission,” Journal of Neurochemistry, vol. 135, no. 6, pp. 1062–1079, 2015. View at Publisher · View at Google Scholar