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神経科学学会-神経学会合同シンポジウム:Neuroimmunology Cutting Edge Symposium: Mechanisms of Immune-mediated Neurological Disease
Joint Symposium of the Japan Neuroscience Society and the Japanese Society of Neurology:Neuroimmunology Cutting Edge Symposium:
Mechanisms of Immune-mediated Neurological Disease

開催日 2014/9/13
時間 9:00 - 11:00
会場 Room A(Main Hall)
Chairperson(s) 吉良 潤一 / Jun-ichi Kira (九州大学大学院医学系研究院 神経内科学 / Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Japan)
神田 隆 / Takashi Kanda (山口大学大学院医学系研究科神経内科学 / Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Japan)

Immue-mediated channelopathy in neuroimmunological diseases

  • S3-A-1-3
  • 渡邊 修 / Osamu Watanabe:1 
  • 1:鹿児島大学大学院医歯学総合研究科 / Depat Neurol, Univ of Kagoshima, Kagoshima, Japan 

Isaacs' syndrome is an antibody-mediated potassium channel disorder. Clinical symptoms of Isaacs' syndrome are characterized by muscle cramp, slow relaxation following muscle contraction, and hyperhidrosis. Hyperexcitability of the peripheral nerve cause these symptoms, which are relieved by administration of Na channel blockers and immunotherapy.
The target channel proteins are voltage-gated potassium channels (VGKCs). The suppression of voltage-gated outward K+current by antibodies induces hyperexcitability of the peripheral nerve. Electrophysiological findings show that antibodies may not directly block the kinetics of VGKCs, but may decrease channel density. From the electrophysiological, pharmacologic and immunologic view points, the site of origin of spontaneous discharges is located principally in the distal portion of the motor nerve.
VGKC antibodies are also detected in Morvan syndrome (severe insomnia with neuromyotonia and various autonomic disorders) and in a form of autoimmune limbic encephalitis. Recent studies indicated that the VGKC antibodies are mainly directed toward associated proteins (for example LGI-1, CASPR-2) that complex with VGKCs themselves. The VGKC antibodies are now usually known as VGKC-complex antibodies. In general, LGI-1 antibodies are most common in limbic encephalitis with SIADH. CASPR-2 antibodies are present in the majority of patients with Morvan syndrome.
Here, we systematically identified and quantified autoantibodies in patient sera with VGKC-complex antibody associated encephalitis and showed the relationship between individual antibodies and patient's symptoms. Furthermore, we revealed how autoantibodies disrupt the physiological functions of target proteins. LGI-1 autoantibodies neutralize the interaction between LGI-1 and ADAM22, reducing the synaptic AMPA receptors; GABAA receptor autoantibodies cause a selective decrease in GABAA receptor surface density and synaptic localization, probably by enhancing the receptor internalization.

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