Exploration of therapeutic targets which are involved in the pathogenesis of Sjogren's syndrome aiming at ion channels.

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09905
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Keio University
• Principal Investigator: Yoshimoto Keiko 慶應義塾大学, 医学部(信濃町), 研究員 (20383292)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: シェーグレン症候群 / BAFF / BAFF受容体 / イオンチャンネル

Outline of Final Research Achievements

BAFF and its receptor (BR3) are involved in the pathogenesis of Sjogren’s syndrome (SS). We demonstrated that the expression levels of BR3 and a voltage-gated sodium channel in SS monocytes were significantly higher than those of healthy controls and that elevation was correlated with serum IgG level of the patients. In addition, we have successfully discovered a low molecular weight compound which has inhibitory activities against both BAFF signaling pathways and a sodium channel. In this study, we tested the effects of this compound on production of autoantibodies and inflammatory cytokines by using autoimmune model mice. As a results, we found that this compound inhibited production of anti-dsDNA antibody and inflammatory cytokines, such as IL-6 and IL-10. Moreover, this compound also suppressed infiltration of B cells into the organs, such as lachrymal glands and kidney. Notably, we have found a novel compound which is expected more efficacy on the suppression of B cell function.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

本研究は免疫難病であるシェーグレン症候群（SS）の患者単球の異常活性化機構と病態への関与を明らかにするものである。具体的には患者末梢血単球で発現が亢進しているイオンチャンネル同定し、これを介したシグナルとBAFFシグナルの関与を明らかにした。さらに研究代表者らはこの機構を阻害する作用を有する独自の化合物を得て、SSモデル動物での薬効薬理試験を実施し、有効性を検証することに成功した。本研究はSSの発症メカニズムを明らかにするという点で学術的に有意義であるばかりでなく、きわめて独創性の高い治療標的を見出すことにつながり、SSの新規な治療法の開発という点においても有用である。