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アトピー性皮膚炎の病態形成におけるORAI1を介したCa2+シグナルの寄与

安藝, 杏梨 筑波大学 DOI:10.15068/0002000805

2021.07.29

概要

アトピー性皮膚炎(AD)は増悪と軽快を繰り返す皮膚湿疹と強い痒みを特徴とする慢性的な皮膚炎で、小児においては 15-30%、成人においても 2-10%と高い有病率となっている(1)。重症の AD 患者では、絶え間ない痒みと容姿など見かけ上の問題により、不眠やうつ症状など不安障害が引き起こされるケースがあり生活の質の低下につながっている。軽症から中等度の AD 患者においては塗布のコルチコステロイド剤やタクロリムス、保湿剤などが主に処方される(2)。中等度から重症の AD 患者においては IL-4Ra の阻害抗体であるデュピルマブの皮下注射やカルシニューリン阻害剤であるシクロスポリン A といった強力な免疫抑制剤などの内服といった全身的な治療が行われる(3)。

AD では皮膚バリアの機能低下に引き続き、ダニ抗原などのアレルゲンへの過剰な免疫応答がその病態を形成している(4)。その中でも T 細胞は AD の病態形成に中心的な役割を担っていることが明らかとなっている(5)。AD の急性期には IL-4、IL-13 などのサイトカインを産生する T 細胞サブセットである Th2が、また慢性期には IFN-γ を産生する Th1 が重要な役割を果たしていると考えられてきた。近年はさらに IL-17 を産生する Th17 や IL-22 を産生する Th22 も好中球の遊走や血管増殖の作用を通じて AD の病態形成に寄与していることが明らかとなった(図 1)(6, 7)。サイクロスポリン A は上述の複数の T 細胞サブセットの活性化を抑制し、AD に強力な治療効果をもたらすが、一方、腎毒性などの副作用の懸念から注意深い使用が求められている。副作用発現のリスクを下げるため、間欠的な投与や定期的な血中濃度の測定を実施する必要があ り、今後 AD の治療においては有効でより安全な医薬品が求められている(8, 9)。

Nuclear factor activated by T cells(NFAT)は T 細胞からの炎症性サイトカインの発現を制御している(10-13)。T 細胞受容体(TCR)の刺激を受けた T 細胞では、CRAC(calcium released-activated calcium)チャネルを介してストア作動性のカルシウム流入が細胞外より引き起こされる(図 2)(14)。細胞外からのカルシウム流入はシクロスポリン A などの標的であるカルシニューリンを活性化 し、NFAT を脱リン酸化によって活性化させる(15)。また CRAC チャネルからのカルシウムの流入はマスト細胞の抗原刺激による脱顆粒にも重要な役割を担っている(16)。CRAC チャネルを形成するポア形成サブユニットには ORAI1、 ORAI2、ORAI3 のサブファミリーが知られているが、ORAI1 は免疫細胞における CRAC チャネルの主要なポア形成サブユニットである(17, 18)。ORAI1 のミスセンス変異のヒトでは、重篤な T 細胞の機能不全を呈し、重症複合免疫不全となることが知られているが、カルシニューリン阻害剤の使用によって問題となっている腎臓の機能への影響は認められていない(19)。

またマウスの Orai1 ノックアウトにおいては、T 細胞のサイトカイン産生能とマスト細胞の活性化の機能が著しく低下することが知られている(20, 21)。マウスにおいて Orai1 は主に免疫細胞、Orai2 は主に脳、肺、脾臓、小腸、Orai3は幅広い臓器で発現が認められている(22, 23)。それゆえ ORAI1 特異的な阻害は T 細胞の寄与が大きい AD や免疫関連疾患に他の組織への副作用が少ない有効なメカニズムの可能性がある。これまで ORAI1 を標的としたノックダウンにより各種細胞等への評価を行った報告等は存在するが、ORAI1 はその他の ORAI1 ファミリーと 4 量体ないし 6 量体のヘテロマーを形成することが知られており(24)、ORAI1 の変異によりドミナントネガティブ的にその他の ORAI ファミリーの機能も抑制していると考えられている(25)。また低分子 CRAC チャネル阻害での作用評価においても、多くの CRAC チャネル阻害においてその他のCa2+チャネルに作用することが知られており、ORAI1 特異性は低い(26)。

そこで本研究では、AD の病態への ORAI1 の寄与するメカニズムの解析を目的に、ORAI1 特異的な抗体を取得し、AD の病態の中心を担う T 細胞およびマスト細胞への作用や、AD の病態を反映したマウスモデルへの ORAI1 の作用を評価した。

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参考文献

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