抗原特異調節性T細胞によるHLA関連自己免疫に対する支配的保護
Joshua D Ooi1, Jan Petersen2,3, Yu H Tan2
1Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria 3168, Australia.
Nature
|May 4, 2017
まとめ
ヒト白血球抗原 (HLA) アレルは自己免疫疾患のリスクに影響します. この研究は,HLA-DR15やHLA-DR1のような特定のHLAアレルが,自己耐性や自己免疫疾患の発達に影響を及ぼすT細胞のバランスを決定する方法を明らかにしています.
科学分野:
- 免疫学
- 遺伝学
- 自己免疫性
背景:
- ヒト白血球抗原 (HLA) の特定のアレルは,I型糖尿病,多発性硬化症,グッドパストゥール病などの自己免疫疾患に対する感受性および保護に関連しています.
- HLAアレルが自己耐性および自己免疫疾患の発症に影響を与える正確な分子メカニズムは,まだ完全に理解されていません.
- Goodpasture病は,自己免疫性腎疾患であり,HLAアレルに関連しており,IV型コラーゲン (α3135-145) の特定のエピトープに対するT細胞反応によって特徴付けられています.
研究 の 目的:
- グッドパストゥール病の文脈で自己耐性に対するHLA媒介効果の基礎となる分子機構を解明する.
- α3135-145エピトープに対するT細胞反応の形成におけるHLA-DR15 (リスクアレル) とHLA-DR1 (保護アレル) の差異的な役割を調査する.
- 高リスクのHLA-DR15アレルを持つ個体におけるHLA-DR1の保護効果のメカニズム的説明を提供すること.
主な方法:
- α3135-145エピトープで免疫されたHLA-DR15変異性マウスモデルを使用して,疾患発症とT細胞浸透を研究した.
- HLA-DR15とHLA-DR1のペプチドレパートリーと結合傾向を分析した.
- テトラマー染色,細胞内サイトカイン分析,転写因子の評価 (例えば,Foxp3) を用いてT細胞フェノタイプ (Tconv vs. Treg) をマウスモデルとヒトドナーの両方で特徴づけました.
主要な成果:
- Goodpasture病の患者およびHLA- DR15変異性マウスの誘発性疾患で自己反応性α3135-145特異性T細胞が拡張した.
- HLA-DR15はα3135-145エピトープを従来型のT細胞 (Tconv) に与え,炎症性サイトカインを分泌し,HLA-DR1が誘導した調節性T細胞 (Treg) は,許容性サイトカインを分泌した.
- HLA-DR1誘発のTreg細胞は,HLA-DR15とHLA-DR1の両方のアレルを持つマウスの病気に対する保護を与え,HLA-DR1を有する健康な個体は,支配的なTregフェノタイプを示した.
結論:
- HLAポリモルフィズムは,炎症を誘発するTconv細胞と自己エピトープに特異的な許容性Treg細胞のバランスを決定することによって,免疫反応を決定的に形作ります.
- HLA- DR1の保護効果は,自己反応反応を抑制するTreg細胞を誘導する能力によって媒介され,それによって自己免疫を予防または緩和します.
- この研究は,自己エピトープ特異のT細胞の生成と機能を調節することによって,HLAアレルが自己免疫疾患における感受性と保護にどのように影響するかについてのメカニズム的枠組みを提供します.
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