ゲルミナルセンターの抗体変異軌道は,自己/外来性の急速な差別によって決定される

Deborah L Burnett^1,2, David B Langley¹, Peter Schofield^1,2

¹Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia.

Science (New York, N.Y.)

|April 14, 2018

まとめ

研究者たちは,免疫システムが外来の侵入者と体内の細胞を区別する方法を発見しました. 最初抑制された自己反応性B細胞は,外来抗原によって活性化され,効果的な防御のために抗体の精製につながります.

科学分野:

免疫学
分子生物学
構造生物学

背景:

抗体は外来抗原と自己抗原を区別するのに不可欠ですが,特異性獲得のメカニズムは不明です.
自己抗原と外来抗原の両方と交叉反応する抗体を表示するB細胞は,この特異性を研究するためのモデルを示しています.
自己抗原の認識はB細胞の無反応状態を誘発する.

研究の目的:

相互に模倣する自己抗原と外来抗原を区別する特異性を獲得する方法を調査する.
抗原模倣に反応する抗体の親和性成熟の基礎となる選択プロセスと分子機構を理解する.

主な方法:

マウスモデルで交互反応性抗体を持つB細胞の生成
自己抗原によるB細胞アナーギーの誘導と,外来抗原によるその逆転.
抗体遺伝子変異と選択ダイナミクスの単細胞分析
抗体と抗原の相互作用の結晶構造の決定

主要な成果:

B細胞アナーギーは高密度外来抗原に挑戦すると逆転し,生殖中心の反応と抗体遺伝子ハイパーミューテーションにつながった.
単細胞分析では,自己親和性を減少させる突然変異の急速な選択と,異種抗原親和性を増加させる突然変異の遅い選択が示された.
結晶構造は,自己エピトープよりも外来エピトープへの高度な好ましい結合のための微妙なトポロジ的差異を搾取する変異を示した (5000倍).

結論:

抗原模倣の解像度は,最適な抗体相性成熟の重要な要因である.
自己反応性B細胞クローンを保持することは,外来からの脅威に対する保護性抗体反応を開発するための貴重な基質を提供します.
この研究は,無害な自己と有害な外体との区別に不可欠な抗体反応の高特異性を得るメカニズムを明らかにしています.

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