抗体遺伝子に対するAID変異結果を標的とする配列内在のメカニズム

Leng-Siew Yeap¹, Joyce K Hwang¹, Zhou Du¹

¹Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine at Boston Children's Hospital, and Department of Genetics, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.

Cell

|November 20, 2015

まとめ

この研究は,AID酵素が抗体変異とクラス切り替えに似た方法でDNAを標的にすることを明らかにし,共通のメカニズムを示唆しています. また,抗体遺伝子の位置がB細胞の変異に特異ではないことも示しています.

科学分野:

免疫学
分子生物学
遺伝学

背景:

活性化されたBリンパ球は,活性化誘発型シチジンデアミナーゼ (AID) という酵素を重要な免疫プロセスに利用する.
AIDは,生殖中心 (GC) 内の親和性成熟のために,抗体変数 (V) エクソンにおける体性高変異 (SHM) を誘発する.
AIDはまた,IgHスイッチ (S) 領域のDNA断裂を誘導し,クラススイッチ再結合 (CSR) を促進する.

研究の目的:

B リンパ球における AID ターゲティングメカニズムと DNA 改変プロセスを調査する.
SHMとCSRの関係を明らかにするために,AIDが乗客の配列に及ぼす影響を研究する.
他の DNA 領域と比較して,V エクソン位置が SHM の AID によるユニークな標的かどうかを決定する.

主な方法:

Vエクソンを置き換える乗客配列のAIDターゲティングを追跡する in vivoアッセイの開発.
V エクソンとS領域の乗客のAID変異頻度の分析
GC B細胞内の様々な非Ig旅客配列におけるAID変異レベルの評価

主要な成果:

AIDはVゾーンとSゾーンの両方のSHMホットスポットを対象に,同様の頻度で乗客を対象にしています.
SHMプロセスは本質的に削除を生成し,CSRとの共有メカニズムをサポートします.
AIDは,GC B細胞の非Ig乗客配列をVエクソンに似たレベルで変異させ,Vエクソン特権の概念に異議を唱える.
ペイヤー・パッチのGCB細胞は,親和性に基づく選択の前に,高度に変異したVエクソンを蓄積する.

結論:

ソマティック・ハイパーミューテーションとクラス・スイッチ・リコンビネーションは,AIDによって引き起こされる共通のDNA改変メカニズムを共有している可能性が高い.
VエクソンはSHMに特異的に"特権"を与えられていません.他のDNA領域はGCB細胞で同様の割合でAIDによって変異します.
ペイヤー・パッチのGCB細胞には,事前に選択された,高度に変異した抗体Vエキソンが存在し,抗体の多様化に関する理解に影響を与えています.

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