Activation-Induced Cytidine Deaminase Expression in Human B Cell Precursors Is Essential for Central B Cell Tolerance

被引：65

作者：

Cantaert, Tineke ^{[1
]}

Schickel, Jean-Nicolas ^{[1
]}

Bannock, Jason M. ^{[1
]}

Ng, Yen-Shing ^{[1
]}

Massad, Christopher ^{[1
]}

Oe, Tyler ^{[1
]}

Wu, Renee ^{[1
]}

Lavoie, Aubert ^{[2
]}

Walter, Jolan E. ^{[3
,4
,5
]}

Notarangelo, Luigi D. ^{[5
]}

Al-Herz, Waleed ^{[6
]}

Kilic, Sara Sebnem ^{[7
]}

Ochs, Hans D. ^{[8
,9
]}

Nonoyama, Shigeaki ^{[10
]}

Durandy, Anne ^{[11
]}

Meffre, Eric ^{[1
]}

机构：

[1] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06511 USA

[2] CHU Quebec, Div Allergy Immunol, Quebec City, PQ G1V 4G2, Canada

[3] Harvard Univ, Massachusetts Gen Hosp, Pediat Allergy & Immunol, Sch Med, Boston, MA 02114 USA

[4] Harvard Univ, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Sch Med, Boston, MA 02114 USA

[5] Boston Childrens Hosp, Div Immunol, Boston, MA 02115 USA

[6] Kuwait Univ, Fac Med, Dept Pediat, Safat 13110, Kuwait

[7] Uludag Univ, Fac Med, Dept Pediat, TR-16285 Gorukle, Turkey

[8] Univ Washington, Seattle Childrens Res Inst, Seattle, WA 98195 USA

[9] Univ Washington, Dept Pediat, Seattle, WA 98195 USA

[10] Natl Def Med Coll, Dept Pediat, Tokorozawa, Saitama 3598513, Japan

[11] INSERM, UMR 1163, F-75015 Paris, France

来源：

IMMUNITY | 2015年 / 43卷 / 05期

关键词：

CLASS-SWITCH RECOMBINATION; SOMATIC HYPERMUTATION; V(D)J RECOMBINATION; AID EXPRESSION; DEFICIENCY; MECHANISMS; BCL6; P53; TRANSLOCATIONS; RECEPTORS;

D O I：

10.1016/j.immuni.2015.10.002

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Activation-induced cytidine deaminase (AID), the enzyme- mediating class-switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes, is essential for the removal of developing autoreactive B cells. How AID mediates central B cell tolerance remains unknown. We report that AID enzymes were produced in a discrete population of immature B cells that expressed recombination-activating gene 2 (RAG2), suggesting that they undergo secondary recombination to edit autoreactive antibodies. However, most AID(+) immature B cells lacked anti-apoptotic MCL-1 and were deleted by apoptosis. AID inhibition using lentiviral-encoded short hairpin (sh)RNA in B cells developing in humanized mice resulted in a failure to remove autoreactive clones. Hence, B cell intrinsic AID expression mediates central B cell tolerance potentially through its RAG-coupled genotoxic activity in self-reactive immature B cells.

引用

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页码：884 / 895

页数：12

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