Format

Send to

Choose Destination
See comment in PubMed Commons below
Immunity. 2015 Nov 17;43(5):884-95. doi: 10.1016/j.immuni.2015.10.002. Epub 2015 Nov 3.

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

Author information

1
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511, USA.
2
Division of Immunology/Allergy, Centre Hospitalier de l'Université de Québec, Québec City, G1V 4G2, Canada.
3
Pediatric Allergy & Immunology and the Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA.
4
Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA.
5
Department of Pediatrics, Faculty of Medicine, Kuwait University, Safat, 13110, Kuwait.
6
Uludag University Medical Faculty, Department of Pediatrics, Gorukle-Bursa, 16285, Turkey.
7
Seattle Children's Research Institute and Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
8
Department of Pediatrics, National Defense Medical College, Namiki, Tokorozawa, Saitama, 359-8513, Japan.
9
INSERM UMR 1163, Paris 75015, France.
10
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511, USA. Electronic address: eric.meffre@yale.edu.

Abstract

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.

KEYWORDS:

AID-deficient patients; B cell development; B cell tolerance; activation-induced cytidine deaminase

PMID:
26546282
PMCID:
PMC4654975
DOI:
10.1016/j.immuni.2015.10.002
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Support Center