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PMID: 18197815 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Review

Regulation of aicda expression and AID activity: relevance to somatic hypermutation and class switch DNA recombination.

Critical reviews in immunology ·Vol. 27 ·No. 4 ·2007-00-00 ·Pages 367-97

Xu Z, Pone EJ, Al-Qahtani A, Park SR, Zan H, Casali P

Abstract

Expression and activity of activation-induced cytidine deaminase (AID) encoded by the aicda gene are essential for immunoglobulin (Ig) gene somatic hypermutation (SHM) and class switch DNA recombination (CSR). SHM and CSR unfold, in general, in germinal centers and/are central to the maturation of effective antibody responses. AID expression is induced by activated B-cell CD40 signaling, which is critical for the germinal center reaction, and is further enhanced by other stimuli, including interleukin-4 (IL-4) secreted from CD4+ T cells or Toll-like receptor (TLR)-activating bacterial and/or viral molecules. Integration of different intracellular signal transduction pathways, as activated by these stimuli, leads to a dynamic aicda-regulating program, which involves both positively acting trans-factors, such as Pax5, HoxC4, E47, and Irf8, and negative modulators, such as Blimp1 and Id2, to restrict aicda expression primarily to germinal center B cells. The phosphatidylinositol 3-kinase (PI 3-K), which functions downstream of activated B-cell receptor (BCR) signaling, likely plays an important role in triggering the downregulation of aicda expression in postgerminal center B cells and throughout plasmacytoid differentiation. In B cells undergoing SHM and CSR, AID activity, and, possibly, AID targeting to the Ig locus are regulated at a posttranslational level, including AID dimerization/oligomerization, nuclear/cytoplasmic AID translocation, and phosphorylation of the AID Ser38 residue by protein kinase A (PKA). Here, we discuss the role of B-cell activation signals, transcription regulation programs, and posttranslational modifications in controlling aicda expression and AID activity, thereby delineating an integrated model of modulation of SHM and CSR in the germinal center reaction.

MeSH Terms
Animals B-Lymphocytes/immunology,metabolism Cell Differentiation/genetics Cytidine Deaminase/genetics,metabolism Gene Expression Regulation, Enzymologic Germinal Center/immunology Humans Hyper-IgM Immunodeficiency Syndrome/immunology,metabolism Immunoglobulin Class Switching Lymphocyte Activation Phosphorylation Receptors, Immunologic/metabolism Recombination, Genetic Signal Transduction Somatic Hypermutation, Immunoglobulin Transcription Factors/metabolism
Chemicals
Receptors, Immunologic Transcription Factors AICDA (activation-induced cytidine deaminase) Cytidine Deaminase
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Xu Zhenming
Center for Immunology, School of Medicine and School of Biological Sciences, University of California, Irvine, CA 92697-4120, USA.
Pone Egest J
Al-Qahtani Ahmed
Park Seok-Rae
Zan Hong
Casali Paolo
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Article Info
Journal
Critical reviews in immunology
Abbr.
Crit Rev Immunol
ISSN
1040-8401
DOI
10.1615/critrevimmunol.v27.i4.60
Published
2007-00-00
Pages
367-97
Language
English
Region
United States
NLM ID
8914819
PMCID
PMC2994649
Subset
IM
Grants
NIAID NIH HHS · T32 AI060573-01A1 · United States
NIAMS NIH HHS · R01 AR040908 · United States
NIAID NIH HHS · T32 AI060573 · United States
NIAID NIH HHS · R01 AI045011-06A1 · United States
NIAID NIH HHS · R01 AI079705 · United States
NIAMS NIH HHS · R01 AR040908-09A1 · United States
NIAID NIH HHS · R56 AI079705 · United States
NIAMS NIH HHS · R01 AR040908-10 · United States
NIAID NIH HHS · T32 AI060573-05 · United States
NIAID NIH HHS · R01 AI045011-07 · United States
NIAID NIH HHS · R56 AI045011 · United States
NIAID NIH HHS · T32 AI060573-07 · United States
NIAID NIH HHS · R56 AI079705-01 · United States
NIAMS NIH HHS · R01 AR040908-11 · United States
NIAID NIH HHS · AI 60573 · United States
NIAID NIH HHS · T32 AI060573-06 · United States
NIAID NIH HHS · R01 AI045011 · United States
NIAID NIH HHS · T32 AI060573-03 · United States
NIAID NIH HHS · AI 45011 · United States
NIAID NIH HHS · T32 AI060573-02 · United States
NIAMS NIH HHS · AR 40908 · United States
External Links
PubMed source DOI: 10.1615/critrevimmunol.v27.i4.60 PMC Full Text View journal details
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