Document Detail


Unique contribution of IRF-5-Ikaros axis to the B-cell IgG2a response.
MedLine Citation:
PMID:  22535200     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
IRF-5 is a transcription factor activated by toll like receptor (TLR)7 and TLR9 during innate immune responses. IRF-5 activates not only Type I IFN, but also inflammatory cytokines. Most importantly, a genetic variation in the IRF-5 gene shows a strong association with autoimmune diseases such as Lupus. Here, we report that IRF5-deficient mice have attenuated IgG2a/c responses to T-cell-dependent and -independent antigens and to polyoma virus infection. This defect is due to the intrinsic deletion of IRF-5 in B cells, as SCID mice reconstituted with Irf5-/- B cells show a decrease in IgG2a/c expression after viral infection compared with mice that received wild-type B cells. Irf5-/-B cells in vitro have diminished TLR and cytokine-induced class switching to IgG2a/c. Addressing the molecular mechanism, we show that IRF-5 regulates IgG2a/c expression by decreasing Ikaros expression; reconstitution of IRF-5 in Irf5-/- B cells downregulates Ikaros levels and increases switching to IgG2a/c. The IRF site in ikzf1 promoter binds IRF-5, IRF-4 and IRF-8. We show that IRF-8 but not IRF-4 activates the ikzf1 promoter, and IRF-5 inhibits the transcriptional activity of IRF-8. Collectively, these results identify the IRF-5-Ikaros axis as a critical modulator of IgG2a/c class switching.
Authors:
C-M Fang; S Roy; E Nielsen; M Paul; R Maul; A Paun; F Koentgen; F M Raval; E Szomolanyi-Tsuda; P M Pitha
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-04-26
Journal Detail:
Title:  Genes and immunity     Volume:  13     ISSN:  1476-5470     ISO Abbreviation:  Genes Immun.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-08-03     Completed Date:  2012-11-16     Revised Date:  2013-06-25    
Medline Journal Info:
Nlm Unique ID:  100953417     Medline TA:  Genes Immun     Country:  England    
Other Details:
Languages:  eng     Pagination:  421-30     Citation Subset:  IM    
Affiliation:
Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens / immunology
B-Lymphocytes / immunology*,  metabolism*
Binding Sites
Cell Line
Cytidine Deaminase / metabolism
Gene Expression Regulation
Germ Cells / metabolism
Humans
Ikaros Transcription Factor / genetics,  metabolism*
Immunity, Humoral
Immunoglobulin Class Switching / genetics,  immunology
Immunoglobulin G / immunology*
Interferon Regulatory Factor-7 / genetics,  metabolism
Interferon Regulatory Factors / genetics,  metabolism*
Lymphocyte Activation / immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
Promoter Regions, Genetic
Signal Transduction*
T-Box Domain Proteins / metabolism
Transcription, Genetic
Transcriptional Activation
Grant Support
ID/Acronym/Agency:
3R01-AI1067632-05S1/AI/NIAID NIH HHS; AI 073651/AI/NIAID NIH HHS; AI067632/AI/NIAID NIH HHS; R01 AI067632/AI/NIAID NIH HHS; R01 CA 66644/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antigens; 0/Immunoglobulin G; 0/Interferon Regulatory Factor-7; 0/Interferon Regulatory Factors; 0/Irf5 protein, mouse; 0/T-Box Domain Proteins; 0/T-box transcription factor TBX21; 0/Zfpn1a1 protein, mouse; 0/interferon regulatory factor-4; 0/interferon regulatory factor-8; 148971-36-2/Ikaros Transcription Factor; EC 3.5.4.-/AICDA (activation-induced cytidine deaminase); EC 3.5.4.5/Cytidine Deaminase
Comments/Corrections

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