Although the concept of VH replacement has a lengthy history, the natural occurrence and molecular basis of VH replacement in human B cells have just been realized from our recent studies. VH replacement occurs through RAG-mediated secondary recombination involving the cryptic RSS (cRSS) within the rearranged VHDJH region and the 23 bp RSS from an upstream VH gene. VH replacement occurs in bone marrow immature B cells during human B cell development and contributes to about 5% of the periphery B cell repertoire in humans. Our recent studies showed that the frequencies of VH replacement products are significantly elevated in autoimmune diseases and in IgH genes encoding anti-viral antibodies, suggesting an unrealized important function of VH replacement. The current proposal focuses on the molecular regulation of VH replacement in human immature B cells. We found that crosslinking BCR strongly induces VH replacement in the EU12

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STATEMENT: VH replacement occurs through RAG-mediated secondary recombination involving the cryptic recombination signal sequence (cRSS) within the rearranged VH gene and a 23 bp RSS of an upstream VH gene. Although the concept of VH replacement has a length history, the molecular basis and natural occurrence of VH replacement in human B lineage cells have just been realized from our recent studies. Normally, VH replacement contributes to about 5% of the IgH repertoire in the periphery B cells of healthy donors. Strikingly, the frequencies of VH replacement products are significantly elevated in IgH genes derived from different autoimmune diseases and in IgH genes encoding various anti-viral antibodies. The current proposal focuses on the molecular regulation of VH replacement in human immature B cells. We found that crosslinking B cell antigen receptor (BCR) strongly induces VH replacement in human immature B cells. Understanding the molecular regulation of VH replacement will have important clinical implications, because the frequencies of VH replacement products are significantly elevated in autoimmune diseases and anti-viral responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI074948-05
Application #
8246521
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Nasseri, M Faraz
Project Start
2008-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$291,090
Indirect Cost
$95,070
Name
University of Nebraska Medical Center
Department
Pathology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Huang, Xin; Huang, Lin; Peng, Hong et al. (2013) ISPTM: an iterative search algorithm for systematic identification of post-translational modifications from complex proteome mixtures. J Proteome Res 12:3831-42
Huang, Lin; Lange, Miles D; Yu, Yangsheng et al. (2013) Contribution of V(H) replacement products in mouse antibody repertoire. PLoS One 8:e57877
Liu, Jing; Lange, Miles D; Hong, Sang Yong et al. (2013) Regulation of VH replacement by B cell receptor-mediated signaling in human immature B cells. J Immunol 190:5559-66
Liu, Jing; Xie, Wanqin; Lange, Miles D et al. (2013) Internalization of B cell receptors in human EU12 ?HC? immature B cells specifically alters downstream signaling events. Biomed Res Int 2013:807240
Liao, Hongyan; Guo, Jun-tao; Lange, Miles D et al. (2013) Contribution of V(H) replacement products to the generation of anti-HIV antibodies. Clin Immunol 146:46-55
He, Ti; Hong, Sang Yong; Huang, Lin et al. (2011) Histone acetyltransferase p300 acetylates Pax5 and strongly enhances Pax5-mediated transcriptional activity. J Biol Chem 286:14137-45