Abstract

The applicant seeks a research project grant (RO1) to study the induction of immunoglobulin gene rearrangements in surface IgM+ B lymphocytes. Preliminary data is presented suggesting that encounter with autoantigen can induce the rearrangement of fight chain genes in immature sIgM+ B-cells of the bone marrow. This was observed in transgenic mice bearing rearranged, functional Ig genes encoding an antibody specific for MHC class I alloantigens, in which the effect of different forms of autoantigen on B-cell development could be assessed. This proposed mechanism for B-cell tolerance in immature B-cells is termed the Receptor Editing hypothesis.
The Specific Aim of this proposal is to test the Receptor Editing hypothesis. This hypothesis proposes that in autoreactive, immature B lymphocytes sIgM crosslinking by self antigens induces secondary immunoglobulin gene rearrangements that can alter their receptors and render them non-autoreactive. The long-term goal of these studies is to understand how the specificities of the pre-immune lymphocyte repertoire are shaped by the internal environment and to identify possible defects in these processes in situations of immune dysfunction.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI033608-01
Application #
3148683
Study Section
Immunobiology Study Section (IMB)
Project Start
1992-12-01
Project End
1997-11-30
Budget Start
1992-12-01
Budget End
1993-11-30
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
National Jewish Health
Department
Type
DUNS #
City
Denver
State
CO
Country
United States
Zip Code
80206

  Publications

Aoki-Ota, Miyo; Torkamani, Ali; Ota, Takayuki et al. (2012) Skewed primary Ig? repertoire and V-J joining in C57BL/6 mice: implications for recombination accessibility and receptor editing. J Immunol 188:2305-15
Tiegs, Susan L; Russell, David M; Nemazee, David (2011) Receptor editing in self-reactive bone marrow B cells. The Journal of Experimental Medicine. 1993. 177: 1009-1020. J Immunol 186:1313-24
Ota, Miyo; Duong, Bao H; Torkamani, Ali et al. (2010) Regulation of the B cell receptor repertoire and self-reactivity by BAFF. J Immunol 185:4128-36
Beck, Kristina; Peak, Mandy M; Ota, Takayuki et al. (2009) Distinct roles for E12 and E47 in B cell specification and the sequential rearrangement of immunoglobulin light chain loci. J Exp Med 206:2271-84
Huber, Christoph; Martensson, Annica; Bokoch, Gary M et al. (2008) FGD2, a CDC42-specific exchange factor expressed by antigen-presenting cells, localizes to early endosomes and active membrane ruffles. J Biol Chem 283:34002-12
Vela, Jose Luis; Ait-Azzouzene, Djemel; Duong, Bao Hoa et al. (2008) Rearrangement of mouse immunoglobulin kappa deleting element recombining sequence promotes immune tolerance and lambda B cell production. Immunity 28:161-70
Verkoczy, Laurent; Duong, Bao; Skog, Patrick et al. (2007) Basal B cell receptor-directed phosphatidylinositol 3-kinase signaling turns off RAGs and promotes B cell-positive selection. J Immunol 178:6332-41
Verkoczy, Laurent; Ait-Azzouzene, Djemel; Skog, Patrick et al. (2005) A role for nuclear factor kappa B/rel transcription factors in the regulation of the recombinase activator genes. Immunity 22:519-31
Ait-Azzouzene, Djemel; Skog, Patrick; Retter, Marc et al. (2004) Tolerance-induced receptor selection: scope, sensitivity, locus specificity, and relationship to lymphocyte-positive selection. Immunol Rev 197:219-30
Verkoczy, Laurent K; Martensson, Annica S; Nemazee, David (2004) The scope of receptor editing and its association with autoimmunity. Curr Opin Immunol 16:808-14

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