This is a research project to study the receptor editing mechanism of immune tolerance. The receptor editing hypothesis proposed that immature, self-reactive B-cells could be controlled by a mechanism, distance from clonal secretion, in which reactive cells are induced to undergo secondary light chain gene rearrangements, which often alters the cells' specificity and rescues them from elimination. In the prior funding period the basic validity of the model was established, albeit in highly contrived experimental models, but many questions remain. How does light chain allelic exclusion occur in the absence of self-antigen and how does autoantigen overcome or reverse this process? To what extent does receptor editing normally occur to immature B-cells? To what extend does receptor editing occur in the peripheral immune system, particularly among cells that are involved in the germinal center reaction. In this proposal, we examine a number of ramifications of the receptor editing model through the following Specific Aims: 1) To determine the scope of receptor edition in normal, lambda+ B-cells by testing the prediction that """"""""edited"""""""" VkappaJkappa exons retained by these cells encoded autoreative receptors. 2) To determine the factors regulating light chain allelic exclusion and receptor editing in vitro. 3) To determine the extent to which receptor editing occurs in peripheral B-cells. The long term goal of this project is to understand the molecular detains and the physiological roles of receptor editing.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Study Section
Immunobiology Study Section (IMB)
Program Officer
Kerr, Lawrence D
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Scripps Research Institute
La Jolla
United States
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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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