EXCEED THE SPACE PROVIDED. This is a renewal application of an RO1 grant to study receptor editing in B lymphocytes. Receptor editing is defined as secondary V(D)J recombinations in surface immunoglobulin positive (slg +) cells that eliminate and replace functional L-chain genes, altering B cell antigen specificity. Our data suggest that editing is a major mechanism of central B cell tolerance. Secondary rearrangements can also occur in sIg cells in the peripheral immune system (known as receptor revision) though there is some debate about the developmental stage of the cells undergoing revision and how recombination is regulated in these cells. Given their potential roles in the prevention of B cell autoreactivity, it is important to understand how receptor editing and revision are regulated, and how editing impacts allelic exclusion of Ig expression. The long term goal of these studies is to determine how B cell receptor signaling regulates recombination. In this proposal we test the hypotheses that the ability of a B cell to undergo receptor editing is developmentally regulated, that cells undergoing editing are similar to small preB cells in their stage of differentiation, that receptor revision is distinct from tolerance-induced editing, though it may involve cells at a similar stage of differentiation, that editing involves destructive rearrangements, including those involving the recombining sequence (RS), that are important in maintaining allelic/isotypic exclusion, and that target genes of BCR regulation that control recombinase can be identified by analysis of RNA expression and transcription factor activity. These hypotheses will be addressed through the following Specific Aims:
Aim l. To test whether or not RS rearrangements promote editing and allelic exclusion.
Aim 2. To test the role of B cell developmental stage on editing.
Aim 3. To determine if tolerance-induce receptor editing occurs in fetal B cells.
Aim 4. To identify functionally relevant changes in gene regulation that promote editing. PERFORMANCE SITE ========================================Section End===========================================
|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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