Programmed cell death, or apoptosis, of lymphocytes is a key mechanism in the homeostatic regulation of immunity. For example, as B cells move through development, apoptosis deletes from the repertoire cells unable to productively rearrange a heavy chain Ig allele, as well as those with strongly self- reactive Ig receptors. During germinal center (GC) responses, B cells that fail to accumulate somatic mutations that improve the affinity of the Ig receptor for antigen are lost by apoptosis. The work in our laboratory supported by this grant has focused on understanding the role of the anti-apoptotic gene bcl-x in regulating survival during B cell development and activation. Our studies suggest that Bcl-XL has a unique role at 3 distinct checkpoints: the pro-B cell stage when heavy chain alleles first begin to rearrange, the pre-B/immature B stage during the period of light chain rearrangement and receptor editing, and during GC B cell immune responses. In the next funding period we propose to test two major hypotheses regarding the function of Bcl-XL at the pre-B/immature B stage and during GC responses: 1) At the late pre-B/early immature B cell stage, Bcl-XL provides an editing """"""""window"""""""" which allows self-reactive cells the opportunity to exchange a self-reactive light chain receptor for one with less auto-reactivity; 2) During GC responses, Bcl-XL is upregulated in cells positively selected by antigen, and is required for affinity maturation. To test these hypotheses we will first explore the role of Bcl-XL in regulating survival of self-reactive B cells during bone marrow light chain receptor editing in gain-of-function transgenic models both in vivo and in vitro. We will also generate an anti-HEL light chain knock-in mouse in which to analyze the function of Bcl-XL in the setting of more physiologic central receptor editing. Finally, we propose to examine the influence of a loss-of-function of bcl-x in B cells using mice carrying floxed bcl-x genes and mice expressing B cell-specific Cre recombinase. These animals will allow us to test whether B cells deficient in bcl-x have the ability to rearrange light chains and receptor edit in the bone marrow, and undergo affinity maturation in GC reactions. Many autoimmune diseases, including systemic lupus erythematosus, are characterized by the loss of tolerance to self antigens. The autoimmune B cell response in SLE appears to be driven by somatic mutation in germinal centers, and patients with this disease show evidence of excessive receptor editing at light chain loci. A better understanding of the mechanisms that regulate survival at the pre-B/immature B stage and in GCs may provide important new insights into the initiation and maintenance of autoimmunity.
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