Millions of B cells are generated daily that express autoreactive antibodies. Recent studies in mice indicate that newly generated immature B cells that react with autoantigens in the bone marrowundergo receptor editing and anergy, and that receptor editing contributes to a significant fraction of the peripheral protective antibody repertoire. These recent studies also suggest that clonal deletion, once thought the predominant mechanism of central tolerance, is probably a default pathway that is carried out when autoreactive B cells are unable to edit their receptors. It is intrinsic to this model that autoreactive B cells must survive for a certain amount of time in order to successfully edit their receptors. Differences in cell survival of autoreactive and non-autoreactive immature B cells ultimately control the selection of these cells and shape the peripheral B cell repertoire. Therefore, we propose that the window of survival of autoreactive immature B cells during which receptor editing takes place is absolutely essential for the development of a protective peripheral antibody repertoire. What physiologically controls the lifespan of immature B cells during receptor editing is not yet clear although likely involves the regulated activity of anti- and pro-apoptotic pathways. In addition to receptor editing, the generation of a specific, effective and innocuous B cell repertoire also relies on the signals that stop further Ig gene rearrangement upon expression of non- autoreactive BCRs and mediate immunoglobulin allelic/isotypic exclusion. Dysfunctions in these pathways may cause either excessive clonal deletion resulting in immunodeficiency or survival of autoreactive B cells resulting in autoimmunity. Available evidences indicate that the expression of non-autoreactive B cell antigen receptors generates tonic signals that are important for survival of non-autoreactive (primary and edited and possibly anergic) immature B cells as well as immunoglobulin allelic/isotypic exclusion. We propose that the NF-KBpathway, BAFF-R signaling and the Bcl-2 family properly translate B cell antigen receptor signaling to regulate cellular lifespan and immunoglobulin gene recombination. We have created mouse strains that generate either non- autoreactive or autoreactive immature B cells, and other strains that have abnormal levels of BCR and BAFF-R expression. Using these biological tools, we propose to determine how the NF-KB pathway and the Bcl-2 family regulate the lifespan of primary immature B cells, and what is the relative contribution of BCR and BAFF-R signaling to cell survival and establishment of Ig allelic/isotypic exclusion. This project will contribute to our understanding of what regulates the lifespan of developing B cells, in particular depending on whether the cells are autoreactive or not. Moreover, our findings will indicate possible mechanisms by which autoreactive B cells escape tolerance and eventually differentiate into autoantibody-forming cells.
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