We have recently discovered that the basic-region leucine zipper transcription factor XBP-1 is required for terminal B cell differentiation. XBP-1-deficient B lymphocytes showed normal proliferation, activation, and germinal center formation, but very little immunoglobulin production of any isotype secondary to failure to generate the plasma cell compartment. XBP-1 transcripts were rapidly upregulated in vitro by stimuli that induce plasma cell differentiation and were found at high levels in plasma cells from rheumatoid synovium. Ectopic expression of XBP-l into B lineage cells resulted either in differentiation to an early plasma cell phenotype or increased apoptosis depending on the state of maturation, Given its clear biologic relevance for the generation of plasma cells, we wish to address the many questions that remain to be answered about the function of XBP-1. For example, we do not know the mechanism by which XBP-1 controls the generation of plasma cells. One approach is to identify whether and how XBP-1 expression and function is regulated both at the transcriptional and posttranslational level by signals (CD40, IL-6) already established to promote antibody production (Aims 1 and 3). We cloned XBP-1 by virtue of its interaction in a southwestern screen with a cyclic AMP response element (CRE) in the MHC class II Aa promoter, but we do not know what genes lie downstream of XBP-1 in B cells. The search for XBP-1-inducible target genes (Aim 2) should help provide insights. Further, XBP-1 might interact with other proteins, possibly transcription factors or proteins important in signal transduction from the membrane to the nucleus. The isolation of novel XBP-1-interacting proteins proposed in Aim 3 should clarify these pathways. Finally, the presence of XBP-1 in plasma cells in rheumatoid synovium suggests a role for this factor in inflammatory/autoimmune diseases characterized by autoantibody production such as RA and SLE as well as in the malignancy multiple myeloma, an hypothesis we will test by the production of a conditional XBP-1 ko bred onto mouse models of autoimmune/malignant disease (Aim 4).
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