Therefore, the loss of ERdj4 may attenuate the anti-apoptotic activity of BiP resulting in reduced Octreotide Acetate survival of B cell progenitors. Approximately 10�C20% of immature B cells produced in the bone marrow reach the spleen to develop into mature follicular or marginal zone B cells. The most recent bone marrow emigrants, splenic T1 cells, were significantly elevated in ERdj4gt/ gt mice. This unexpected finding could be the result of increased egress from the bone marrow and/or increased survival. Although transitional cells were not impaired, their predecessors, mature follicular B cells, were reduced in ERdj4gt/gt mice. These longlived, recirculating B cells are maintained in the periphery through homeostatic proliferation, which was unaffected by ERdj4 deficiency. Recent studies described development of follicular B cells from immature precursors in the bone marrow. Thus, a likely explanation for the lower number of follicular B cells is reduced maturation in the bone marrow, further underscoring the importance of ERdj4 in B cell development. Mature B cells Temocapril HCl terminally differentiate into antibody-secreting plasma cells upon encounter with antigen. This process is heavily dependent on the IRE1a/XBP1 branch of the UPR to increase the secretory apparatus required for antibody production. ERdj4 is highly upregulated by XBP1 during plasma cell differentiation, suggesting a potential role for this chaperone in immunoglobulin synthesis. Unexpectedly, naive ERdj4gt/gt mice exhibited significantly elevated levels of isotype-switched antibodies, including IgG, IgA and IgE. Consistent with these findings, the loss of ERdj4 in B cells enhanced proliferation, survival and isotype switching in response to LPS in vitro. Class switch recombination is regulated by both activating and inhibitory cell surface receptors, including the BCR, CD40, CD22, Toll-like receptors and cytokine receptors. ERdj4 may be required for productive folding and expression of one or more of these receptors.Although the relevant substrates have yet to be identified, these findings suggest that the chaperone activity of ERdj4 is required for negative regulation of B cell activation and isotype switching in the context of non-specific antibody production.