Furthermore, NF B cells from BXD2 lupus-prone mice overexpress IFN compared to WT NF B cells. follicles are follicular (FO) B cells. B Lobucavir cells in marginal zones are marginal zone (MZ) B cells. B cells in bone marrow (BM) are BM B cells, and the B cells in GALT are GALT B cells. Some B cells simply dont stay put and recirculate throughout the body. Many of the recirculating B cells are newly minted and have just left the BM. These newly formed (NF) na?ve B cells in some respects are like teenagers leaving home for the first time, young adults but not experienced adults. They havent yet gone through all of lifes checkpoints to obtain a final specificity. They can be selected against and die young. Or in the presence of inflammatory or other signals, they can proliferate, secrete Abs or produce cytokines. In healthy humans, about 40% of the Abs made by what Wardemann et al. termed immature B cells are autoreactive (1, 2). NF B cells are present in the peripheral B-cell pool throughout life, but are the most abundant peripheral B cell subset in neonates, before the na?ve B cell pool is established. NF B cells are also the main peripheral B cell population in patients undergoing B cell-depletion therapy (3) and in some patients with immunodeficiency (4). One widely accepted classification of B cells newly arriving to the spleen has been to define them as immature in contrast to mature FO or MZ B cells. The immature B cells in mice are surface IgM (sIgM)++ and surface IgD (IgD)+ while the mature B cells are sIgM+sIgD++ (5, 6). A number of differences were identified between immature and mature B cells (6). Neonatal and immature B cells are particularly sensitive to clonal deletion or tolerance induction (7). Given the importance of defining how autoreactive B cells and Abs are selected against, the field has tended to focus on how NF B cells are altered or selected to become FO or MZ B cells, rather than on the possible Rabbit Polyclonal to Granzyme B functions of the NF B cells BAFFR also plays a Lobucavir significant role in NF B cell differentiation and survival (21-23). BCR and BAFFR signaling engage in complex crosstalk (24-27). In NF B cells, BCR engagement drives the production of p100, which in turn is used by BAFFR signaling to promote cell survival (25). The expression of BAFFR on NF B cells appears to require a tonic BCR signal (28). The absence of BAFF or BAFFR results in a reduction of peripheral B cells and a failure in B cell differentiation passed the NF B cell stage (22, 28). BAFF transgenic (Tg) mice that overexpress BAFF, on the other hand, have expanded peripheral B cells and develop systemic autoimmunity similar to human systemic lupus erythematosus (SLE) and Sj?grens syndrome (29). This might be due to the rescue of autoreactive NF B cells from negative selection (30, 31) or be associated with the activation of NF B cells capable of class switch recombination (CSR) and producing IgG auto-Abs (32, 33). Since BAFF levels can become elevated during infections, and in some patients with autoimmune diseases, the effects of BAFF on NF B cells are relevant to human disease. In addition to BCR/BAFFR crosstalk, NF B cell selection and survival may depend on CD40 signaling (34, 35) or signals to endosomal TLRs (as discussed in more details below). Unlike FO and MZ B cells, NF B cells constitutively express activation-induced deaminase (AID) (32, 36-38). This suggests they may rapidly respond to Ags and undergo CSR or even somatic hypermutation (SHM) (36). Alternatively, Kuraoka et al. (39) and Lobucavir others (40) have found that AID must be expressed in NF B cells for developing autoreactive B cells to be removed. Just how AID mediates this effect is not Lobucavir known. However, several groups have reported that TLR signals can upregulate AID in NF B cells (32, 41). Wardemann et al. cloned Abs from single B cells derived from the BM and blood of healthy donors and tested them for reactivity against nuclear and cytoplasmic Ags. About 40% of newly emigrated blood B cells (i.e., NF B cells) react with more than one self-Ag (e.g., are autoreactive/polyreactive) (1, 2). Martin et al. (42) isolated pre-B cells and B cells.