This conclusion is consistent with the 55% smaller spot sizes seen in B-1 cell ELISPOT assays, further demonstrating that B-1 cells secrete less IgM than do LPS-treated B splenocytes (51)
This conclusion is consistent with the 55% smaller spot sizes seen in B-1 cell ELISPOT assays, further demonstrating that B-1 cells secrete less IgM than do LPS-treated B splenocytes (51). are also defective in providing early protection against influenza infection. B-1 B cells represent an important and functionally distinct subset of B cells that reside predominately in pleural EPHB2 and peritoneal cavities, Limonin in the gut lamina propria, and to a minor extent in the spleen. They can be distinguished from their conventional B-2 counterparts by differences in their surface phenotype because B-1 cells are B220loIgMhiIgDloCD43+CD21CD23. Cavity B-1 cells also express CD11b/CD18 (Mac1), and B-1a and B-1b subsets differ in the presence or absence of CD5, respectively (1,2). B-1 cells develop primarily from LinCD45RloCD19+precursors in the fetal BM and fetal liver but can also arise from adult BM progenitors (1,35). Several genetic studies have shown B cell receptor (BCR) signal strength to be Limonin crucial for B-1 cell development. Defects in signaling molecules that decrease BCR signaling result in an increase in B-1 cell populations, and defects Limonin in those molecules that increase BCR signals reduce B-1 cells (1,6). Thus, strong BCR antigen signals appear to be important for the decision to become a B-1 cell. Unlike B2 cells, which have limited life spans and are constantly replenished from BM progenitors, B-1 cells are maintained by homeostatic proliferation (self-renewal) as shown by adoptive transfer experiments of B-1 cells into immunodeficient recipients (7,8). Interestingly, the spleen is required for the generation and maintenance of a large fraction of B-1a cells (9), and B-1 cells are also a major source for IgA-secreting plasma cells that inhabit the lamina propria of the gut (10,11). A defining feature of B-1 cells is their ability Limonin to secrete so-called natural antibodies in the absence of apparent infection or immunization (2,7,10). The repertoire of these antibodies is limited. They lack N region additions and somatic hypermutations and often recognize highly conserved, T-independent type 2 bacterial and viral antigens (1,1220). Self- and oxidized self-antigens are thought to be responsible for the positive selection and maintenance of B-1 cells expressing natural antibodies (2123). In addition to providing immunity against several pathogens, B-1specific antibodies also reduce atherosclerotic lesions, activate T cell responses, contribute to autoimmunity, and promote ischemia/reperfusion injury (2332). Finally, important functional differences have been identified for B-1a and B-1b cells. B-1a cells spontaneously secrete protective natural antibodies, whereas B-1b cells respond to pathogens by generating long-lasting immunity independent of T cell help (32,33). In humans, B-1 lymphocytes are present at the time of birth and persist into adulthood. Although less is known about their function, human B-1a and B-1b cells resemble murine B-1 cells in their expression of surface CD5, in their anatomical placement within the peritoneal cavity (PerC), spleen, and peripheral blood, and in their secretion of poly-specific, autoreactive antibodies (34,35). In spite of such diverse and important roles for natural antibodies, the mechanisms that regulate antibody secretion by B-1 cells are poorly understood. Our current molecular understanding of antibody secretion comes almost entirely from the investigation of B-2derived plasma cells. Recent studies have revealed a network of transcription factors that regulate plasmacytic differentiation (36,37). One principle player in this process is the transcriptional repressor, B lymphocyteinduced maturation protein 1 (Blimp-1; reference38). Blimp-1 orchestrates a gene expression program that drives B cells to become plasma cells through the repression of genes involved in B cell proliferation, antigen presentation, germinal center reactions, BCR signaling, and BT cellcell interactions (39). Importantly, Blimp-1 also promotes the Ig secretion program (3945). A crucial direct target of Blimp-1 for inducing the secretory program isPax5, which encodes B cell lineage-specific activator protein and represses genes encoding Ig heavy chain, J chain protein, and X-box binding protein 1 (XBP-1; references4648). Blimp-1 relievesPax5-dependent repression of XBP-1, which in turn functions as the proximal transcriptional activator for most of the genes necessary for the dramatic phenotypic changes in plasma cells associated with antibody secretion, including increases in cell and ER size, ribosomal Limonin and mitochondria number and function, and expression of numerous genes involved in the secretory pathway (49). Like Blimp-1, XBP-1 is required for plasma cell formation and antibody secretion (50). Blimp-1 is also required for processing of heavy chain transcripts to the secreted form (S), although the molecular mechanism is not understood (42). Recently, Tumang et al. (51) studied Bcl-6, Pax5, Blimp-1, and XBP-1 mRNA and protein levels in purified, Ig-secreting PerC B-1 cells and compared them to those of splenic B-2 cells activated with LPS to undergo plasmacytic differentiation to antibody-secreting cells. Similar to plasmacytic development of B-2 cells, these authors found that Bcl-6 and Pax5 mRNAs were decreased in B-1 cells whereas mRNAs encoding Blimp-1 and XBP-1.