B lymphocytes are generated throughout life by differentiation from hematopoietic stem progenitors. Cells that engage in the B cell lineage in the bone marrow execute a programmed development, first sequentially rearranging immunoglobulin (Ig) heavy (H)-chain genes at the pro-B cell stage, then undergoing multiple rounds of clonal expansion at the pre-B cell stage and, finally, assembling Ig light (L)-chain genes to give rise to newly formed surface IgM+ immature B cells. However, the random Ig variable (V) gene rearrangements can produce autoreactive lymphocytes that must be tolerized by negative selection before emigrating to peripheral lymphoid organs. In the bone marrow, immature self-reactive B lymphocytes are eliminated by apopto-sis (clonal deletion), are functionally silenced (anergy), or undergo secondary V gene rearrangements to extinguish their autoreactivity (receptor editing). After undergoing these selection processes, newly formed B cells can migrate to the periphery, express IgD, and give rise to mature naive B cells, which can be categorized in three functionally and phenotypically distinct populations: conventional FO (or B-2) B cells, MZ B cells of the spleen, and B-1a B cells in the peritoneal cavity. Upon new encounters with self-Ags not present in the bone marrow, B cells must again be tolerized in the periphery before they enter the long-lived pool of B cells (reviewed in Radic and Zouali, 1996; Nemazee et al., 2000).
At the mature stage, B cells possess a system that can sense the presence of microorganisms and contribute to their destruction. In addition to secreting Igs, B cells are able to present Ags (Roosnek and Lanzavecchia, 1991), upreg-ulate costimulatory molecules, express antimicrobial activity by producing reactive oxygen intermediates and other inflammatory cytokines, and secrete factors that can directly mediate microbial destruction (Yi et al., 1996; Lee and Koretzky, 1998). More recently, it was recognized that B cells can express toll-like receptors (TLRs) (Applequist et al., 2002; Bourke et al., 2003). This expression is augmented following engagement of the BcR or the costimulatory molecule CD40 or by stimulation with S. aureus Cowan I bacteria or unmethy-lated CpG DNA. Since TLR9 recognizes unmethylated CpG motifs characteristic of bacterial DNA and is involved in the immediate response to a wide range of microbes, B cells may, in addition to their role as Ab-producing cells during the adaptive immune response, respond to pathogens in a manner associated with the innate branch of immune defense. Inducible expression of TLRs in B cells may provide a link between the innate and adaptive branches of the immune system. Additionally, two B cell subpopulations with innate-like functions are present in the peripheral lymphocyte compartment: B-1 and MZ B cells. Because of their anatomical location and their functional properties, these two B cell subsets are involved in T cell-independent, innate-like immunity and represent an immune mechanism of first-line defense against pathogens.
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