The production of B lymphocytes begins to decline steadily early in adult life and is severely compromised in the elderly. This occurrence has been attributed to intrinsic defects in early hematopoietic progenitors and B cell precursors as well as to microenvironmental changes in aged bone marrow. The aim of this review is to present an overview of B lymphocyte senescence and its underlying causes, and to discuss its impact on immune function and leukemogenesis in aged individuals.

B lymphocyte development occurs in the bone marrow in defined stages characterized by the status of immunoglobulin gene rearrangement in populations of cells that express specific combinations of cell surface antigens (Hardy and Hayakawa, 2001; Igarashi et al., 2002). There is as of yet no agreement on a terminology to delineate the most immature lymphoid specified progenitors that are directly derived from HSC. However, one candidate for such a progenitor, referred to as the early lymphocyte progenitor (ELP) (Hirose et al., 2002), was shown to differentiate into T cells in the thymus (Allman et al., 2003) and common lymphoid progenitors (CLP) (Kondo et al., 1997), which are now considered to be early B lineage specified progenitors, in the bone marrow (Bhandoola et al., 2003; Montecino-Rodriguez and Dorshkind, 2003). CLP sequentially differentiate into pre-pro-B and pro-B cells. During this differentiation process, these cells undergo immunoglobulin (Ig) heavy chain gene rearrangements. Successful rearrangement results in cytoplasmic μ expression, and transition to the pre-B cell stage. Pre-B cells initiate Ig light chain gene rearrangement and eventually mature into surface IgM⁺ (sIgM) B cells. The newly produced sIgM⁺ B cells undergo further maturation in the periphery where they ultimately encounter antigen. B lymphocytes derived from the bone marrow in this fashion are referred to as B-2 B cells (Figure 1).

The reduced production of B lineage cells in the aged was first noted as a decrease in the frequency and number of pre-B cells present in the bone marrow of old mice (Kirman et al., 1998; Kline et al., 1999; Stephan et al., 1996; Van der Put et al., 2004). However, more recent studies have shown that, in fact, the frequency and numbers of all B cell progenitors, including ELP, CLP, pre-pro-B and pro-B cells, are reduced in old bone marrow (Allman and Miller, 2005; Labrie et al., 2004; Miller and Allman, 2003; Min et al., 2006; Van der Put et al., 2004). It is becoming increasingly evident that diminished B lymphopoiesis is not an event that occurs abruptly at old age. Rather, studies of mice ranging from 2 to 24 months of age indicate that the decline in B cell production begins relatively early in adult life and progresses gradually thereafter (Miller and Allman, 2003). This observation suggests that declines in B cell production may be the result of a senescence mechanism that is preprogrammed in hematopoietic progenitors (Montecino- Rodriguez and Dorshkind, 2006).

Both the reduced production and the diminished quality of aged B lineage cells have a significant impact on immunity in old mice (Linton and Dorshkind, 2004). The number of naïve B cells that migrate from the bone marrow to the spleen is reduced in aged mice, and in turn is thought to contribute to the diminished production of follicular B cells (Johnson et al., 2002b). In addition, the function of peripheral B cells may also be compromised by aging, and this in turn contributes to a diminished immune response (Solana et al., 2006; Weng, 2006). The latter diminution of function may be secondary to age related defects in T cells. However, given the intrinsic changes in B lymphoid progenitors described above, it would not be surprising if cell autonomous changes in B cells from old mice underlie, at least in part, decreased isotype switching (Nicoletti and Cerny, 1991), reduced expression of costimulatory molecules (Zheng et al., 1997), and defects in B cell receptor signaling (Whisler and Grants, 1993).

In addition to changes in immune responsiveness, the changing patterns of lymphopoiesis may alter the development of hematological disease in the elderly. For instance, while the majority of pediatric leukemias are of lymphoid origin, leukemias that present in adults more frequently involve myeloid lineage cells. One such example is chronic myeloid leukemia (CML), which primarily develops in adults following a chromosomal translocation t(9q34;22q11) (Rowley, 1973) that occurs in HSC (Fialkow et al., 1967; Fialkow et al., 1977; Takahashi et al., 1998) and results in the formation of the BCR-ABL fusion oncogene (Ben-Neriah et al., 1986). Despite originating in HSC (Kabarowski and Witte, 2000), CML presents as a myeloid hyperplasia with infrequent lymphoid involvement (Wong and Witte, 2004). CML presents almost exclusively in adults, particularly in the elderly (CDC, 2005), when lymphopoid cell production is most severely compromised. Thus, the lower than expected lymphoid involvement in CML may be a consequence of the reduced production of lymphocytes in the elderly.

As discussed above, the patterns of B lymphocyte development follow a distinctive pattern with age. Populations of B lineage progenitors peak early in life, in some cases during fetal development, and decline steadily thereafter (Figure 1). It will be of interest to determine if the early decline in lymphocyte production, which does not correlate with chronological age, is related to the unique necessity of lymphoid progenitors to repair double stranded DNA breaks during antigen receptor gene rearrangement. Defects in this gene rearrangement machinery may in turn increase the risk of chromosomal translocations, DNA mutations, and subsequent malignant transformation. Consequently, the relatively high rate of acute lymphocytic leukemia observed in children is not necessarily surprising given that lymphocyte production is at its peak at this stage of life.