Bone marrow microenvironmental changes in aged mice compromise V(D)J recombinase activity and B cell generation

Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, 55 Lake Ave North, Worcester, MA 01655, USA.
Seminars in Immunology (Impact Factor: 6.12). 11/2005; 17(5):347-55. DOI: 10.1016/j.smim.2005.05.012
Source: PubMed

ABSTRACT B cell generation and immunoglobulin (Ig) diversity in mice is compromised with aging. Our recent work sought to understand mechanism(s) that contribute to reduced B cell production in aged mice. Using in vivo labeling, we found that reduction in marrow pre-B cells reflects increased attrition during passage from the pro-B to pre-B cell pool. Analyses of reciprocal bone marrow (BM) chimeras reveal that the production rates of pre-B cells are controlled primarily by microenvironmental factors, rather than intrinsic events. To understand changes in pro-B cells that could diminish production of pre-B cells, we evaluated rag2 expression and V(D)J recombinase activity in pro-B cells at the single cell level. The percentage of pro-B cells that express rag2 is reduced in aged mice and is correlated with both a loss of V(D)J recombinase activity in pro-B cells and reduced numbers of pre-B cells. Reciprocal BM chimeras revealed that the aged microenvironment also determines rag2 expression and recombinase activity in pro-B cells. These observations suggest that extrinsic factors in the BM that decline with age are largely responsible for less efficient V(D)J recombination in pro-B cells and diminished progression to the pre-B cell stage. These extrinsic factors may include cytokines and chemokines derived from BM stromal cells that are essential to the development of B cell precursors. The changes during aging within the BM hematopoietic microenvironment most likely are linked to the physiology of aging bone. Bone degrades with age (osteoporosis) due to decreased formation of new bone by osteoblasts. Marrow stem cells (MSC) are considered the progenitor of both adipocytes, osteoblasts and hematopoietic stromal cells and a controlled reciprocal regulation exists of osteoblast versus adipocyte differentiation; with age adipocytes increase, and osteoblast decrease. It is possible that stromal cell generation from MSC is compromised during aging. Currently, understanding of BM microenvironmental factors that regulate rag gene expression is very limited. However, as early progenitors differentiate, it is increasing clear that a limited set of transcription factors (e.g. ikaros, PU.1, E2A, EBF, pax5) regulate B-lineage specific genes, and that expression and stability of these factors is responsive to the microenvironment. Current and future work by several groups will strive to understand mechanisms that regulate these factors and how aging impacts these regulatory circuits.

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Available from: Rachel M Gerstein, Aug 25, 2015
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    • "This is most readily observed as a decline in the number of pre-B cells within the bone marrow, but more recent studies also indicate that early B cell precursors, including common lymphoid progenitors and pro-B cells, are also adversely affected by the aging process (Riley et al., 1991; Stephan et al., 1996; Sherwood et al., 1998; Miller et al., 2003; Van der Put et al., 2003; Labrie et al., 2005). The consequences of diminished B cell development in old mice are not well characterized, but may contribute to alterations in B cell longevity (Johnson et al., 2002; Kline et al., 1999; Labrie et al., 2005) and composition of the B cell receptor repertoire (Klinman et al., 1997; Wilson et al., 2005) during senescence. Whether similar alterations in B cell development are observed in humans is speculative; however, naïve B cells are reduced in number in the periphery in old age (Nunez et al., 1996; Huppert et al., 1999; Ogawa et al., 2000; Rossi et al., 2003) Previously, it has been shown that old murine bone marrow cells deficient in surface IgM, when used as a source of pre-B cells, generated new B cells with substantial changes in the antibody repertoire to the phosphorylcholine (PC) epitope (Klinman et al., 1997). "
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