Impaired regeneration of the peripheral B cell repertoire from bone marrow following lymphopenia

European Journal of Immunology (Impact Factor: 4.03). 02/2001; 31(2):500 - 505. DOI: 10.1002/1521-4141(200102)31:2<500::AID-IMMU500>3.0.CO;2-C


Aging is associated with a decreased production of B cells by the bone marrow and an increased life-span of peripheral B cells. To determine whether the decreased bone marrow B cell production is linked to the increased life-span of B cells in old mice, B cell regeneration following lymphopenia was studied in young and old mice. The rate of bone marrow pre-B cell and of splenic B cell regeneration is slower in irradiated, old compared to irradiated, young recipients of young, congeneic bone marrow. This finding reflects an age-associated defect in the bone marrow microenvironment. As the bone marrow is the only source of a diverse population of B cells, we measured the diversity of the splenic B cell repertoire regenerated following drug-induced lymphopenia in old and young mice. The heterogeneity of mRNA size from IgH complementarity determining region 3 (CDR3) was more restricted in splenic B cells from old compared to young mice providing additional evidence for an age-associated impairment in B cell production by the bone marrow.

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Available from: Paul Szabo, Oct 10, 2014
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    • "The above conclusions, however, may not be applicable to the B lineage in aging, where it undergoes dramatic alterations in the cellular composition [8,11,13]. Early studies have shown that BM or purified HSCs from old mice failed to reconstitute the peripheral B cell compartment upon short-term of B cell ablation by cyclophosphamide or in BM chimeras [8,26,60], thereby supporting the argument that age-related changes in B lymphopoiesis are not the consequence of homeostatic regulations. More recent studies, however, proposed that HSCs in aging subjects have a different clonal composition with decreased lymphoid-biased HSCs [24,61], which could explain the inefficient B lineage reconstitution in the above studies. "
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    ABSTRACT: Age-related alterations in the cellular composition of the B lineage are a major cause of the poor antibody response to vaccination and to infectious agents among the elderly population. The mechanisms leading to these changes are poorly understood. Recently, we have shown that these changes reflect, at least in part, homeostatic pressures imposed by long-lived B cells that accumulate with aging, and that aging in the B lineage can be reversed upon alteration of B cell homeostasis by depletion. Here we discuss homeostatic causes for B lineage immunosenescence, and the potential for its rejuvenation.
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    • "Accordingly, stromal cell cultures established from aged mice are less supportive of proliferation and development of pro-B cells than cultures established from younger mice [53] [54]. A defect in the in vivo microenvironment was indicated by the finding that the number of pre-B cells in old mice receiving young marrow was diminished [11]. To test whether age of the microenvironment constrains the generation of pre-B cells, aged → young and young → aged bone marrow chimeras were generated and the magnitude, turnover and renewal rates of each marrow B cell compartment determined. "
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    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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    • "Two other groups investigating HSCs recently corroborated those findings [25,26]. Further studies conducted both in our laboratory [12] and in that of Weksler [27], in which the rate of new B cell production was determined in aged as compared with young mice following lymphopenia induced by γ-irradiation or cyclophosphamide, demonstrated that the absolute numbers of B cells generated per unit time in both the BM and spleen are markedly reduced. "
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    ABSTRACT: Immunosenescence is associated with a decline in both T and B lymphocyte function. Although aged individuals have normal numbers of B cells in the periphery and are capable of mounting robust humoral responses, the antibodies produced are generally of lower affinity and are less protective than those produced by young animals. Here we review multiple studies that address the mechanisms that contribute to this decline. Taken together, these studies suggest that age-associated loss of the ability to generate protective humoral immunity results in part from reduced B lymphopoiesis. As the output of new, naïve B cells declines, homeostatic pressures presumably force the filling of the peripheral B cell pool by long-lived antigen-experienced cells. Because the antibody repertoire of these cells is restricted by previous antigenic experience, they make poor quality responses to new immunologic insults.
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