Impaired B lymphopoiesis in old age: a role for inflammatory B cells?

Abstract

Continued generation of new B cells within the bone marrow is required throughout life. However, in old age, B lymphopoiesis is inhibited at multiple developmental stages from hematopoietic stem cells through the late stages of new B cell generation. While changes in B cell precursor subsets, as well as alterations in the supporting bone marrow microenvironment, in old age have been known for the last 20 years, only more recently have insights into the cellular and molecular mechanisms responsible become clarified. Our recent discovery that B cells in aged mice are pro-inflammatory and can diminish B cell generation within the bone marrow suggests a potential mechanism of inappropriate "B cell feedback" which contributes to a bone marrow microenvironment unfavorable to B lymphopoiesis. We hypothesize that the consequences of a pro-inflammatory microenvironment in old age are (1) reduced B cell generation and (2) alteration in the "read-out" of the antibody repertoire. Both of these likely ensue from reduced expression of the surrogate light chain (λ5 + VpreB) and consequently reduced expression of the pre-B cell receptor (preBCR), critical to pre-B cell expansion and Vh selection. In old age, B cell development may progressively be diverted into a preBCR-compromised pathway. These abnormalities in B lymphopoiesis likely contribute to the poor humoral immunity seen in old age.

Fig. 1

Old age impairs multiple stages in B lymphopoiesis. The relative effects of old age on the sizes of the myeloid-biased hematopoietic stem cells (My-HSC), lymphoid-biased hematopoietic stem cells (Ly-HSC), common lymphoid progenitor cells (CLP), pro-B cells, and pre-B cells are illustrated. The expression of the SLC proteins λ5 and VpreB is reduced in aged mice and likely compromises the preBCR checkpoint. Two types of newly formed immature B cells are shown: CD43/S7⁻, the conventional immature B cell, and CD43/S7⁺ immature B cells which exhibit characteristics of activation, anergy, and are speculated to express autoreactive specificities. In old age, B lymphopoiesis is diminished overall, but the production of CD43/S7⁺ new B cells, favored when preBCR is poorly expressed, is maintained [63]

Fig. 2

Old age impairs the transcriptional network necessary for B lineage development and limits preBCR expression. a The hierarchical interrelationships among the E2A, EBF1, and Pax-5 transcription factors are shown. In addition, the roles of these transcription factors in the production/function of proteins key to the proper assembly and function of the preBCR are indicated. b The relative levels of total EBF proteins (EBF 1, 2, 3) in representative young (Y) and old (O) pro-B cells, after expansion in vitro in IL-7 supported cultures, are shown as determined by Western blot analysis. The protein Ubc9 served as a control. Similarly, the relative levels of EBF, E47/E2A, Pax-5, and Bob-1 proteins in old pro-B cells are shown as a percentage of their values in young pro-B cells. Data are summarized from [28]

Fig. 3

Age-associated B cells (ABC) promote a pro-inflammatory bone marrow environment which causes apoptosis in pro-B cells. Age-associated B cells (ABC) from aged mice are capable of TNFα secretion; TNFα is a potent inducer of apoptosis in pro-B cells [8]. TNFα also activates bone marrow macrophages, likely leading to production of a variety of cytokines and biomediators, in addition to TNFα, which cause apoptosis in B cell precursors [8]. The follicular (FO) and recirculating mature B cells in old mice also produce TNFα, but a subset produces IL-10 as well [8, 70]. IL-10 “protects” pro-B cells from TNFα-induced apoptosis [8]. As the numbers of FO B cells within the bone marrow decline and ABC become the predominant mature B cell population, the pro-inflammatory effects of ABC are hypothesized to cause extensive pro-B cell apoptosis and compromise late stages of B lymphopoiesis