Effect of age on the expressed B cell repertoire: role of B cell subsets

121

111

Aging is accompanied by greatly reduced B cell production in the bone marrow, yet peripheral B cell numbers do not decline. We hypothesize that this may reflect filling of the peripheral pool with B cells that are long-lived as a consequence of specificity for, and chronic stimulation by, environmental Ags. To begin to explore this possibility, we analyzed the effects of aging on B cell population dynamics in the anti-H2k/b 3-83μδ Ig-transgenic mouse. We predicted that, because they presumably do not bind environmental Ags, B cells bearing the transgenic receptor may be lost in aged animals. As seen in nontransgenic animals, total splenic B cell numbers remained constant with age in the Ig-transgenic animals despite reduced B cell production. Importantly, although the few newly produced B cells in the bone marrow of aged mice are 3-83 positive, the peripheral compartment of these mice is dominated by B cells that express endogenous Ig genes rather than the transgenes. This population includes large numbers of marginal zone-like and CD21low/−CD23low/−IgMlow B cells, as well as elevated numbers of CD5+ B cells. Many of these cells express only non-B220 CD45 isoforms, suggesting that they may be memory cells. A significant proportion of aged transgenic animals produce autoantibodies that are reactive with ssDNA, dsDNA, or histones. Results support the hypothesis that, in the face of severely reduced production with age, B cells are selected based on reactivity to environmental Ags, accumulate, and display activated phenotypes. Cells bearing 3-83-transgenic receptors are excluded from this population due to their specificity. Beyond their importance in aging, these findings define a novel form of receptor revision in which B cells are selected rather than deleted based on Ag reactivity.

Section: Discussionsupporting

confidence: 75%

“…These changes include a skewing of V-gene use (20 -23), increased accumulation of CD5 ϩ B cells (24,25), and decreased inducibility of the costimulatory molecule CD86 (B7.2) (26). The latter may be attributable to age-related defects in signal transduction through the B cell Ag receptor (BCR) 3 (27,28).…”

mentioning

confidence: 99%

Aging-Dependent Exclusion of Antigen-Inexperienced Cells from the Peripheral B Cell Repertoire

Johnson

Rozzo

Cambier

2002

121

111

“…Nonetheless, several recent reports have shown intrinsic changes in the B cell pool affecting B cell responses. These include clonal expansion of CD5 ϩ B cells (48,49), impaired signal transduction events through the BCR (50), reduced inducibility of costimulatory molecules (30), and also reduced expression and activity of E2A-encoded transcription factors (herein). Moreover, it has been demonstrated that peripheral B cells from old mice are phenotypically distinct from those found in young mice and that these unique B cell populations arise and are maintained as a consequence of chronic antigenic stimulation (51).…”

Section: Discussionmentioning

confidence: 99%

Decreased E12 and/or E47 Transcription Factor Activity in the Bone Marrow As Well As in the Spleen of Aged Mice

Frasca

Nguyen

Riley

et al. 2003

The E2A-encoded transcription factors E12 and E47 are key regulators of B cell functions. They bind to the E-box site, found in regulatory regions of B cell-specific genes; promote cell survival of early pre-B cells; help to initiate Ig rearrangements; and are also involved in class switch in mature B cells in the periphery. We have investigated the expression and function of E47 and E12 in IL-7-expanded pro-B/pre-B cell precursors and in unstimulated or LPS-activated splenic B cells from young and old BALB/c mice. Results show that B cell precursors from the bone marrow of old mice exhibit a reduced expression of E2A proteins and a reduced ability to bind DNA, as compared with young mice. In the spleen, E2A protein expression and DNA binding are present in unstimulated B cells from young mice and, to a significantly lesser extent, from old mice. These are both strongly induced by activation in splenic B cells from young mice but only moderately induced in old mice, indicating that aging affects the expression and activity of E2A-encoded genes and also that DNA binding correlates with the amount of protein expression. The levels of E2A DNA binding in the spleen correlate with those in the bone marrow for individual mice. In splenic mature B cells, only E47/E47 complexes bind DNA; whereas in bone marrow B cell precursors, E47/E12 complexes participate in DNA binding. Only nuclear extracts of splenic mature B cells, but both nuclear and cytoplasmic extracts of bone marrow B cell precursors, exhibit DNA binding.

“…B cell function is also diminished with age, which is in part, due to the decline in T cell production and subsequent lack of T cell help. However, there are also significant age-associated changes inherent to B cell function (20). Despite B cell numbers remaining relatively constant throughout life due to tightly regulated homeostatic mechanisms, there is a decrease in export from the bone marrow (BM) and a subsequent clonal expansion of peripheral B cells and thus a narrowing of the Ab repertoire (21).…”

mentioning

confidence: 99%

“…Decreased Ab responses to foreign Ags in the aged are thought to be primarily due to a decline in T cell help (20,22). However, defective class switching (23) and a preferential loss of high-affinity Abs may play a role (24).…”

mentioning

confidence: 99%

Enhanced Immune Reconstitution by Sex Steroid Ablation following Allogeneic Hemopoietic Stem Cell Transplantation

Goldberg

Alpdoğan

Muriglan

et al. 2007

Delayed immune reconstitution in adult recipients of allogeneic hemopoietic stem cell transplantations (HSCT) is related to age-induced thymic atrophy. Overcoming this paucity of T cell function is a major goal of clinical research but in the context of allogeneic transplants, any strategy must not exacerbate graft-vs-host disease (GVHD) yet ideally retain graft-vs-tumor (GVT) effects. We have shown sex steroid ablation reverses thymic atrophy and enhances T cell recovery in aged animals and in congenic bone marrow (BM) transplant but the latter does not have the complications of allogeneic T cell reactivity. We have examined whether sex steroid ablation promoted hemopoietic and T cell recovery following allogeneic HSCT and whether this benefit was negated by enhanced GVHD. BM and thymic cell numbers were significantly increased at 14 and 28 days after HSCT in castrated mice compared with sham-castrated controls. In the thymus, the numbers of donor-derived thymocytes and dendritic cells were significantly increased after HSCT and castration; donor-derived BM precursors and developing B cells were also significantly increased. Importantly, despite restoring T cell function, sex steroid inhibition did not exacerbate the development of GVHD or ameliorate GVT activity. Finally, IL-7 treatment in combination with castration had an additive effect on thymic cellularity following HSCT. These results indicate that sex steroid ablation can profoundly enhance thymic and hemopoietic recovery following allogeneic HSCT without increasing GVHD and maintaining GVT.