Abstract
In aged mice, new B-cell development is diminished and the antibody repertoire becomes more autoreactive. Our studies suggest that (i) apoptosis contributes to reduced B lymphopoiesis in old age and preferentially eliminates those B-cell precursors with higher levels of the surrogate light chain (SLC) proteins (λ5/VpreB) and (ii) λ5low B-cell precursors generate new B cells which show increased reactivity to the self-antigen/bacterial antigen phosphorylcholine (PC). Pro-B cells in old bone marrow as well as pro-B cells from young adult λ5-deficient mice are resistant to cytokine-induced apoptosis (TNFα TGFβ), indicating that low λ5 expression in pro-B cells is sufficient to cause increased survival. Transfer of TNFα-producing 'age-associated B cells' (ABC; CD21/35- CD23-) or follicular (FO) B cells from aged mice into RAG-2 KO recipients led to preferential loss of λ5high pro-B cells, but retention of λ5low, apoptosis-resistant pro-B cells. In old mice, there is increased reactivity to PC in both immature bone marrow B cells and mature splenic FO B cells. In young mice, absence of λ5 expression led to a similar increase in PC reactivity among bone marrow and splenic B cells. We propose that in old age, increased apoptosis, mediated in part by TNFα-producing B cells, results in preferential loss of SLChigh pro-B cells within the bone marrow. Further B-cell development then occurs via an 'SLClow' pathway that not only impairs B-cell generation, but promotes autoreactivity within the naïve antibody repertoires in the bone marrow and periphery.
Original language | English (US) |
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Pages (from-to) | 382-390 |
Number of pages | 9 |
Journal | Aging Cell |
Volume | 14 |
Issue number | 3 |
DOIs | |
State | Published - Jun 1 2015 |
Keywords
- Aging
- Autoreactivity
- B cells
- B lymphopoeisis
- Inflammation
- Phosphorylcholine
- Senescence
- TNF alpha
ASJC Scopus subject areas
- Aging
- Cell Biology