1. In aged mice, low surrogate light chain promotes pro‐ <scp>B</scp> ‐cell apoptotic resistance, compromises the <scp>P</scp> re <scp>BCR</scp> checkpoint, and favors generation of autoreactive, phosphorylcholine‐specific <scp>B</scp> cells
- Author
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Sandra S. Zinkel, Daniela Frasca, Jacqueline A. Wright, Sarah Alter, Michelle Ratliff, Wasif N. Khan, Kelly McAvoy, Richard L. Riley, and Bonnie B. Blomberg
- Subjects
0303 health sciences ,Aging ,Phosphorylcholine ,Cellular differentiation ,CD23 ,Cell Biology ,Biology ,Molecular biology ,B-1 cell ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Immunology ,medicine ,biology.protein ,Tumor necrosis factor alpha ,Bone marrow ,Antibody ,B cell ,030304 developmental biology ,030215 immunology - 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) λ5(low) 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 λ5(high) pro-B cells, but retention of λ5(low), 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 SLC(high) pro-B cells within the bone marrow. Further B-cell development then occurs via an 'SLC(low)' pathway that not only impairs B-cell generation, but promotes autoreactivity within the naive antibody repertoires in the bone marrow and periphery.
- Published
- 2015