Sandra Zinkel
Assistant Professor of Medicine
Last active: 3/26/2019

In aged mice, low surrogate light chain promotes pro-B-cell apoptotic resistance, compromises the PreBCR checkpoint, and favors generation of autoreactive, phosphorylcholine-specific B cells.

Ratliff M, Alter S, McAvoy K, Frasca D, Wright JA, Zinkel SS, Khan WN, Blomberg BB, Riley RL
Aging Cell. 2015 14 (3): 382-90

PMID: 25727904 · PMCID: PMC4406667 · DOI:10.1111/acel.12302

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 naïve antibody repertoires in the bone marrow and periphery.

© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

MeSH Terms (9)

Animals Apoptosis Cell Cycle Checkpoints Cell Differentiation Immunoglobulin Light Chains, Surrogate Lymphocyte Activation Mice, Inbred C57BL Phosphorylcholine Precursor Cells, B-Lymphoid

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