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

Aging Cell

Michelle Ratliff²  Sarah Alter²  Kelly McAvoy²  Daniela Frasca²  Jacqueline A. Wright²  Sandra S. Zinkel¹  Wasif N. Khan²  Bonnie B. Blomberg² 

[1] Department of Medicine, Division of Hematology/Oncology, Vanderbilt University School of Medicine, Nashville, TN, USA;Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, FL, USA

关键词: aging;    autoreactivity;    B cells;    B lymphopoeisis;    inflammation;    phosphorylcholine;    senescence;    TNF alpha;   

DOI  :  10.1111/acel.12302

来源: Wiley

【 摘 要 】

Summary

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.

【 授权许可】

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

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