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. Issue 3 (27th February 2015)

• Record Type: Journal Article
• Authors: Ratliff, Michelle; Alter, Sarah; McAvoy, Kelly; Frasca, Daniela; Wright, Jacqueline A.; Zinkel, Sandra S.; Khan, Wasif N.; Blomberg, Bonnie B.; Riley, Richard L.
• Is Part Of: Aging cell. Volume 14:Issue 3(2015:Jun.)
• Page Start: 382
• Page End: 390
• Publication Date: 2015-02-27
• Subjects: Cells -- Aging -- Periodicals; 571.8783605
• DOI: 10.1111/acel.12302
• Languages: English
• ISSNs: 1474-9718

Abstract

<abstract abstract-type="main" id="acel12302-abs-0001"> <title>Summary</title> <p>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<sup>low</sup> 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<sup>−</sup> CD23<sup>−</sup>) or follicular (FO) B cells from aged mice into RAG‐2 KO recipients led to preferential loss of λ5<sup>high</sup> pro‐B cells, but retention of λ5<sup>low</sup>, 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<sup>high</sup> pro‐B cells within the bone marrow. Further B‐cell development then occurs via an 'SLC<sup>low</sup>' pathway that not only impairs B‐cell generation, but promotes autoreactivity within the naïve antibody repertoires in the bone marrow and periphery.</p> </abstract>