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

Michelle Ratliff, Sarah Alter, Kelly Mcavoy, Daniela Frasca, Jacqueline A. Wright, Sandra S. Zinkel, Wasif N. Khan, Bonnie B. Blomberg, Richard L. Riley

Research output: Contribution to journalArticle

10 Scopus citations

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 languageEnglish (US)
Pages (from-to)382-390
Number of pages9
JournalAging Cell
Volume14
Issue number3
DOIs
StatePublished - Jun 1 2015

Keywords

  • Aging
  • Autoreactivity
  • B cells
  • B lymphopoeisis
  • Inflammation
  • Phosphorylcholine
  • Senescence
  • TNF alpha

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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