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.
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.
Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
Michelle
M
Ratliff
Sarah
S
Alter
Kelly
K
McAvoy
Daniela
D
Frasca
Jacqueline A
JA
Wright
Sandra S
SS
Zinkel
Wasif N
WN
Khan
Bonnie B
BB
Blomberg
Richard L
RL
Riley
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D059447:Cell Cycle Checkpoints / Q000276:immunology*; D002454:Cell Differentiation / Q000502:physiology; D054444:Immunoglobulin Light Chains, Surrogate / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008810:Mice, Inbred C57BL; D010767:Phosphorylcholine / Q000276:immunology*; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism*
D054444:Immunoglobulin Light Chains, Surrogate; D010767:Phosphorylcholine
B cells; B lymphopoeisis; TNF alpha; aging; autoreactivity; inflammation; phosphorylcholine; senescence