Age-associated B cells (ABC) inhibit B lymphopoiesis and alter antibody repertoires in old age

With old age (similar to 2 y old), mice show substantial differences in B cell composition within the lymphoid tissues. In particular, a novel subset of IgM(+) CD21/35(lo/-) CD23(-) mature B cells, the age-associated B cells or ABC, increases numerically and proportionately. This occurs at the expense of other B cell subsets, including B2 follicular B cells in spleen and recirculating primary B cells in bone marrow. Our studies suggest that ABC have a distinctive antibody repertoire, as evidenced by relatively high reactivity to the self-antigens phosphorylcholine (PC) and malondialdehyde (MDA). While PC and MDA are found on apoptotic cells and oxidized lipoproteins, antibodies to these antigens are also cross-reactive with epitopes on bacterial species. In old mice, ABC express TNFa and are pro-inflammatory. ABC can inhibit growth and/or survival in pro-B cells as well as common lymphoid progenitors (CLP). In particular, ABC cause apoptosis in pro-B cells with relatively high levels of the surrogate light chain (SLC) and, consequently, promote an "SLC low" pathway of B cell differentiation in old mice. SLC together with mu heavy chain comprises the pre-B cell receptor (preBCR) critical for pre-B cell expansion and selection of the mu heavy chain Vh repertoire. The low level of SLC likely impairs normal preBCR driven proliferation and alters mu heavy chain Vh selection thereby affecting the antibody specificities of new B cells. In this manner, ABC may contribute to both qualitative and quantitative disruptions of normal B lymphopoiesis in old age.