In old BALB/c mice, bone marrow pre-B cell and surrogate light chain reduction is associated with increased B cell reactivity to phosphorylcholine, but reduced T15 idiotype dominance

Abstract

In young adult BALB/c mice, antibodies to phosphorylcholine (PC) bearing the T15 (TEPC 15) idiotype confer protection against pneumococcal infections. In old age, even though PC reactive B cells are often increased, the proportion of T15+ antibodies declines. We hypothesize that limited surrogate light chain (SLC) and compromise of the pre-B cell receptor checkpoint in old mice contribute to both reduced new B cell generation and changes in the anti-PC antibodies seen in old age. In old mice: 1) early pre-B cell loss is most pronounced at the preBCR checkpoint; however, the reduced pool of early pre-B cells continues to proliferate consistent with preBCR signaling; 2) increased PC reactivity is seen in bone marrow immature B cells; 3) deficient SLC promotes increased B cell PC reactivity and diminished T15 idiotype within a subset of young adult mice; and 4) in old mice, as pre-B cell losses and reduced SLC become progressively more severe, increased T15 negative PC reactive B cells occur. These results associate a reduction in pre-B cells, imposed at the preBCR checkpoint, with increased reactivity to PC, but more limited expression of the protective T15 idiotype among PC reactive antibodies in old age.

Inflammatory immune cells may impair the preBCR checkpoint, reduce new B cell production, and alter the antibody repertoire in old age

“…It is likely that the differences in types of mature B cells populating the periphery in old mice affects both B cell activity and the specificity of antibodies elicited in immune responses. Analysis of anti-phosphorylcholine (PC) antibodies and their idiotypes have proven to be a useful tool in assessing changes in antibody/B cell repertoires in old age (Zharhary and Klinman, 1986; Riley, et al, 1989; Khomtchouck, et al, 2017). In particular, the T15 (TEPC 15) idiotype dominates the B cell responses to PC in young adult BALB/c mice (Zharhary and Klinman, 1986; Riley, et al, 1989), but is reduced as a percentage of the total anti-PC response in old age.…”

“…In particular, the T15 (TEPC 15) idiotype dominates the B cell responses to PC in young adult BALB/c mice (Zharhary and Klinman, 1986; Riley, et al, 1989), but is reduced as a percentage of the total anti-PC response in old age. This is seen both among total splenic B cells (Zharhary and Klinman, 1986; Riley, et al, 1989) and the B2 follicular splenic B cell subset (Khomtchouck, et al, 2017). In old mice, this results mainly from a marked increase in anti-PC B cells which are T15 neg in their idiotype (Zharhary and Klinman, 1986; Riley, et al, 1989; Khomtchouk, et al, 2017).…”

“…Reduced expression of bioactive IL-7 growth factor as well as diminished responsiveness to IL-7 may also contribute to pro-B cell apoptosis and reduced growth in old age (Stephan, et al, 1997; Stephan, et al, 1998). Pro-B cells in old mice are deficient in IL-7-mediated recruitment into mitosis in vitro (Sherwood, et al, 2003) and show somewhat lower mitotic activity in vivo (Sherwood, et al, 1998; Sherwood, et al, 2000; Khomtchouck, et al 2017). Signer, et al (2008) have shown that B lineage precursors in aged mice have elevated levels of p16 Ink4a and Arf and that these proteins are critical in inhibiting cell cycle, and induce apoptosis in a variety of aging and senescent cell types.…”