B cells and aging: molecules and mechanisms

Abstract

Recent advances allow aging-associated changes in B-cell function to be approached at a mechanistic level. Reduced expression of genes crucial to lineage commitment and differentiation yield diminished B-cell production. Moreover, intrinsic differences in the repertoire generated by B-cell precursors in aged individuals, coupled with falling B-cell generation rates and life-long homeostatic competition, result in narrowed clonotypic diversity. Similarly, reductions in gene products crucial for immunoglobulin class switch recombination and somatic hypermutation impact the efficacy of humoral immune responses. Together, these findings set the stage for integrated analyses of how age-related changes at the molecular, cellular and population levels interact to yield the overall aging phenotype.

Figure 1

Aging-related changes in B-cell generation and function. The general timeline (left to right) of B-cell development and differentiation, from generation in the bone marrow (blue) to peripheral preimmune (green) and antigen-experienced (red) subsets. Colored Y-shaped molecules indicate B-cell receptors (BCRs) and corresponding antibodies of different antigenic specificities. Major aging-associated changes are listed below the corresponding subsets. FO, follicular B cell; HSC, hematopoietic stem cell; IMM, immature; MZ, marginal zone; PRE, pre-B cell stage; PRO, pro-B cell stage; TR, transitional B cell.

Figure 2

Model for differential activation of E47 mRNA turnover in B cells in young versus old mice. In response to lipopolysaccharide and other stimuli, phospho-p38 mitogen activated protein kinase is lower in B cells from aged compared with those from young adults. This results in a decrease in phospho-tristetraprolin (TTP) that, together with increased TTP levels in old B cells, yields greater TTP binding to 3′ untranslated regions with AU-rich elements, as in E47 mRNA, resulting in increased degradation rates. See Frasca et al. [36,61]. LPS, lipopolysaccharide; MAPK, mitogen activated protein kinase; TTP, tristetraprolin. The large pink oval refers to the AU-rich sequences in the 3′UTR and the small pink ovals refer to the poly-A tail.