The ageing human B cell repertoire: a failure of selection?

Abstract

B cells undergo a number of different developmental stages, from initial formation of their B cell receptor (BCR) genes to differentiation into antibody-secreting plasma cells. Because the BCR is vital in these differentiation steps, autoreactive and exogenous antigen binding to the BCR exert critical selection pressures to shape the B cell repertoire. Older people are more prone to infectious disease, less able to respond well to vaccination and more likely to have autoreactive antibodies. Here we review evidence of changes in B cell repertoires in older people, which may be a reflection of age-related changes in B cell selection processes.

Keywords: B cell; ageing; antibodies; repertoire; selection.

Figure 1

Generation of antibody diversity. A number of different genes exist in three loci in the genome, for heavy chain [immunoglobulin (IG)H], kappa light chain (IGK) and for lambda light chain (IGL). Gene rearrangement occurs between the variable (IGHV), diversity (IGHD) and joining (IGHJ) regions of heavy chain, such that one of each type of gene is brought together with the help of recombination activating genes (RAG1 and RAG2). Similarly, the light chain genes are rearranged, either kappa or lambda, but without any diversity regions. Random recombination of heavy and light chain genes results in 9516 or 520 different combination possibilities, respectively. Random assortment of heavy and light chain gene rearrangements further increases the number of possibilities, in a multiplicative manner, to 4·9 × 10⁶. Inaccurate joining of the V(D)J regions further increases the possibility for diversity. Antibody CDR3 regions are at the junction of the different genes, and therefore the CDR3 regions have the highest diversity.

Figure 2

Selection events in B cell development. B cells undergo a number of developmental stages in the bone marrow and in the periphery. At various stages there will be positive selection to enrich for B cells with attributes useful for binding exogenous antigens (green arrows) and negative selection to ensure that autoreactive B cells do not survive (red arrows).