B cells and aging: Balancing the homeostatic equation

Abstract

The interplay of selective and homeostatic processes dominates the behavior of B lineage subsets following B cell antigen receptor (BCR) expression, and extends to determinants of immune response quality and the persistence of immunologic memory. A key concept emerging from these considerations is that primary events acting upstream of mature B lymphocyte pools can profoundly impact downstream populations as the system attempts homeostatic adjustments. Since advancing age is accompanied by profound changes in B cell generation and homeostasis, establishing the relative contributions of primary lesions versus compensatory homeostatic processes is critical to understanding these perturbations. Exploration of this problem requires an understanding of: 1) the identity, dynamics, and progenitor/successor relationships of marrow and peripheral B cell subsets; 2) the nature and interactions of selective and homeostatic processes acting in these subsets; and 3) how these change with age. Our data show that BLyS and its receptors mediate peripheral B cell homeostasis, and that the size, dynamics and behavior of all B cell subsets influenced by B Lymphocyte Stimulator change with age. These findings suggest that homeostatic processes mediated through B Lymphocyte Stimulator are altered with age, and that these perturbations may primarily reflect compensatory homeostatic adjustments to upstream reductions in B cell generation.

A novel B cell population revealed by a CD38/CD24 gating strategy: CD38−CD24− B cells in centenarian offspring and elderly people

“…Moreover, the inability of old individuals to effectively respond to vaccines results in less effective immunizations against viruses and bacteria, thus increasing the risk of infections and diseases (Miller and Cancro 2007;Cancro et al 2009;Gibson et al 2009;Dunn-Walters and Ademokun 2010;Frasca and Blomberg 2011). Indeed, it is well documented that the immune response to vaccination declines with age, although the reasons for this are poorly understood (Kumar and Burns 2008;Frasca et al 2010;McElhaney et al 2012).…”

“…It has been widely reported that elderly people show changes in B cell number, low levels of antibody production, and poor responses to recall antigens, and a collapse in B cell receptor repertoire diversity correlated with poor health status and the impairment of antibody response (Miller and Cancro 2007;Kumar and Burns 2008;Cancro et al 2009;Gibson et al 2009;DunnWalters and Ademokun 2010;Frasca et al 2010;Frasca and Blomberg 2011;McElhaney et al 2012). Lower numbers and percentages of B cells also form part of the cluster of immune parameters collectively known as the "Immune Risk Profile" associated with 2-, 4-, and 6-year mortality of the very elderly in the Swedish OCTO/ NONA longitudinal studies (Pawelec et al 2005).…”

B cells and immunosenescence: A focus on IgG+IgD−CD27− (DN) B cells in aged humans

“…Others have suggested that it is not the bone marrow output by itself that is crucially impaired but rather the ability of naïve B cells from older mice to colonise peripheral compartments that is reduced (Johnson et al, 2002). Even though the reduced influx of fresh naïve cells into the periphery, the total numbers of peripheral B cells in mice remain the same (Miller and Cancro, 2007). There are several mechanisms that can explain this anomaly.…”

“…These changes include shifts in the magnitude of all B cell compartments, specificity repertoire changes, modified peripheral B cell dynamics, and weakened humoral responses (Miller and Cancro, 2007).…”

Chronic B Cell Deficiency from Birth Prevents Age-Related Alterations in the B Lineage

“…Other studies have shown agerelated changes in clonal composition of HSCs (15) or expansion of a functionally distinct HSC population (16). Based on these findings, it is thought that in normal mice and humans, the peripheral B cell compartment adapts to the declined B lymphopoiesis by accumulating long-lived memory cells (17,18), thus maintaining the peripheral B cell numbers unchanged (4).…”