Cell signaling and the aging of B cells

Abstract

The uniqueness of each B cell lies in the structural diversity of the B-cell antigen receptor allowing the virtually limitless recognition of antigens, a necessity to protect individuals against a range of challenges. B-cell development and response to stimulation are exquisitely regulated by a group of cell surface receptors modulating various signaling cascades and their associated genetic programs. The effects of these signaling pathways in optimal antibody-mediated immunity or the aberrant promotion of immune pathologies have been intensely researched in the past in young individuals. In contrast, we are only beginning to understand the contribution of these pathways to the changes in B cells of old organisms. Thus, critical transcription factors such as E2A and STAT5 show differential expression or activity between young and old B cells. As a result, B-cell physiology appears altered, and antibody production is impaired. Here, we discuss selected phenotypic changes during B-cell aging and attempt to relate them to alterations of molecular mechanisms.

Introduction

As mammals age, their tissues undergo physiological transformations paralleled by the appearance of pathologies like rheumatoid arthritis (RA) (Bektas et al., 2017; Franceschi et al., 2018). The consequences of aging diverge extensively between individuals as underscored by the range of health status present in the human elderly population, from vigorous to frail (Hagen and Derudder, 2019; Pansarasa et al., 2019). The variety of age-related phenotypes observed in cells and tissues results from the combined effects of an array of influences, including environmental factors (e.g., pollution, nutrition, chronic infection), intrinsic homeostasis (e.g., inflammation, senescence) and epigenetic/genetic inheritance (e.g., single nucleotide polymorphisms) (Bulati et al., 2017; Campisi et al., 2019; Ferrucci and Fabbri, 2018; Franceschi et al., 2016; Melzer et al., 2019; Pinti et al., 2016; Singh et al., 2019).

One such tissue affected by aging is the immune system. Immunity preserves the integrity of the body by eradicating or neutralizing challenging threats, such as infection or cancer. The immune system comprises a collection of cooperating cell-types, broadly categorized into the myeloid (e.g., neutrophils and dendritic cells) and lymphoid (e.g., B and T cells) lineages. These cells derive from uncommitted hematopoietic stem and progenitor cells localized in the bone marrow of adult humans and mice (Beerman et al., 2010; Northrup and Allman, 2008). Aging has been reported to extensively reshape the generation and function of immune cells. Thus, in old humans and mice the hematopoietic stem cell pool appears biased toward myeloid cell production (Beerman et al., 2010; Pang et al., 2016), and elderly individuals accumulate a pro-inflammatory terminally-differentiated effector-type of T cells (Pinti et al., 2016). B cells serve a unique role in immunity as the sole producers of antibodies upon differentiation into plasma cells. In mice and humans, aging has profound effects on B-cell physiology, culminating in an altered distribution of mature B-cell subsets as well as compromised activation upon stimulation (Bulati et al., 2017; Hagen and Derudder, 2019; Kogut et al., 2012; Pinti et al., 2016).

One consequence of the age-dependent remodeling of the immune system is the deteriorated quality of antibody responses in vulnerable elderly and old mice (Bulati et al., 2017; Linterman, 2013; Nikolich-Žugich, 2017; Pinti et al., 2016; Weinberger, 2018). Of note, chronic inflammation is a reported trigger of the declining immunity in aging, when unrestrained by anti-inflammatory molecules (Franceschi et al., 2000; Franceschi et al., 2006; Hagen and Derudder, 2019; Pinti et al., 2016). However, the exact contribution of various pro-inflammatory cytokines or the existence of effective (local) concentrations remain to be established (Nikolich-Žugich, 2017).

Here, we discuss changes in signaling pathways at the molecular level in relation to remarkable alterations in the physiology of old mouse and human B cells. In addition, this review focuses on the impact of aging on B2 cells, the main lineage of B cells in adult animals. The situation in B1 cells, primarily generated early during life, will not be considered.