New Cells in Old Mice: The ABCs of Humoral Immunosenescence

Abstract

Dampened humoral immune responses and increased propensity for autoimmune and inflammatory diseases are hallmarks of aging. Here, we summarize recent progress in understanding how aging affects humoral immunity, focusing on the discovery of a phenotypically and functionally unique B cell subset in aged mice, its potential role in immunosenescence, and its relationship to increased inflammation and autoimmunity.Keywords: Age, B cell homeostasis, function. OVERVIEWAging is a complex process characterized by functional declines in multiple physiologic systems. Age-related alterations in the immune system, a spectrum of changes that are in toto termed "immunosenescence," yield enhanced susceptibility to infectious diseases, increased propensity for inflammatory responses and autoantibody production, and consequently, increased morbidity and mortality [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. Understanding the mechanisms through which age-associated phenomena yield the overall immunosenescent phenotype presents a fundamental and challenging biological problem. Multiple factors contribute to this general deterioration of immune activity, encompassing both cell-intrinsic changes and alterations in lymphoid organ microenvironments. In particular, determining how age-associated changes result in modified homeostatic relationships among steady-state lymphocyte pools, and how this in turn impacts the initiation and quality of adaptive immune responses, may provide the keys to effective prophylaxis and intervention. In this review, we briefly summarize global shifts in humoral immune responsiveness that emerge with age, followed by a detailed consideration of changes in the genesis and homeostasis of B lymphocyte populations. Finally, we focus on a recently described B lineage subset that emerges with age [15,16], and discuss how the shifting palette of functional B cell subsets may contribute to the global landscape of immunosenescence. AGING ALTERS HUMORAL IMMUNE RESPONSESProtective humoral immunity requires maintaining both naïve and antigen-experienced B cell subsets that respond robustly to pathogens, yet maintain self-tolerance. Multiple studies have revealed that, in contrast to healthy young adults, aged individuals display blunted humoral responses to both new and previously encountered antigens, as well as increases in autoantibody levels [4,7,11,13,[17][18][19]. Accordingly, studies over the last several decades have interrogated the basis for this array of features. Table I summarizes some of the changes in B cell development, dynamics and function that have been revealed by these efforts.Early work focused primarily upon whether the frequency or clonal composition of responsive B cells changes in aged individuals, as well as whether hallmarks of effective humoral immune responses are altered. Examinations of how aging influences responding B cell frequencies, using model antigens in mice, have yielded mixed results. For example, aged mice have decreased frequencies of B cells responsive to some...