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, focus- ing on the discovery of a phenotypically and functionally unique B cell subset in aged mice, its potential role in and its relationship to increased inflammation and autoimmunity. Aging is a complex process characterized by functional declines in multiple physiologic systems. Age-related altera- tions in the immune system, a spectrum of changes that are in toto termed immunosenescence, yield enhanced suscep- tibility to infectious diseases, increased propensity for in- flammatory responses and autoantibody production, and consequently, increased morbidity and mortality (1-14). Un- derstanding 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 lym- phocyte 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 respon- siveness that emerge with age, followed by a detailed con- sideration of changes in the genesis and homeostasis of B lymphocyte populations. Finally, we focus on a recently de- scribed 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 RESPONSES Protective humoral immunity requires maintaining both naive 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