Trends in Immunology
ReviewImmune senescence special issue. Free access sponsored by the National Institutes of HealthB cells and aging: molecules and mechanisms
Introduction
Advancing age yields numerous immune system changes, in aggregate termed immunosenescence 1, 2, 3, 4, 5. These changes result in refractory responses to vaccination or infection, declines in previously established protective immunity and increased disease morbidity 5, 6, 7, 8 (also see other articles in this special issue). B cells play central roles in the establishment and maintenance of protective immunity, including the generation of protective antibodies, antigen presentation, and more recently, appreciated regulatory functions [9]. Accordingly, assessments of how age impacts the production and behavior of B cells, as well as the accompanying effects on incipient and established humoral immunity, are fundamental to understanding immunosenescence. Early descriptive studies of age-associated changes in the B-cell lineage revealed reductions in the functional capacities of B cells and their progenitors, changes in the sizes of different subsets and shifts in the diversity and clonotypic composition of the antigen-responsive repertoire 10, 11, 12, 13, 14. Recent advances in our understanding of the molecular and cellular mechanisms underlying B-cell differentiation, homeostasis and activation are now fostering analyses of the basis for the age-associated changes summarized in Figure 1.
Section snippets
B-cell production wanes with age
In adults, B cells are generated continuously from bone marrow (BM) hematopoietic stem cells (HSCs) (Box 1). Descriptive studies have revealed substantial changes in the functional potential and sizes of developing B-cell subsets with age. For example, the frequency of precursors capable of generating B cells in vitro is reduced 13, 15, and the pre-B and immature (IMM) BM pools are smaller [16]. These findings prompted the question of whether such changes reflect upstream shifts in B-lineage
Homeostatic relationships shift with age
Clearly, reduced BM output will impact the dynamics of mature, pre-immune B-cell pools. Moreover, studies in mice reveal that follicular (FO) B-cell numbers remain relatively constant with age, implying that they must turn over more slowly in the aged than in young mice 29, 31. In vivo labeling studies confirm this prediction, indicating two- to fivefold reductions in mature B-cell turnover in aged individuals 29, 30, 31. Recent progress in our understanding of how primary B-cell selection and
BCR diversity truncates with age
Regardless of the exact manner in which homeostatic and selective parameters interact with advancing age, all potential outcomes predict that the clonotypic composition of primary B-cell pools will change as the aging phenotype emerges. Early findings in several mouse model systems suggested changes in the pre-immune B-cell repertoire with age 10, 11, 14, 44. The advent of technologies that allow more global repertoire assessments (e.g. spectratyping) have yielded additional insights,
Key activation processes change with age
Age-related changes in the behavior of antigen-experienced B cells (Box 3) are generally evidenced by diminished responses to infection or vaccination, as well as declines in existing humoral immunity (also see the article by Chen et al in this special issue). The picture is complex, because it clearly involves changes intrinsic to B cells and the accessory cells that must act in concert to generate immune memory.
Studies in humans have often focused on antigens that engender T-independent (TI)
Overview and perspective
Conceptual and technical advances have permitted mechanistic studies aimed at understanding previously reported age-associated changes in B-cell populations and function. A common emerging feature is altered levels of crucial gene products involved in the genesis, survival and activation of B cells. These changes, coupled with the interplay of microenvironmental and homeostatic processes, generate the overall aging phenotype. Future studies will focus on the detailed interrogation of epigenetic
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