Effects of aging on B cell function

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Ability to make an optimal immune response to vaccines and infectious agents declines with age in humans and animal models. Recent advances have shown intrinsic B cell defects in aged mice and humans, including decreases in Ig class switch recombination (CSR), activation-induced cytidine deaminase (AID), and E47 transcription factor. Effects on somatic hypermutation (SHM) have been varied depending on the system studied. Increase of AID in mice has shown improved CSR but not SHM. The reported microarray analysis of human B cell subsets may now be used to delineate B cell defects with aging and all the advances presented should lead to selecting agents for improved immune response in the elderly.

Introduction

B, T, and cells of the innate immune system have previously been implicated in a suboptimal immune response in aged humans and mice, but clarity concerning the importance of intrinsic B cell contributions to this decline and precise molecular biomarkers for B cell deficiencies with age has only recently been elucidated. Herein we review recent contributions in this area as well as others relating to specific B cell deficiencies with age and summarize key classic reports in light of these new findings. The significance of these findings is that they offer specific biological markers to measure the quality of the humoral immune response and as well should lead to protocols to directly improve these and the immune response in the elderly as well as potentially in other immunocompromised individuals.

High affinity antibodies are produced as a consequence of affinity maturation processes which occur in the germinal centers (GCs) of B cell follicles [1]. During GC reactions, many activated B cells undergo apoptosis and only a minority survive and differentiate into centroblasts that undergo clonal expansion in the dark zone of the GC. During proliferation, the process of somatic hypermutation (SHM) introduces base-pair changes into the V region of the rearranged genes encoding the IgV of the heavy and light chains. Centroblasts then differentiate into centrocytes and move to the light zone, where the B cell receptor, with the help from T cells and follicular dendritic cells, is selected for improved binding to the antigen. Newly generated centrocytes that produce an unfavorable antibody undergo apoptosis and are removed. A subset of centrocytes undergoes Ig class switch recombination (CSR), a DNA recombination mechanism through which the heavy chain class of the antibody produced by an activated B cell changes from IgM and IgD to either IgG, IgA, or IgE. The process occurs within GCs, but also outside of GCs in both T cell-dependent (TD) and T cell-independent (TI) responses [2, 3]. Antigen-selected centrocytes eventually differentiate into memory B cells which can either differentiate into plasmablasts, or remain as nonsecreting precursors for antigen recall [4]. The short-lived plasmablasts migrate to the bone marrow, where they differentiate into long-lived plasma cells and provide humoral antibody. Plasmablasts and plasma cells are maintained for long periods of time and compete for space in distinct ‘survival niches’ formed by stromal elements [5]. Thus, humoral antibody results from competition between newly generated plasmablasts and plasma cells [5].

Section snippets

Aging decreases humoral responses

The changes in the humoral immune response with age are both qualitative and quantitative, as affinity, specificity, and class of antibody produced are changed. A progressive decline in both the number and the size of GCs has been reported [6], as evaluated by immunohistochemistry and flow cytometry using monoclonal antibodies specific for peanut agglutinin (PNA) and GL-7 [6] or PNA and CD38 [7] (see Table 1). The impairment in GC reactions occurring during aging results from not only T cell

Specific antibody responses are impaired in aged mice and humans

Aging in mice is associated with a decreased production of precursor B cells in the bone marrow [19, 20, 21], which also likely reflects a decrease in precursor/stem cells with age [22, 23]. However, the population of mature splenic B cells is maintained, in part, in aged mice because of their increased life-span [24]. This seems to occur because the peripheral pool is filled with B cells that are long-lived at least in part as a consequence of specificity for, and chronic stimulation by,

Molecular mechanisms for the reduced activity of B cells in aged mice and humans

The inability of B cells from old individuals to respond to vaccination is due to a defect in the molecular events leading to the production of secondary isotypes by CSR. In this process, activation-induced cytidine deaminase (AID) is required [44, 45]. AID initiates CSR by the deamination of cytidine residues in S regions, thus creating uracils, and the resulting mismatches are recognized by specific enzymes and excised, leading to DNA double strand breaks [44, 46]. AID is also necessary for

Conclusions

Results in mice and humans provide a possible molecular mechanism for a B cell intrinsic defect in the humoral immune response with aging. Although there are defects in T cells as well as in B cells during aging, these results suggest that improving the aged immune response will likely require methods to directly improve the function of B cells as well as T cells in elderly individuals.

References and recommended reading

Papers of special interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work is supported by NIH AG-23717 and AG28586 (BBB).

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