Jean L. Scholz

Tonic B cell antigen receptor signals supply an NF-κB substrate for prosurvival BLyS signaling

The survival of transitional and mature B cells requires both the B cell antigen receptor (BCR) and BLyS receptor 3 (BR3), which suggests that these receptors send signals that are nonredundant or that engage in crosstalk with each other. Here we show that BCR signaling induced production of the nonclassical transcription factor NF-κB pathway substrate p100, which is required for transmission of BR3 signals and thus B cell survival. The capacity for sustained p100 production emerged during transitional B cell differentiation, the stage at which BCR signals begin to mediate survival rather than negative selection. Our findings identify a molecular mechanism for the reliance of primary B cells on continuous BR3 and BCR signaling, as well as for the gradual resistance to negative selection that is acquired during B cell maturation.

BLyS inhibition eliminates primary B cells but leaves natural and acquired humoral immunity intact

We have used an inhibiting antibody to determine whether preimmune versus antigen-experienced B cells differ in their requisites for BLyS, a cytokine that controls differentiation and survival. Whereas in vivo BLyS inhibition profoundly reduced naïve B cell numbers and primary immune responses, it had a markedly smaller effect on memory B cells and long-lived plasma cells, as well as secondary immune responses. There was heterogeneity within the memory pools, because IgM-bearing memory cells were sensitive to BLyS depletion whereas IgG-bearing memory cells were not, although both were more resistant than naïve cells. There was also heterogeneity within B1 pools, as splenic but not peritoneal B1 cells were diminished by anti-BLyS treatment, yet the number of natural antibody-secreting cells remained constant. Together, these findings show that memory B cells and natural antibody-secreting cells are BLyS-independent and suggest that these pools can be separately manipulated.

A B-cell subset uniquely responsive to innate stimuli accumulates in aged mice

We have discovered a distinct mature B-cell subset that accumulates with age, which we have termed age-associated B cells. These cells comprise up to 30% of mature B cells by 22 months. Despite sharing some features with other mature B-cell subsets, they are refractory to BCR and CD40 stimulation. Instead, they respond to TLR9 or TLR7 stimulation and divide maximally on combined BCR and TLR ligation, leading to Ig production and preferential secretion of IL-10 and IL-4. Although similar to follicular B cells in both B-lymphocyte stimulator (BLyS) receptor expression and BLyS binding capacity, these cells do not rely on BLyS for survival. They are neither cycling nor the result of intrinsically altered B lymphopoiesis in aged BM, but instead appear to be generated from mature B cells that exhaustively expand during the individuals lifetime. Finally, they present Ag effectively and favor polarization to a TH17 profile. Together, these findings reveal that while the magnitude of the mature primary B-cell niche is maintained with age, it is increasingly occupied by cells refractory to BCR-driven activation yet responsive to innate receptor stimulation.

B cells and aging: molecules and mechanisms.

Recent advances allow aging-associated changes in B-cell function to be approached at a mechanistic level. Reduced expression of genes crucial to lineage commitment and differentiation yield diminished B-cell production. Moreover, intrinsic differences in the repertoire generated by B-cell precursors in aged individuals, coupled with falling B-cell generation rates and life-long homeostatic competition, result in narrowed clonotypic diversity. Similarly, reductions in gene products crucial for immunoglobulin class switch recombination and somatic hypermutation impact the efficacy of humoral immune responses. Together, these findings set the stage for integrated analyses of how age-related changes at the molecular, cellular and population levels interact to yield the overall aging phenotype.

B cell maintenance and function in aging.

In this review we discuss the changes that occur in the B lymphocyte compartment of mice and humans as they progress to old age, focusing on recent advances in this important area of research. Primary areas considered include increased morbidity and mortality in the elderly following infection, and decreased responsiveness to vaccines that evoke primary humoral immune responses, as well as those that evoke responses by memory B cells generated following vaccination and natural infection earlier in life. We then consider some of the mechanisms that may underlie these observed declines in humoral immune function. This includes a discussion of alterations in B cell repertoire and subcompartment distribution, as well as defects in B lymphopoiesis, cell development and homeostasis that may contribute to these alterations, and ultimately to declining protective quality of antibodies produced in the elderly.

Local BLyS production by T follicular cells mediates retention of high affinity B cells during affinity maturation

BLyS expression by GC follicular T cells is required for the efficient selection of high-affinity GC B cells.

Targeting BLyS in rheumatic disease: the sometimes-bumpy road from bench to bedside

Purpose of reviewBLyS family ligands and receptors are key players in the selection and survival of most mature B lymphocytes. The fundamental role of BLyS in transitional B cell selection, coupled with the relative BLyS-independence of memory B cells and plasma cells, suggests that BLyS may be a useful therapeutic target in strategies directed against preimmune B cell pools. Several agents that target BLyS are in clinical trials now, and we summarize recent results here, with a focus on systemic lupus erythematosus (SLE). Recent findingsBelimumab, a human neutralizing anti-BLyS monoclonal antibody, has delivered moderate but positive results in two separate phase III clinical trials for SLE, and was recently recommended for approval by an FDA advisory panel. Additional agents targeting BLyS or other members of this cytokine receptor family are also being tested in clinical trials. SummaryTogether, these trials should yield novel therapies for a debilitating and often intractable illness and offer insights that in turn should foster subsequent generations of personalized, targeted therapies for rheumatic diseases.

A comparative review of aging and B cell function in mice and humans.

Immune system function declines with age. Here we review and compare age-associated changes in murine and human B cell pools and humoral immune responses. We summarize changes in B cell generation and homeostasis, as well as notable changes at the subcellular level; then discuss how these changes help to explain alterations in immune responses across the adult lifespan of the animal. In each section we compare and contrast findings in the mouse, arguably the best animal model of the aging immune system, with current understanding of B cell immunity in humans.

Homeostatic control of B lymphocyte subsets

Lymphocyte homeostasis poses a multi-faceted biological puzzle, because steady pre-immune populations must be maintained at an acceptable steady state to yield effective protection, despite stringent selective events during their generation. In addition, activated, memory and both short- and long-term effectors must be governed by independent homeostatic mechanisms. Finally, advancing age is accompanied by substantial changes that impact the dynamics and behavior of these pools, leading to cumulative homeostatic perturbations and compensation. Our laboratory has focused on the overarching role of BLyS family ligands and receptors in these processes. These studies have led to a conceptual framework within which distinct homeostatic niches are specified by BLyS receptor signatures, which define the BLyS family ligands that can afford survival. The cues for establishing these receptor signatures, as well as the downstream survival mechanisms involved, are integrated with cell extrinsic inputs via cross talk among downstream mediators. A refined understanding of these relationships should yield insight into the selection and maintenance of B cell subsets, as well as an appreciation of how homeostatic mechanisms may contribute to immunosenescence.

BLyS-mediated modulation of naïve B cell subsets impacts HIV Env-induced antibody responses

Neutralizing Abs provide the protective effect of the majority of existing human vaccines. For a prophylactic vaccine against HIV-1, broadly neutralizing Abs targeting conserved epitopes of the viral envelope glycoproteins (Env) are likely required, because the pool of circulating HIV-1 variants is extremely diverse. The failure to efficiently induce broadly neutralizing Abs by vaccination may be due to the use of suboptimal immunogens or immunization regimens, or it may indicate that B cells specific for broadly neutralizing Env determinants are selected against during peripheral checkpoints, either before or after Ag encounter. To investigate whether perturbation of B cell subsets prior to immunization with recombinant Env protein affects the vaccine-induced Ab response in mice, we used B lymphocyte stimulator (BLyS), a cytokine that regulates survival and selection of peripheral B cells. We show that the transient BLyS treatment used in this study substantially affected naive B cell populations; in particular, it resulted in more B cells surviving counter-selection at the transitional stages. We also observed more mature naive B cells, especially marginal zone B cells, in BLyS-treated mice. Intriguingly, provision of excess BLyS prior to immunization led to a consistent improvement in the frequency and potency of HIV-1 Env vaccine-induced neutralizing Ab responses, without increasing the number of Env-specific Ab-secreting cells or the Ab-binding titers measured after boosting. The results presented in this article suggest that an increased understanding of BLyS-regulated processes may help the design of vaccine regimens aimed at eliciting improved neutralizing Ab responses against HIV-1.