Obesity decreases B cell responses in young and elderly individuals

Abstract

Objective To evaluate the effects of obesity-associated inflammation on influenza vaccine responses. Methods We measured in young and elderly individuals, both lean and with obesity, antibody responses to influenza vaccination. Results We found a decrease in in vivo vaccine responses, circulating switched memory and transitional B cells and an increase in pro-inflammatory late/exhausted memory B cells. In vitro B cell function was measured by activation-induced cytidine deaminase (AID) and E47, markers of optimal antibody responses. Moreover, IL-6 production was increased, whereas IL-10 production was decreased, in cultures of B cells from individuals with obesity. Markers of immune activation (TNF-α, TLR4, micro-RNAs) in unstimulated B cells were also found increased and were negatively correlated with B cell function. In order to reveal potential mechanisms, we stimulated B cells from lean individuals in vitro with leptin, the adipokine increased in obesity. Leptin increased phospho-STAT3, crucial for TNF-α production, and decreased phospho-AMPK, the energy sensing enzyme upstream of phospho-p38 MAPK and E47. Leptin-induced phospho-STAT3 and phospho-AMPK levels were similar to those in B cells from individuals with obesity. Conclusions These results demonstrate that leptin can be responsible for decreased B cell function in obesity.

The generation of memory B cells is maintained, but the antibody response is not, in the elderly after repeated influenza immunizations

“…These defects include a reduction in activation-induced cytidine deaminase (AID), the enzyme for class switch recombination (CSR) and somatic hypermutation; E47, encoded by the E2A gene, a key transcription factor regulating AID [27, 28], and the ability to generate higher affinity antibodies to a new antigen. We hypothesize that individuals with good E47/AID/CSR will have good primary and secondary antibody responses and those with reduced CSR will have defects in the generation of memory B cells and therefore their response to a new vaccine would be severely impacted, but the number of existing memory B cells might be maintained/amplified by repeated immunization.…”

B Cell–Specific Biomarkers for Optimal Antibody Responses to Influenza Vaccination and Molecular Pathways That Reduce B Cell Function with Aging

“…37,42,43,48,52,53 These defects include (1) reduced activation-induced cytidine deaminase (AID), the enzyme for class switch recombination (CSR), and somatic hypermutation (SHM);(2) reduced E47, encoded by the E2A gene, a key transcription factor regulating AID 54,55 ; and (3) reduced ability to generate higher affinity antibodies to a new antigen. Table 1 summarizes our major results obtained during consecutive influenza vaccine seasons (2011–2014).…”

“…We found CpG-induced AID before vaccination to be a good B cell biomarker that is reduced in B cells from elderly individuals when compared to young individuals, and to be significantly correlated with in vivo antibody response to the vaccine. 42,43,55 For this reason, we proposed AID as good predictive biomarkers for response to vaccines and infectious agents in humans. 42,43 Levels of the transcription factor E47 in CpG-stimulated B cells were also correlated with in vivo response to the vaccine.…”

“…42,43 Levels of the transcription factor E47 in CpG-stimulated B cells were also correlated with in vivo response to the vaccine. 55 …”

“…Switched memory B cells (CD19+IgD−CD27+), which are also good B cell biomarkers, are reduced in elderly individuals 48,55,85,86 when compared to young individuals and are significantly correlated with in vivo antibody response to the vaccine. 42,43 Switched memory B cells are generated from naïve and/or IgM memory B cells that have undergone CSR.…”