High TNF-α levels in resting B cells negatively correlate with their response

Abstract

Aging significantly decreases the influenza vaccine-specific response as we and others have previously shown. Based on our previous data in aged mice, we hypothesize that the inflammatory status of the individual and of B cells themselves would impact B cell function. We here show that the ability to generate a vaccine-specific antibody response is negatively correlated with levels of serum TNF-α. Moreover, human unstimulated B cells from elderly make higher levels of TNF-α than those from young individuals and these positively correlate with serum TNF-α levels. These all negatively correlate with B cell function, measured by activation-induced cytidine deaminase (AID), the enzyme of class switch recombination and somatic hypermutation. Only memory B cells (either IgM or switched), but not naïve B cells, make appreciable levels of TNF-α and more in elderly as compared to young individuals. Finally, an anti-TNF-α antibody can increase the response in cultured B cells from the elderly, suggesting that TNF-α secreted by memory B cells affects IgM memory B cells and naïve B cells in an autocrine and/or paracrine manner. Our results show an additional mechanism for reduced B cell function in the elderly and propose B cell-derived TNF-α as another predictive biomarker of in vivo and in vitro B cell responses.

Aging, cytomegalovirus (CMV) and influenza vaccine responses

“…Importantly, levels of TNF-a before stimulation are negatively correlated with the response of the same B cells after in vitro stimulation which is measured by AID. 77 In line with these results, an anti-TNF-a antibody was found to significantly increase the response in cultured B cells from elderly individuals, providing a proof of principle that it is possible to improve class switch in elderly individuals by counteracting autocrine TNF-a. 77 These findings may help to explain the reduced antibody response of elderly individuals to vaccines and also provide biomarkers for good responsiveness and crucial targets for development of more effective vaccines.…”

“…77 In line with these results, an anti-TNF-a antibody was found to significantly increase the response in cultured B cells from elderly individuals, providing a proof of principle that it is possible to improve class switch in elderly individuals by counteracting autocrine TNF-a. 77 These findings may help to explain the reduced antibody response of elderly individuals to vaccines and also provide biomarkers for good responsiveness and crucial targets for development of more effective vaccines. Results from this study indeed identify TNF-a as another B cell-specific biomarker, which can help to predict the quality of in vivo and in vitro B cell responses.…”

“…44,46,77,78,79 Some of the B cell defects we have identified include a reduction in activation-induced cytidine deaminase (AID), the enzyme necessary for class switch recombination (CSR) and SHM; E47, a key transcription factor regulating AID 80 ; and the ability to generate higher affinity antibodies to a new antigen. In the last 5 influenza vaccine seasons (2009-2013), we have measured the antibody response to the seasonal and pandemic influenza vaccines in serum and we have associated this response with the B cell response after vaccination to the vaccine in vitro.…”

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

“…52 Human unstimulated B cells from elderly individuals produce higher levels of TNF-α than those from young individuals, and these higher levels positively correlate with serum TNF-α levels. B cell and serum TNF-α levels negatively correlate with B cell function as measured by AID.…”

“…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).…”