SUMMARY Systems approaches have been used to describe molecular signatures driving immunity to influenza vaccination in humans. Whether such signatures are similar across multiple seasons and in diverse populations is unknown. We applied systems approaches to study immune responses in young, elderly, and diabetic subjects vaccinated with the seasonal influenza vaccine across five consecutive seasons. Signatures of innate immunity and plasmablasts correlated with and predicted influenza antibody titers at 1 month after vaccination with >80% accuracy across multiple seasons but were not associated with the longevity of the response. Baseline signatures of lymphocyte and monocyte inflammation were positively and negatively correlated, respectively, with antibody responses at 1 month. Finally, integrative analysis of microRNAs and transcriptomic profiling revealed potential regulators of vaccine immunity. These results identify shared vaccine-induced signatures across multiple seasons and in diverse populations and might help guide the development of next-generation vaccines that provide persistent immunity against influenza.

Elderly humans have compromised humoral and cellular immune responses, which lead to reduced protection to infectious agents and to vaccines. Currently, available vaccines suboptimally protect the elderly population. The capacity to class switch the Ig H chain is critical to the effectiveness of humoral immune responses in mice and humans. We have previously shown in mice that the E2A-encoded transcription factor E47, which regulates many B cell functions, is down-regulated in old splenic B cells. This leads to a reduction in the activation-induced cytidine deaminase (AID), which is known to induce class switch recombination and Ig somatic hypermutation. The old activated murine B cells also have less AID and less switched Abs. We have extended our study here to investigate whether aging also affects Ab production and E47 and AID expression in B cells isolated from the peripheral blood of human subjects (18–86 years). Our results obtained with activated CD19+ B cells show that the expression of E47, AID, and Igγ1 circle transcripts progressively decrease with age. We also show an age-related decline in the percentage of switch memory B cells (IgG+/IgA+), an increase in that of naive B cells (IgG−/IgA−/CD27−) for most individuals, and no decrease in that of IgM memory cells in peripheral blood, consistent with our data on the decrease seen in class switch recombination in vitro. Our results provide a possible molecular mechanism for a B cell intrinsic defect in the humoral immune response with aging and suggest avenues for improvement of vaccine response in elderly humans.

Major advances in preventing, delaying or curing individual pathologies are responsible for an increasingly long life span in the developed parts of our planet, and indeed reaching 8–9 decades of life is nowadays extremely frequent. However, medical and sanitary advances have not prevented or delayed the underlying cause of the disparate pathologies occurring in the elderly: aging itself. The identification of the basis of the aging processes that drives the multiple pathologies and loss of function typical of older individuals is a major challenge in current aging research. Among the possible causes, an impairment of the immune system plays a major role, and indeed numerous studies have described immunological changes which occur with age. Far from the intention of being exhaustive, this review will focus on recent advances and views on the role that modifications of cell signalling and remodelling of the immune response play during human aging and longevity, paying particular attention to phenomena which are linked to the so called inflammaging process, such as dysregulation of innate immunity, altered T-cell or B-cell maturation and differentiation, as well as to the implications of immune aging for vaccination strategies in the elderly.

Both the innate and adaptive immune systems decline with age, causing greater susceptibility to infectious diseases and reduced responses to vaccination. Diseases are more severe in elderly than in young individuals and have a greater impact on health outcomes such as morbidity, disability and mortality. Aging is characterized by increased low-grade chronic inflammation, called “inflammaging”, measured by circulating levels of TNF-α, IL-6 and CRP, as well as by latent infections with viruses such as cytomegalovirus (CMV). Inflammaging has received considerable attention because it proposes a link between changes in immune cells and a number of diseases and syndromes typical of old age. In this review we aim at summarizing the current knowledge on pathways contributing to inflammaging, on immune responses down-regulated by inflammation and mechanisms proposed. The defects in the immune response of elderly individuals presented in this review should help to discover avenues for effective intervention to promote healthy aging.

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.

Both humoral and cellular immune responses are impaired in aged individuals, leading to decreased vaccine responses. Although T cell defects occur, defects in B cells play a significant role in age-related humoral immune changes. The ability to undergo class switch recombination (CSR), the enzyme for CSR, AID (activation-induced cytidine deaminase) and the transcription factor E47 are all decreased in aged stimulated B cells. We here present an overview of agerelated changes in human B cell markers and functions, and also discuss some controversies in the field of B cell aging.

We have evaluated the serum response to seasonal influenza vaccination in subjects of different ages and associated this with the specific B cell response to the vaccine in vitro. Although the serum response has previously been shown to decrease with age, this has largely been associated to decreased T cell functions. Our results show that in response to the vaccine, the specific response of B cells in vitro, as measured by AID (activation-induced cytidine deaminase), the in vivo serum HI (hemagglutination inhibition) response, and the in vivo generation of switch memory B cells are decreased with age, as evaluated in the same subjects. This is the first report to demonstrate that intrinsic B cell defects with age contribute to reduced antibody responses to the influenza vaccine. The level of AID in response to CpG before vaccination can also predict the robustness of the vaccine response. These results could contribute to developing more effective vaccines to protect the elderly as well as identifying those most at risk.

The increase in the prevalence of obesity represents a worldwide phenomenon in all age groups and is pathologically and genetically correlated with several metabolic and cardiovascular diseases, representing the most frequent age-related diseases. Obesity superimposed on aging drastically increases chronic low-grade inflammation (inflammaging), which is an important link between obesity, insulin resistance, and age-associated diseases. Immune cells of both the innate and the adaptive immune systems infiltrate the adipose tissue (AT) and during obesity induce inflammatory responses associated with metabolic switches and changes in phenotypes and function of immune cell subsets. Obesity poses new health problems especially when it occurs in the context of other diseases, many of them frequently affect elderly subjects. An emerging problem is the decreased proportion of patients with obesity achieving clinical response to therapy. In this review, we will discuss the reciprocal influences of immune cell and AT inflammation in aging and age-associated diseases and the complex relationship of nutrient and energy-sensing homeostatic checkpoints, which contribute to shape the phenotype of the AT. We will specifically examine type-2 diabetes, rheumatoid arthritis, osteoarthritis, cognitive impairment, and dementia, where obesity plays a significant role, also in shaping some clinical aspects.