Cytomegalovirus (CMV) seropositivity decreases B cell responses to the influenza vaccine
Introduction
Aging represents a complex remodeling in which innate and adaptive immune responses deteriorate, leading to greater susceptibility to infectious diseases and reduced responses to vaccination [1]. Aging is characterized by increased levels of circulating proinflammatory cytokines, such as TNF-α and IL-6 [2], [3], [4], which have been associated with functional disability/mortality of the elderly. The age-related increase in inflammation is called “inflammaging” [5].
Humoral and cellular immune responses are impaired in aged individuals, leading to decreased antibody responses to vaccination and reduced specific titers. Although defects in T cells [6], [7] and antigen-presenting cells [8], [9] occur, we [10], [11] and others [12], [13] have shown that intrinsic B cell defects occur in aging. 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 somatic hypermutation, and the ability to generate optimal switched memory B cells as well as high-affinity antibodies. AID and switched memory B cells, both measured before vaccination, positively correlate with the serum response, and therefore, are good predictors of the response to vaccines and infectious agents in humans [14], [15], [16], [17], [18].
Cytomegalovirus (CMV) is a β-herpes virus, which latently infects a large proportion (40–70%) of the human population and this proportion increases with age [19]. The infection is asymptomatic in immunocompetent individuals, but may cause severe diseases in immunocompromised hosts. CMV has been postulated to be one of the major driving forces of immunosenescence. CMV infection is associated with premature mortality and is a component of the immune risk phenotype, which predicts remaining longevity in the very elderly [4]. CMV induces the production of a variety of proinflammatory mediators which in turn induce CMV reactivation [20], [21]. It has been shown that CMV-positive elderly have higher levels of inflammatory mediators than CMV-positive young, which may be due to a better control of inflammation by the immune system of young individuals [22].
The CMV-induced changes in vaccine responses of elderly individuals are well documented for T cells [6], [23], but little is known about how CMV infection affects B cell responses. In the present study, we measured CMV effects on in vivo/in vitro B cell responses to the seasonal influenza vaccine and found a significant negative association of CMV-seropositivity with these responses.
Section snippets
Subjects
Experiments were conducted using blood from 62 healthy individuals, 36 young (20–59 years) and 26 elderly (≥60 years), after signed informed consent, and were approved with IRB protocol #20070481. We have previously shown [14], [16], [17], [18] that those aged ≥60 had similar characteristics for the markers we measure (AID). We have also previously shown no gender differences in either the young or elderly groups. The individuals participating in the study were screened for diseases known to
Study population
Demographic characteristics of the individuals participating in the study are in Table 1. Pro-inflammatory status of these individuals is also in Table 1. We have measured plasma levels of the following markers of inflammation: TNF-α, IL-6, CRP, Hsp60, and leptin. Results show increased levels of these in CMV-positive elderly individuals only. We also measured plasma LPS and its ligand, sCD14, which indicate microbial translocation following intestinal permeability [26], and found increased
Discussion
Our knowledge to date about the effect of CMV on B cells is virtually nil. We here show a negative association between CMV-seropositivity and the B cell predictive biomarkers of optimal vaccine responses, switched memory B cells and AID [14], [16], [17]. Another predictive B cell biomarker is TNF-α. Here we show that the levels of intracellular TNF-α in B cells at t0 are increased in CMV-positive individuals, either young or old, and this pre-activated status of the B cells negatively impacts
Conflict of interest statement
No potential conflicts of interest relevant to this article are reported.
Contributors
All authors reviewed, edited and approved the manuscript.
Acknowledgements
This study was supported by NIH AG-32576 (BBB), NIH 5R21AI096446-02 and 1R21AG042826-01 (BBB and DF).
The authors thank the volunteers who participated in this study. The authors also thank the personnel of the Department of Family Medicine and Common Health at the University of Miami Miller School of Medicine, in particular Dr. Robert Schwartz, Chairman and Susie Batista (RN) for the recruitment of healthy volunteers; Dr. Sandra Chen-Walta, Employee Health Manager; and Sylvester Comprehensive
References (36)
- et al.
Ageing and immunity: addressing immune senescence to ensure healthy ageing
Vaccine
(2010) - et al.
Distinct categories of immunologic changes in frail elderly
Mech Ageing Dev
(2000) - et al.
Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly
Am J Med
(1999) - et al.
The immune risk phenotype is associated with IL-6 in the terminal decline stage: findings from the Swedish NONA immune longitudinal study of very late life functioning
Mech Ageing Dev
(2006) - et al.
Aging of the innate immune system
Curr Opin Immunol
(2010) - et al.
B cells and aging: molecules and mechanisms
Trends Immunol
(2009) - et al.
Intrinsic defects in B cell response to seasonal influenza vaccination in elderly humans
Vaccine
(2010) - et al.
Young and elderly patients with type 2 diabetes have optimal B cell responses to the seasonal influenza vaccine
Vaccine
(2013) - et al.
The impact of CMV infection on survival in older humans
Curr Opin Immunol
(2012) The ′indirect′ effects of cytomegalovirus infection
Am J Transplant
(2009)
Stimulation of the human cytomegalovirus IE enhancer/promoter in HL-60 cells by TNFalpha is mediated via induction of NF-kappaB
Virology
Inflammation, ageing and chronic disease
Curr Opin Immunol
Cytomegalovirus-associated accumulation of late-differentiated CD4 T-cells correlates with poor humoral response to influenza vaccination
Vaccine
Immunosenescence: what does it mean to health outcomes in older adults?
Curr Opin Immunol
Biomarkers of human immunosenescence: impact of cytomegalovirus infection
Curr Opin Immunol
Role of cytomegalovirus in the T cell changes seen in elderly individuals
Clin Immunol
Association between cytomegalovirus infection, enhanced proinflammatory response and low level of anti-hemagglutinins during the anti-influenza vaccination—an impact of immunosenescence
Vaccine
The unmet need in the elderly: how immunosenescence, CMV infection, co-morbidities and frailty are a challenge for the development of more effective influenza vaccines
Vaccine
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