Senescence of the Human Immune System
Introduction
Dysregulated or compromised immunity is commonly assumed to be the cause of the increased susceptibility and sensitivity to infectious disease in old people and their poor responses to vaccination. Animal models are consistent with this idea, but are mostly limited to work in mice and limited data from rhesus monkeys. Over the years, many reports of associations between morbidity and mortality and changes in certain immune parameters in people have been published. However, most data are derived from cross-sectional studies on different young and old populations. Here, we focus on the search for immune biomarkers representing a risk profile for morbidity and mortality in the elderly. These can, nonetheless, never establish causality, only association. We propose that due to the marked effect of infection with the persistent herpesvirus cytomegalovirus (CMV) on immune parameters, studies of biomarkers of immune ageing must always take this into account. Moreover, people differ markedly from one another in the circumstances of their development, their genetic background, lifelong environment and nutrition. Studies in mouse models are inadequate to parallel such human characteristics. Studying companion animals longitudinally would offer a unique opportunity for comparative immunogerontology under conditions including a high degree of sharing of the day-to-day living environment.
Section snippets
The Immune Risk Profile
The concept of the immune risk profile (IRP) emerged from the longitudinal Swedish OCTO/NONA-immune studies of free-living people >85 years of age, with OCTO participants selected for very good health, whereas NONA participants were representative of the population (only around 10% in really excellent health). The IRP is currently characterized by a 100% infection rate with CMV (as opposed to 85% in the non-IRP elderly of the same age) and a CD4:8 ratio of <1 due to an accumulation of
Overall Changes to Human Immunity Thought to be Age-Associated
While we cannot say whether observed changes to immune parameters are caused by the ‘ageing process’ itself or by events occurring independently of strict chronological time, but requiring a certain duration for their effects to be felt (e.g. multiple infections for different periods of time), data from both cross-sectional and the few longitudinal studies available point to age-associated changes in B cells and innate immune cells to some extent (Della-Bella et al., 2007, Agrawal et al., 2008,
What Effects do these Changes have on Responses to Vaccination in the Elderly?
There is an extensive literature on the effect of ageing on responses to influenza vaccination in people (reviewed in Aspinall et al., 2007, Grubeck-Loebenstein et al., 2009), in general concluding that whereas current vaccines are 70–90% effective in generating what is assumed to be protective levels of antibody in young adults, this figure may be only 17–53% in the elderly (Goodwin et al., 2006). However, the common belief that even when elderly people do respond to the vaccine, antibody
Impact of CMV: Cause of Age-Associated Immune Changes?
Many studies now show that immune signatures rapidly change to a more ‘elderly’ profile on CMV infection. This happens quite quickly after primary infection in apparently healthy people as well as those immunosuppressed for transplantation (Khan et al., 2007, Waller et al., 2008, van de Berg et al., 2008). Perhaps many of the ‘age-associated’ changes seen in human immune profiles can in fact be attributed to CMV infection and intermittent reactivation throughout life (Lang et al., 2002), which
Conclusions
Taken together, chronic stimulation of the immune system, either by infectious agents, which could be other than CMV in companion animals (Foley et al., 1997), or other chronic stresses such as the amyloid precursor protein family, may have an important impact on the immune system and on mortality in fine. Therefore, ageing of the immune system must be measured not only in chronological time, but in terms of the ‘immunological history’ of the individual. Thus, each individual will experience a
Conflict of Interest
The first author was an invited speaker at the Merial European Comparative Vaccinology Symposium and received travel expenses and an honorarium for this presentation.
Acknowledgments
The authors' work was supported by the Deutsche Forschungsgemeinschaft (DFG PA361-11/1) and the European Commission (EU-LSHG-CT-2007-036894 ‘LifeSpan’).
References (48)
- et al.
A fingerprint left by cytomegalovirus infection in the human T cell compartment
Journal of Clinical Virology
(2008) - et al.
Peripheral blood dendritic cells and monocytes are differently regulated in the elderly
Clinical Immunology
(2007) - et al.
Human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space
Vaccine
(2000) - et al.
Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans
Mechanisms in Ageing and Development
(2007) - et al.
Antibody response to influenza vaccination in the elderly: a quantitative review
Vaccine
(2006) - et al.
Aging and T-cell diversity
Experimental Gerontology
(2007) - et al.
Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor
Immunity
(2009) - et al.
Chronic herpesvirus reactivation occurs in aging
Experimental Gerontology
(2007) - et al.
No immune risk profile among individuals who reach 100 years of age: findings from the Swedish NONA immune longitudinal study
Experimental Gerontology
(2007) - et al.
Association between cytomegalovirus infection, enhanced proinflammatory response and low level of anti-hemagglutinins during the anti-influenza vaccination – an impact of immunosenescence
Vaccine
(2003)
Lower GrB+ CD62Lhigh CD8 TCM effector lymphocyte response to influenza virus in older adults is associated with increased CD28null CD8 T lymphocytes
Mechanisms of Ageing and Development
Biology of dendritic cells in aging
Journal of Clinical Immunology
Challenges for vaccination in the elderly
Immunity and Ageing
Predicting behavioral changes associated with age-related cognitive impairment in dogs
Journal of the American Veterinary Medical Association
Regulatory T cells and infection: a dangerous necessity
Nature Reviews Immunology
Dendritic cell programming by cytomegalovirus stunts naive T cell responses via the PD-L1/PD-1 pathway
Journal of Immunology
Cytomegalovirus seropositivity has a profound influence on the magnitude of major lymphoid subsets within healthy individuals
Clinical and Experimental Immunology
B cell immunosenescence in the elderly and in centenarians
Rejuvenation Research
Biomarkers of human immunosenescence: impact of cytomegalovirus infection
Current Opinion in Immunology
Socioeconomic disparities in the seroprevalence of cytomegalovirus infection in the US population: NHANES III
Epidemiology and Infection
Prevaccine determination of the expression of costimulatory B7 molecules in activated monocytes predicts influenza vaccine responses in young and older adults
Journal of Infectious Diseases
Risk factors for feline infectious peritonitis among cats in multiple-cat environments with endemic feline enteric coronavirus
Journal of the American Veterinary Medical Association
B-cell diversity decreases in old age and is correlated with poor health status
Aging Cell
Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals
Journal of Virology
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