The Immune System in the Elderly: A Fair Fight Against Diseases?

Anis Larbi; Paulina Rymkiewicz; Anusha Vasudev; Ivy Low; Nurhidaya Binte Shadan; Seri Mustafah; Shamini Ayyadhury; Tamas Fulop

Disclosures

Aging Health. 2013;9(1):35-47. 

In This Article

Immunity in Age-related Diseases

On the Stratification of Elderly

One issue in the field of aging is the heterogeneity of the elderly population. Many studies for immunogerontological studies have been performed using the SENIEUR protocol. The SENIEUR protocol has been initially established to normalize the categories of individuals participating in such studies and avoid discrepancies due to different inclusion/exclusion criteria and selection processes. However, based on the discrepancies of immunological data in aging, it is likely that the SENIEUR protocol is not routinely used in the field. This highlights the necessity to better stratify the individuals selected for such studies. The 'apparently healthy' elderly often have underlying conditions such as diabetes, hypertension or high levels of proinflammatory molecules (e.g., CRP and IL-6) and, thus, may display different immune alterations than the 'successful aging' individuals. The correct use of the SENIEUR protocol enables us to identify responders versus nonresponders following influenza vaccination.[22] The SENIEUR elderly responded to vaccination, while hyporesponsiveness was associated with circulatory diseases and cognition. Thus, the stratification of elderly individuals is necessary at the benchside because it is used at the bedside.[23] A comprehensive review of the immunological studies involving SENIEUR versus non-SENIEUR would be necessary to better evaluate the age-associated changes versus age-related diseases/conditions. The following sections will focus on the relationship between diseases in the elderly and the immune system.

Infectious Diseases

The aged immune system is not as efficient in recognizing and eliminating new invaders or in preventing their spread. Age-associated alterations in systemic immunity contribute to the increased incidence and severity of infectious diseases in older people.[24] Infectious diseases are disorders caused by organisms such as bacteria, viruses, fungi or parasites. The symptoms are fever, fatigue, loss of appetite, weight loss and pain. These organisms often encounter less resistance after invading the elderly. The mechanical barrier, the skin, is the first line of defense against invasion and shows signs of thinning of epidermis and decreased granular secretions resulting in more infections following trauma and injuries in older people. Infections may occur early in life and persist for years/decades if not cleared from the organism. This is the case for CMV, one of the most immune-dominant antigens that stimulates immune responses of unprecedented magnitude. CMV is asymptomatic in most individuals and only in rare cases CMV disease develops.[25] This is the case of HIV-infected and CMV-seropositive individuals under immunosuppressive therapy (e.g., transplant patients) and during pregnancy. The prevalence for CMV varies from 45 to 100% according to age, location and hygiene conditions. CMV prevalence is lower in Europe/USA and higher in Africa/Asia, but within continents and large countries significant differences exist.[25] Old individuals experience accumulation of CMV specific CD8+ T cells and reduction of the number and frequency of circulating naive T cells. The accumulation by clonal expansion reduces the space for CD8+ T cells carrying receptors that are specific for antigens other than CMV.[26] This results in the filling of the immunological space with clones specific for limited antigens. Although dormant CMV does not seem to be a problem in healthy individuals, it has profound effects on the overall immune system even at a younger age and health that may lead to chronic conditions.[16] Influenza remains the leading cause of death by infection among elderly people. It is also the most important agent of outbreaks of respiratory illness.[27] The risk of influenza-related death increases exponentially after the age of 65 years.[28] Influenza per se is not directly inducing death, but the events associated with influenza are detrimental, especially in elderly individuals with poor resilience (Figure 2).

Figure 2.

Impact of cytomegalovirus infection on immunity and health. With aging there is an elevated proinflammatory profile that is enhanced by CMV infection. Associated comorbidities and poor resilience will add up to the existing condition and may lead individuals to be at risk later in life, as suggested by the IRP. This will be reflected into different mortality, morbidity and quality of life grades.
+: Present; +++: Very high; ---: Very low; CMV: Cytomegalovirus; IRP: Immune Risk Profile.

The lifelong exposure to a multitude of pathogens leads to a relative increase in the proportion of memory T cells. The most observable phenotypic and functional changes occur in the CD8+ T-cell subsets. The continuous stimulation of memory cells by the respective antigens (mostly the persistent antigens such as CMV) leads to their progressive exhaustion. This is usually characterized by the loss of costimulatory molecules (CD28 and CD27), shortening of telomeres and terminal differentiation (CD45RA+CD57+). These cells are differently responsive to mechanisms involved in homeostasis, proliferation and apoptosis, explaining their accumulation. The loss of CD28 expression is permanent and these cells can be used to assess the immunological aging induced by the multiple pathogens over a lifetime. There is a significant association between proportions of CD8+CD28 T cells and antibody responses to influenza vaccination[29] and seropositivity for CMV.[30] It is expected that CD8+CD28 memory T cells expand in response to persistent infections such as CMV, but in the absence of CMV other candidates such as Epstein-Barr virus (EBV) exist. It has been shown that the presence of CMV and CMV-specific T cells hinders the response to co-infections such as EBV.[31] Indeed, while elderly individuals display high numbers of CMV-responding cells, the response to EBV antigens is affected by the CMV serostatus. Only CMV seronegative cells display increased response to EBV with age, while elderly individuals with CMV history display no increased levels of immunity to EBV.

In elderly individuals, accumulation of these virus-specific CD8+ T cells compromises immune function and restricts the overall immune repertoire. CMV infection has been associated with the Immune Risk Profile (IRP), a cluster of parameters predicting mortality in the elderly (Figure 2). Apart from CMV seropositivity, increased frequency numbers of CD8+CD28 T cells, an inverted CD4:CD8 ratio (<1) and low B-cell numbers are part of the IRP.[32] It has been reported that CMV-specific T cells are largely terminally differentiated TEMRA cells.[33] Several studies have questioned whether chronic CMV infection is the major driving force for age-related changes in CD8+ T-cell subsets,[32] and some have clearly shown that CMV- and HIV-specific T cells have similar profiles compared with EBV- or hepatitis C virus-specific T cells.[33] The association between CMV infection and the IRP was shown not to be present in cohort studies that took into account the genetic aspect of longevity.[34] However, CMV seropositivity did correlate with metabolic conditions, such as glucose regulation, which suggest that stratification of the elderly population is necessary to better understand aging and age-associated conditions.[35]

The phenomenon discussed above is not restricted to viral antigens. Cancer patients also display expansion of the CD8+CD28 T-cell population. This expansion over the course of the disease is slowing down after tumor resection, confirming the hypothesis that chronic antigenic stimulation is driving CD8+ T cells towards end-stage differentiation and functional erosion. CD8+CD28 T cells also exhibit suppressor activities which may alter antigen presentation, possibly contributing to the well-documented changes in dendritic cell function during aging.[36] In contrast to the CD8+ population during aging, CD4+ T cells are less affected by replicative senescence. A normal CD4+ T-cell response, in response to influenza vaccination, is observed in older adults, but over the long term, the memory CD4+ T-cell response is impaired.[37] Overall, CD8+, CD4+ and putative antigen presenting cell changes may underlie an altered interaction between these cells leading to reduced vaccine efficacy.

Alzheimer's Disease

Alzheimer's disease (AD) is an age-related neurological disorder that leads to progressive dementia. AD is histopathologically characterized by extracellular amyloid plaques formed by amyloid-β (Aβ) peptide and by intracellular neurofibrillary tangles. The inflammation resulting from deposits of highly aggregated Aβ fibrils plays an important role in the pathogenesis of AD.[38] AD patients demonstrate changes in the distribution of lymphocyte subsets in the peripheral blood compared with controls coming from elderly donors, thereby the number of natural killer (NK) cells stays constant, whereas the numbers of T cells, especially the CD8+ population, and B cells decreases.[39] As for helper versus cytotoxic T cells, a slight increase of the percentage of CD4+ and decrease of CD8+ lymphocytes was found. Lower percentages of naive CD4+ cells (CD45RA+CCR7+) and higher percentages of effector memory (CD45RACCR7) and TEMRA (CD45RA+CCR7) cells have been detected in the Canadian pilot study of AD patients. Reduced numbers of Treg cells (CD4+CD25high) were found.[40] By contrast, no differences in the CD8 population were detected. This is probably due to the high susceptibility of CD8+ T cells to viral antigens, such as CMV, that are inducing a strong immunological aging. We propose that changes to the CD4 compartment might be the result of chronic stimulation by Aβ present in the blood.[41]

In the brain, microglia express MHC class I and II molecules after activation. This can be caused by neurodegeneration or ischemia.[42] By contrast, the activation of microglia in the brain of AD patients is caused by Aβ. As a result of the activation, the activated microglia cluster at sites of Aβ deposition.[43] It is known that microglia from elderly donors show changes in their cytoplasmic structure, which can lead to functional defects and thus to the development of AD in the elderly, but it still remains unknown how the activation of microglia is influenced by age and senescence.[43]

Cardiovascular Diseases

The aging process is accelerated when metabolic and cardiovascular diseases are present, and this impacts on the susceptibility for other diseases.[44] Cardiovascular heart disease is the leading cause of death in elderly individuals over the age of 65 years.[45] Several risk factors that can contribute to heart disease include stress, lifestyle (e.g., lack of exercise, smoking and high consumption of alcohol), family history, obesity, hypertension, high cholesterol levels and diabetes. There are several types of cardiovascular diseases associated with aging. This is linked to higher prevalence of coronary disease, hypertension, diabetes, ventricular hypertrophy, fibrosis and aging/senescence of cardiac cells leading to events that may predict more severe cardiac failure.[46,47]

In the case of atherosclerosis, there is a strong immune component that includes T cells and monocytes/macrophages. In the very early atherosclerotic lesions T cells prevail.[48] These plaques are composed of activated helper T cells and also γ/δ T cells, macrophages, smooth muscle cells and CD1a+ dendritic cells, whereas B cells and NK cells were absent.[49] These cells present in atherosclerotic plaques are sitting and also inducing a proinflammatory milieu that favors maintenance of the inflammation and the development of the lesions. As aging is associated with increased levels of proinflammatory molecules, it is hypothesized that altered immunity in the elderly is the driving force synergizing with other dysfunctional systems to induce and sustain such pathologies. Patients suffering from stroke display signs of an inflammatory phenotype, especially in brain microvessels. Innate cells such as neutrophils participate in the development of ischemic stroke. CD4+ T cells will modulate immune response by secreting type-2 cytokines (IL-4 and IL-10) or type-1 cytokines (IL-12, IFN-γ and TNF-α). The majority of the T cells present in atherosclerotic plaques are memory cells lacking CD28 expression. These cells have a poor proliferative capacity but a higher proinflammatory/cytotoxic (IFN-γ and TNF-α) profile.[15] Increasing the frequency of circulating senescent T cells may increase the access of atherosclerotic lesions to such cells that will sustain the local inflammation and drive disease progression.

Cancer

Immunosurveillance against cancer is a daily fight of the immune system. It allows the killing of nascent tumor and the dissemination of cancer cells.[50] The incidence of cancer increases with advancing age.[51] This is due to a cumulative number of events such as exposure to carcinogens, accumulation of mutations and diminishing of immune functions. Among the alterations that diminish immune function in aged people are: decreased functional B and T cells; modifications in the production and secretion of cytokines; reduced cytotoxic activity of CD8+ T cells; qualitative deficiency of B lymphocytes with reduced response to exogenous antigens; NK cell activity decline; and also possible deficiency in antigen-presenting cells.[51] One of the most important cell types for cancer killing is the NK cells and there are several studies clearly showing alterations in phenotype and functionality of NK cells with aging. While the CD56bright population decreased there are more of the CD56dim mature cells.[52] In healthy elderly individuals, the killing, proliferative and response of NK cells to triggering was shown to be reduced.[53,54] More recently, it was shown that the reduced killing may be explained by the altered perforin release and interaction at the immunological synapse site of the target cell.[55] While the formation of the immunological synapse, CD69 expression and intracellular levels of perforin/granzyme B were still comparable in NK cells from young versus elderly individuals, there was a reduced binding of perforin to the target cell membrane. This mechanism can explain the reason why elderly individuals are more susceptible to cancers. There is also a decrease in naive T-cell population and an increase in memory T cells. The filling of the immunological space by virus-specific T cells is initiated by the filling of the immunological space and, thus, reducing receptor diversity, enabling identification and the fight against new antigens such as cancer cells. Such an imbalance of the memory/naive subpopulations can cause the hyporesponsive state of the elderly. Thymic involution is a well-described phenomemon, and the age-related T-cell dysfunctions and immunosenescence, in general, are candidates to explain the increased susceptibility to infections with aging, but the impact of immunosenescence on cancer immunosurveillance has not been clearly described. However, it has been clearly described that immune-compromised individuals (e.g., HIV patients) are more susceptible to non-Hodgkin's lymphoma and cervical cancer.[56] It has been reported that the wild-type mice show less carcinogen-induced and spontaneous cancers than immune-deficient mice.[57] To link inflammation and cancer emergence, it was shown that tumors induce a local inflammation that suppresses the adaptive immune system and favor tumor development.[58] The reduced thymopoiesis with age may explain why elderly individuals are less susceptible to acute lymphoblastic leukemia, while immunesenescence may explain why elderly individuals are more susceptible to chronic lymphocytic leukemia.

Diabetes

Type 2 diabetes is one of the many health problems of the 21st century, and it has become an epidemic, especially in the elderly.[59] Studies reported a continuous increase in the rate of this disease worldwide with no signs of slowing down.[60] The prevalence of this chronic disease was observed to be higher in developed countries, with the majority of diabetic patients falling in the range of 45–64 years.[61] Type 2 diabetes is noninsulin-dependent, where the pancreas β-cell function declines gradually and does not produce sufficient insulin.[62] Thus, the body becomes resistant to insulin, resulting in high blood sugar levels. As a person ages, they experience changes in body composition such as sarcopenia and fat accumulation.[61] As the muscles decrease in size the associated lack of motility leads to a decrease in energy expenditure that will favor fat accumulation. Over the years, studies have shown that obesity and age are a major risk factor for Type 2 diabetes, mainly because the body gains excess body fat between the fourth and seventh decades of their life, due to an increased prevalence of sedentary lifestyle. Other factors that might have also increased the risk of this disease are insufficient exercise, smoking, alcohol, weight gain and an unbalanced diet.[63] At the immunological level, there is a strong link between inflammation, diabetes and metabolic syndrome. Whether unbalanced inflammation with aging can be a cause or consequence of diabetes is unclear. One of the most direct relationships between diabetes and CMV is the study from Hjelmesæth et al., which demonstrated that following kidney transplantation in nondiabetic recipients, asymptomatic CMV infection was associated with the onset of diabetes (adjusted odds ratio: 4) and insulin release.[64] This strongly suggests that CMV infection and the associated events can initiate/accelerate the onset of diabetes.[65] Consistent with this is the recent finding that CMV seropositivity is associated with the regulation of glucose levels in elderly individuals.[35] Although aging is associated with an increased susceptibility to diabetes, there are very few data to support the link between immune senescence and onset or progression of the disease. Therefore, it is likely that diabetes and metabolic syndrome are factors that influence immune senescence. Fulminant Type 1 diabetes is defined as a subtype of Type 2 diabetes, with a remarkably acute onset. It has been reported that viral infection would contribute to the development of this subtype and that regulation of the immune response may be a driving force. Cytotoxic T-lymphocyte antigen-4 expression in patients with fulminant type diabetes is significantly lower than in Type 1A diabetes, Type 2 diabetes and control subjects. This reduced cytotoxic T-lymphocyte antigen-4 expression may induce lower inhibition of T-cell activation and proliferation that may explain the loss of β cell and the development of fulminant Type 1 diabetes.[66] It has been reported that aged nonobese diabetic mice, which develops Type 1 diabetes, gradually switch the balance between effector T cells and Tregs toward effector T-cell dominance for diabetes.[67] Altogether, this suggests that although lifestyle may be a dominant factor for the development of diabetes, the aging of the immune system may sustain such events.

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