Senescent remodeling of the immune system and its... : Chinese Medical Journal (original) (raw)
Worldwide, the number of older persons (aged 60 years or over) will increase by a factor of 2.6, going from 759 million in 2010 to 2 billion in 2050.1 Clinical observations indicate that some infections are more prevalent and have poorer outcomes in the elderly than in younger adults. The most commonly encountered infections are due to pyogenic bacteria, in particular urinary tract infection, pneumonia, diverticulitis, endocarditis, bacteremia, skin and soft tissue infections. Except for influenza, viral gastroenteritis, and herpes zoster reactivation (shingles), viral infections are rarer in the elderly than in younger populations.2 Immunosenescence, a state of gradual deterioration of the immune system brought on by natural aging, is felt to be a significant contributor to this increased risk.3 Careful analyses of healthy people ranging in age from neonates to centenarians suggest that a complex and continuous remodeling of the immune system occurs with age. Terms such as alteration, deterioration and decline do not account for the complexity of immunosenescence.4 Hence, we propose the more appropriate term of “senescent immune remodeling”.
INNATE IMMUNITY
The innate immune system is the first line of defense against infections. Although it is generally accepted that some aspects of innate immunity are well preserved in aging, cumulative evidence in the last decade supports the notion that immunosenescence not only affects adaptive immunity but also innate immunity.5 Advanced age is associated with a breakdown of the epithelial barriers of the skin, lungs and gastrointestinal tract, which enables invasion of delicate mucosal tissues by pathogenic organisms. Thus, there is an increased challenge for the innate immune system in aged subjects, as the portals of pathogen entry become more accessible to infectious agents.6 Among cellular components of the innate immune system, polymorphonuclear neutrophils (PMNs) and macrophages are the first to arrive at the site of infection. Their role is to initiate an inflammatory response, phagocytose the pathogen, recruit natural killer (NK) cells, and facilitate the maturation and migration of dendritic cells (DCs) that will regulate and determine the nature of the T-cell mediated outcome.7
Neutrophils
Throughout aging the total number of PMNs remains constant and the ability to mount adequate neutrophilia during infections is preserved. PMN adhesion to vascular endothelium and extravasation are reported to be unchanged or slightly increased.8 Most aspects of PMN function in the elderly are decreased, which includes chemotaxis, microbial phagocytosis and generation of reactive oxygen species (ROS) in response to stimulation by granulocyte macrophage-colony stimulating factor (GM-CSF), lipopolysaccharide (LPS), formyl-Methionyl-Leucyl-Phenylalanine lipopolysaccharide (fMLP) or opsonized bacteria.9 Furthermore, PMNs from elderly donors, unlike those from young donors, cannot be rescued from apoptosis when incubated with proinflammatory mediators that extend their lifespan. Thus, PMNs from elderly donors have fewer effective functions and a shorter call of duty when fighting infections. There is also a greater chance of developing persistent chronic infections or frailty because of incomplete clearance of apoptotic PMNs by macrophages at the site of infection and progressing to secondary necrosis.8,10
The environment probably plays an important role in the functional activity of PMNs. So the secretion of cortisol during certain stress situations and the non-compensated secretion of dehydroepiandrosterone sulphate, which decreases with age, could favor PMNs dysfunction.6
Toll-like receptors (TLR) 2 and 4 respond to bacterial lipopeptides and LPS respectively. With aging, the expression of TLR2 and TLR4 is not affected, but the intracellular signaling could be.11 Triggering receptor expressed on myeloid cells (TREM-1) induced functions in PMNs are impaired with aging. It would be interesting to know whether the levels of soluble TREM-1 (sTREM-1) in plasma are altered with aging because poor outcome of critically ill patients with sepsis is associated with the sustained presence of sTREM-1 in plasma.10
Macrophages
Despite numerous studies on the effect of aging on macrophages, conflicting results have been reported, which could be attributed to factors such as strain and sex of experimental subjects, distinct macrophage origin, and differences in experimental conditions. Additionally, these studies are hampered because of the lack of a clear definition of what constitutes a “healthy elderly subject”, and by the tendency to study monocytes in human blood, which do not accurately reflect the status of the various types of tissue macrophages.12 There is no clear evidence as to whether the generation of macrophages from their monocyte precursors is affected by aging. While the number of blood monocytes does not appear to change with age, reduced cellularity, increased apoptosis, and a decreased percentage of macrophages were reported in the bone marrow of aged volunteers ranging in age from 80 to 100 years old. Other studies in mice have found increased macrophage progenitors in the marrow of aged mice.13 Substantial data are available regarding chemotaxis and phagocytosis in macrophages and their monocyte counterparts but the mechanisms by which these properties are altered with age remain unclear. Some studies reported decreased chemotaxis and phagocytosis in macrophages from aged humans and mice, while others using aged rats reported completely opposite results or found these functions to remain unaltered with age.14
LPS-stimulated ROS and nitric oxide production are significantly reduced in alveolar macrophages from aged rats. Similarly, studies using aged mice show diminished production of reactive nitrogen species and decreased expression of inducible nitric oxide synthase (iNOS) mRNA from splenic and peritoneal macrophages.9 Conversely, enhanced iNOS mRNA and nitrite production by macrophages of aged mice have also been reported.15
Macrophages secrete a wide range of cytokines, chemokines, growth factors and enzymes in response to pathogens and “danger” signals. Any dysregulation in their production is likely to result in poor responses to infections. However, the effect of aging on cytokine and chemokine secretion from activated macrophages is ambiguous. Most studies on rodents indicate an age-related decline in the secretion of macrophage-derived proinflammatory cytokines and chemokines. But some in vitro studies using human monocytes activated with mitogens and LPS reported an increase in the levels of proinflammatory factors, others found decreased levels or even no changes at all.16 Activated macrophages from aged mice and humans produce more prostaglandin E2 (PGE2) than younger individuals which could contribute to dysfunctional immune responses in the elderly. PGE2 alters the function of DCs, the most potent antigen presenting cells (APCs) of the immune system, by suppressing interlukin (IL)-12 secretion, decreasing surface expression of class II MHC and increasing IL-10 production in mice; increased IL-10 production also being associated with a decline in T-cell function. PGE2 also decreases IL-2 production which lowers T-cell proliferative responses.15,16
Aging is associated with the loss of TLR1/2-induced IL-6 and tumor necrosis factor (TNF)-α production in monocytes, partly explained by diminished surface expression of TLR1 and TLR4. Defective TLR4 signaling associated with decreased proinflammatory cytokine production may significantly contribute to increased susceptibility to infection and elicit a poor adaptive immune response in the elderly.8,9 The reported decrease of TLR-induced CD80 up-regulation on monocytes might be associated with a failure to generate a protective antibody response to influenza vaccination, with consequences for adaptive immunity.8,17 Dysregulation of TLR responses, as has been reported for the increased TLR3 expression observed following infection of aged human macrophages with West Nile virus (WNV), may contribute to morbidity from viral infections in elderly individuals.8,9,17
Lastly, studies of excision wound healing in mice demonstrate a delay in monocyte and macrophage infiltration with age. Furthermore, aged mice macrophages show lower levels of vascular endothelial growth factor (VEGF). Diminished VEGF production and angiogenesis may delay wound closure, allowing more time for bacteria to circumvent the natural skin barrier and develop into a full infection.13
Natural killer cells
NK-cells are cytotoxic lymphocytes involved in the early defense against virus-infected and tumor cells. Studies using very healthy elderly people and centenarians show that the overall NK-cell number tends to increase with age and NK-cells are also more likely to have a mature phenotype as shown by a decrease in CD56bright cells and an expansion of CD56dim cells.5 NK-cell cytotoxicity on a per cell basis is decreased and levels of cytokines and chemokines such as RANTES, MIP1α, and IL-8 produced upon NK-cell activation are also reduced with aging.17 NK-cell production of interferon (IFN)-γ, TNF-α, IL-2 and IL-12 is also decreased in elderly individuals and may contribute to T-cell deficits associated with aging.9
Natural killer T cells
Natural killer T (NKT) cells are considered to be a unique T-cell subset and play an important role in viral and antitumor cytolytic activity.9 Absolute numbers and relative percentages of NKT-cells increase with advancing age, increases of 150%-400% have been reported in circulating, splenic, hepatic, mesenteric lymph node, and peripheral lymph node counts in humans and rodents.15 Although NKT-cells are known for their capacity to influence both APCs and T-cell function, only a few studies have examined the role of NKT-cell in immunosenescence.14
With aging the cytokine profile secreted by NKT-cells changes. Recent in vitro studies using cell cultures enriched for invariant NKT (iNKT) cells indicate that iNKT-cells from old individuals shift from a T helper (Th)-1 toward a Th-2 cytokine profile compared with iNKT-cells from young individuals.18 Compared to iNKT-cells from young mice, iNKT-cells from aged mice infected with herpes simplex virus (HSV)-2 demonstrated elevated expression and production of IL-17A that was associated with increased hepatic damage.9
DCs
DCs are the most potent APCs that link the innate and adaptive immune system by not only instructing T- and B-lymphocytes, but also by activating NK-cells and producing IFNs.19 Similar to the results obtained from animal studies, the numbers of DCs, their distribution, and potentially their generation and development from hematopoietic precursors in vivo are markedly reduced in elderly humans.20
Plasmacytoid DCs (pDCs) are innate sensors that produce IFN-α in response to viral infections.18 pDCs from old mice have decreased production of IFN-α upon HSV-2 infection, with defective induction of IFN-regulatory factor 7 expression upon TLR9 activation.17 In humans, while comparing healthy young and elderly subject groups it has been shown that aging is associated with a numerical and functional decline in pDCs but not myeloid DCs (mDCs). However, a declining health status in the elderly can have a profound negative impact on mDCs. The age-related changes in pDCs are likely to contribute to the impaired immune response to viral infections in elderly persons, especially when combined with the mDCs dysfunction in those with compromised health.21 Recently, a study by Panda et al22 on TLR function in primary human DCs provided evidence of immunosenescence in both pDCs and mDCs; notably, defects in cytokine production were strongly associated with a poor antibody response to influenza immunization, a functional consequence of impaired TLR function in the aging innate immune response.
Follicular DCs (fDCs) are critical to the formation of plasma cells in the germinal centers (GCs) of secondary lymphoid organs and the subsequent generation of antibodies.15 fDCs from old mice have reduced levels of receptors for complement and antibody and show reduced trafficking to B-cell follicles. These combined defects are likely to contribute to reduced GC formation and humoral immunity in aged mice and might well contribute to the compromised vaccination response in terms of antibody titer, affinity and repertoire seen in aged humans.
Finally, monocyte-derived DCs from older, compared with younger individuals, were found to have increases in LPS and single-stranded RNA-induced TNF-α and IL-6 production, as well as increased self-DNA-induced IL-6 and IFN-α production. These increases in cytokine output were accompanied by defective phagocytosis and migration in vitro.17
ADAPTIVE IMMUNITY
Humoral immunity
The humoral immune response, maintained by the B-cell compartment, has a key role in an effective immune system, not only in producing high affinity antibodies that are crucial for vaccination strategies, but also in assisting with the function of other components of the immune system.23 With aging there is a decrease in the frequency and absolute number of pro-B lymphocytes in the bone marrow, along with a reduction in their ability to differentiate into pre-B lymphocytes. In aged Balb/c mice, an increased proportion of NK-cells were found in an early B-cell bone marrow developmental population; depletion experiments revealed that this NK population may directly inhibit surrogate light chain expression in developing B-cells, thereby potentially contributing to B-cell immunosenescence. However, the number of peripheral B-cells remains more or less constant as the equilibrium between memory and naïve B-cells is altered. There is an accumulation of the CD19+CD27+ phenotype memory B-cells and a decreased turnover of naïve B-cells.6 Colanna-Romano et al24,25 studied the B-cell compartment in old people and centenarians' offspring. In both cohorts they observed a decreased B-cell count. However, in centenarians' offspring, naive B-cells (IgD+ CD27-) were more abundant whereas exhausted memory cells (DN B-cells, IgD- CD27-) did not show the increase that had previously been demonstrated in healthy elderly donors. Thus, centenarians' offspring do not have the typical populations of memory/naïve B-cell subsets observed in elderly people. This reservoir of naive B-cells might be one of the reasons why centenarian offsprings' are able to keep fighting off new infections, hence prolonging their life.
Although immunoglobulin (Ig) levels increase with age, especially IgA and IgG, the B-cell receptor repertoire of B-cells is altered with a decrease in affinity and diversity of antibody response.6 GCs in the lymph nodes of healthy elderly donors are smaller and contain fewer IgM-producing cells compared with those in young donors. Antibodies produced in the elderly have reduced avidity because of impaired somatic hypermutation, a process dependent on cognate interactions between antigen-activated B-cells and CD4+ T-cells inside the GCs. Age-dependent deficits in CD4+ T-cells can therefore reduce cognate B-T interactions and in doing so reduce antibody avidity.26 Hence, the quality of the humoral immune response declines with age.
Cellular immunity
Cellular immunity is mediated by T-lymphocytes. Studies in aged mice show a reduction in the number and proliferation of early T lineage progenitors as defined by surface expression of Lin-, CD44+, c-Kithi, and IL-7Rαneg/lo cells.27 Even when the percentages of the main T-cell subsets remain unchanged in most aged donors, the absolute number of CD3, CD4 and CD8 T-cells decreases with age.28 Izaks et al29 showed that a low lymphocyte count is associated with an increased mortality risk in older persons without obvious disease. This association is not only for the total lymphocyte count but also for the CD4+, CD8+, and CD16+ lymphocyte subset counts. In mice, generation of T cell responses is compromised in old age, but maintenance of the pool of memory T-cells is not affected by the aging30 process.30
The decline in T-cell function is considered a result of thymic involution.28 The progressive loss of thymic epithelial space and functional thymopoiesis with human aging results in a decreased output of naïve T-cells to the periphery and the disadvantageous creation of a restricted peripheral T-cell repertoire.31
Importantly, declines in the function of CD4+ T-cells with aging are thought to contribute to the decrease in high affinity antibody production in older individuals.32 Naïve CD4+ T-cells from T-cell receptor (TCR) transgenic aged mice do not form immunologic synapses as efficiently as do cells from young mice _in vitro._33 Because of reduced synapse formation, the initial signaling cascades generated in the aged naïve CD4+ T-cells are less intense32 than those in young T-cells.32 The ultimate result of this defect is that aged naïve CD4+ T-cells do not expand, produce cytokines, and differentiate as well as those from young mice. The most striking phenotype of aged naive CD4+ T-cells is their inability to produce significant levels of IL-2 upon TCR stimulation. This subsequently leads to the generation of poorly polarized Th-1 and Th-2 subsets.33 However, aged naïve CD4+ T-cells retain the ability to generate functional Th-17 effectors. This propensity to skew toward Th-17 polarization appears to be an intrinsic property of the aged naïve CD4+ T-cells. Not only can aged Th-17 effectors produce high levels of IL-17 family cytokines (IL-17, IL- 21, and IL-22), but they are also potent helper T-cells in an adoptive transfer model, leading to extensive antigen specific B-cell expansion and GC formation.32
New antigens are predominantly recognized by naive CD8+ T-cells. Consequently, maintenance of a diverse repertoire of naïve cells is important for a vigorous and effective response to new antigens and vaccination.34 Thus the decrease in CD8 TCR repertoire diversity has been shown to negatively impact on the capacity of aged CD8+ T-cells to respond to influenza infection.32 Perturbations in the aged CD8+ T-cell repertoire can be attributed to the nonmalignant expansion of individual CD8+ T-cell clones which not only occupy >50% of the memory pool but also negatively impact the TCR repertoire in response to both influenza infection and HSV-1 infection.32–34
Regulatory T-cells (Treg) are responsible for maintaining immunological self-tolerance and reducing damage following an immune response. With aging the population of Treg increases in mice which might contribute to diminished CD8+ T-cell response to primary influenza infection.35
SENESCENT IMMUNE REMODELING AND INFECTIOUS DISEASES
The waning of the immune responsiveness in the elderly makes this population increasingly susceptible to infectious diseases such as influenza and pneumonia, and leads to the resurgence of latent infections such as herpes zoster, and also to infection by opportunistic organisms such as Clostridium and Staphylococcus. These infections contribute significantly to morbidity in this age group, and frequently lead to irreversible frailty and dependence.36 The problem with infections in the elderly is that they frequently present with non-specific signs and symptoms, and clues of focal infection are often absent or obscured by underlying chronic conditions.28 There probably exists a link between immunosenescence and infections but we lack longitudinal prospective studies to establish a formal correlation between immunosenescence and infectious susceptibility.6 Besides immunosenescence reasons for infectious susceptibility include epidemiological elements, malnutrition, as well as a large number of age-associated physiological and anatomical alterations.2 For instance with pneumonia which is a leading cause of death in the elderly, in addition to senescent immune remodeling, various secondary factors and comorbidities appear to play major roles in predisposing the elderly to bacterial pneumonia. These include depressed oral clearance, swallowing disorders, diminished mucociliary clearance, malnutrition, declining immune function (disease-related, alcoholism, immunosuppressive therapy), parenchymal lung disease, congestive heart failure, recent hospitalization, institutionalization, and viral infections.37 With aging, the immune response against known antigens might be conserved but the capacity for immunization against new antigens markedly declines, which could explain the greater predisposition to new pathogens.6 Epidemiological evidence reveals that older individuals are often the first to be affected by new or emerging pathogens such as WNV, severe acute respiratory syndrome (SARS), and pandemic influenza.27,32 The 2002 epidemic of WNV in the United States caused 284 deaths with the median age of the deceased being 78 years old.27
Immunological biomarkers
Very limited studies in man have begun to reveal biomarkers of immune aging that are increasingly recognized as an immune risk phenotypes/profiles (IRP) and which predict mortality in the elderly.38 Aging biomarkers are useful to define anti-aging strategies aimed at slowing the aging process and postponing death by preventing infectious diseases and delaying the onset of age-related diseases.39 The longitudinal Swedish Octogenarians/Nonagenarians (OCTO/NONA)-immune studies of free-living people >85 years of age identified an “IRP” predicting 2, 4 and 6 year mortality.40 The IRP is currently characterized by a 100% infection rate with cytomegalovirus and a CD4/CD8 <1 due to an accumulation of late stage differentiated T-cells.38 It would be interesting to consider adding biomarkers of the B-cell compartment in an attempt to expand the IRP. As has been discussed earlier, changes in the memory/naïve B-cell compartment are potential candidates since they could represent a hallmark of successful or unsuccessful aging and could be used as a biomarker of human life span.24,25 Recently, Crétel et al41 in their study of the immune profile of elderly patients admitted into a geriatric short care unit stated that alongside the IRP described by the Swedish study, anomalies of the immune system could constitute a new marker of frailty in the elderly; especially total and B-cell lymphopenia, for which vitamin D insufficiency (<30 ng/ml) is a predictive factor.
It has been hypothesized that failures in innate immunity observed in frail elderly are related to those alterations described in adaptive immunity defined as the IRP.42 Reduced neutrophil and NK-cell activity predictive of increased mortality, dysregulation of TLR function affecting vaccine responsiveness and hyper- responsiveness to viral infection in elderly individuals could be used to define an innate IRP in order to complement and expand the already established adaptive IRP.18 Review of several studies support the notion that preserved NK-cell cytotoxicity should be considered a biomarker of healthy aging, whereas low NK-cell cytotoxicity is a predictor of morbidity and mortality due to infection.5 In assays of NK-cell markers it would be important to also consider the trace element zinc which is an essential co-factor for optimal NK-cell activity.42 There is also a growing body of evidence indicating that age-associated defects in APCs may also contribute to the waning of the immune response and may be an effective biomarker of health and immune competence.43 DCs, the main APCs in humans, have a reduced ability to induce T-cell proliferation, decreased expression of co-stimulatory molecules, and lower IL-12 production in the frail elderly. In addition, the production of IL-10 which suppresses DC maturation is elevated in frail older adults.44
In summary, with aging both the innate and adaptive branches of immunity undergo senescent remodeling. It remains a complex process to be defined as some functions are reduced while other functions are enhanced or remain unchanged. As exemplified by centenarians, some elderly achieve healthy aging despite the “continuous remodeling” process. However, in other elderly people it leads to defects in immunological defense reactions predisposing them to infectious and other age-related diseases, which contribute to early morbidity and mortality in that age group. At present, data available on healthy immunological aging still have some areas of ambiguity. Therefore, more research using SENIEUR (SENIor EURopean) protocol are required to define senescent immune remodeling patterns in healthy aging. Emerging immunological biomarkers, though still in their early days, are a promising tool to help predict healthy aging, immune competence and mortality risk in the elderly. They could also help in guiding the establishment of early intervention methods to prevent or alter the senescent immune remodeling pattern, consequently helping to extend the period of life enjoyed in good health. To be able to achieve that goal, more research in heterogeneous elderly groups needs to be carried out.
Acknowledgements:
We thank Dr. BABOOA Niralee (Children's Hospital of Fudan University) for her critical review.
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Keywords:
senescent immune remodeling; elderly; immunosenescence; infections; innate immunity; adaptive immunity; immune risk profile; immunological biomarker
© 2012 Chinese Medical Association