Immune senescence

IMMUNE SENESCENCE
(see also Multi-organ failures (MOFs) : aging

)

The gradual deterioration in immune function that occurs with aging is manifest both as reduced in vitro immune responsiveness and impaired immune response to

acute infection.
vaccination (e.g. intramuscular (IM) influenza vaccines are only 30-40% effective in preventing clinical illness among the frail elderly individuals vs. 70-90% in young adults, and their effectiveness in eliciting mucosal response may be even lower. Subjects who respond to influenza vaccination show a significant increase in serum HLA class I levels 2 weeks after immunization : 2 forms of sHLA class I molecules of relative mass of M_r 42,000 and 40,000 are immunoprecipitated from the serum of nonresponders whereas only the M(r) 40,000 form is detected in the sera of young controls and of elderly responders^ref. A novel inactivated intranasal (IN) trivalent whole influenza virus vaccine is significantly more effective than the IM vaccine in inducing mucosal IgA response in nursing-home elderly^ref)

Innate immunity : the functions of NK cells, macrophages, and neutrophils, crucial cellular components of innate immunity, are decreased with aging. In the aged mouse

dendritic cells : old immature bone marrow-derived CD4^-CD8a^- DCs (imDCs) from C57BL/6 mice were 4 times less effective than were young DCs in stimulating syngeneic CD4⁺ T-cell proliferation. Old imDCs also have decreased DC-SIGN expression compared to young DCs. Interestingly, mice treated with the ovalbumin peptide-pulsed young DCs exhibited significantly greater tumor regression than with ovalbumin peptide-pulsed old DCs. Old terminally differentiated bone marrow-derived DCs (tDC) also have increased IL-10, but decreased IL-6 and TNF-a production. Taken together, these results have important implications in the clinical application of DC-based tumor immunotherapy in elderly persons^ref
alveolar macrophages are decreased in number and are not efficient at presenting Ag to T cells, and more macrophages are needed to effectively activate a T cell
neutrophils have impaired chemotaxis, degranulation, and phagocytosis : the detrimental effect of stress on the immune response increases with age, though the mechanisms responsible are not fully understood. The physiological response to stress is regulated in part by the adrenocortical system. Adrenal hormones dehydroepiandrosterone sulphate (DHEAS) and cortisol have opposing effects on the innate immune system, DHEAS enhances while cortisol suppresses immunity and the molar ratio of cortisol to DHEAS increases with age. Ederly hip fracture patients produced a robust neutrophilia after injury, but circulating neutrophils showed an impaired antibacterial response. Adrenocortical hormones mediate the heightened immunosuppression seen in the elderly after injury. Neutrophil function and adrenocortical hormone levels were examined in elderly (> 65 years) hip fracture patients and age-matched healthy controls. Thirteen out of 35 elderly patients acquired infections following hip fracture. Neutrophil superoxide production was lower in elderly hip fracture patients compared with controls (P < 0.005) and lower in patients who acquired infection following injury compared with those who did not (P < 0.05). Serum cortisol:DHEAS ratio was higher in elderly hip fracture patients (0.56 +/- 0.38) compared with either age-matched controls (0.36 +/- 0.21; P < 0.05) or young fracture patients (0.087 +/- 0.033; P < 0.0001). Moreover, cortisol: DHEAS was increased in elderly patients who succumbed to infection compared with those who did not (0.803 +/- 0.42 vs. 0.467 +/- 0.28; P < 0.02). In vitro cortisol significantly decreased neutrophil superoxide generation (P < 0.05) and this was prevented by coincubation with DHEAS. Increased cortisol:DHEAS ratios may contribute to reduced immunity following physical stress in the elderly^ref.
NK lymphocytes : the number of NK (CD56⁺CD3^-) cells within peripheral blood did not change with increasing age. The number of CD56^dim NK cells also remained stable with ageing. In contrast the absolute number of CD56^bright NK cells within peripheral blood declined by 48% with ageing from a mean of 15.6/ml in individuals aged 20-40 years to 8.1/ml in those aged 60+ years^ref
iNKT cells : healthy ageing associates with a significant decline in the percentage and proliferative response of peripheral blood iNKT, despite no significant differences were found in the expression of CD27, CD28, CD45RO, CD45RA^bright, CD161, CD94 and NKG2D on iNKT cells from young and elderly individuals^ref

Because macrophages, NK cells, and neutrophils provide the first line of defense against bacterial and viral infections, the decline in function could possibly explain the increased incidence of bacterial and viral pneumonias and gastrointestinal and skin infections in the aged as well as diminished protective immune responses to pneumococcal and influenza vaccines. Both splenic and activated peritoneal macrophages from aged mice express significantly lower levels of al TLRs and secrete lower IL-6

and TNF-a

when stimulated.

Adaptive immunity : people older than 60 who showed shorter-than-average telomeres have 86% higher death rate over the next 15 years than others, especially from heart disease and pneumonia. They run a 3-fold higher risk of dying from heart disease and an 8-fold higher risk of death from infectious disease, almost entirely pneumonia. Their rates of death from stroke and cancer are higher, but by too little to be considered meaningful. That might mean that short telomeres leave immune system cells with less capacity to multiply for fighting off infections.

cell-mediated immunity

the expression of CAMs on APCs and T cells declines, possibly contributing to immune dysfunction
as the thymus atrophies with age, there are fewer naive T cells available to respond to new pathogens and neoantigens, with a concomitant accumulation of (oligo)clonally expanded memory CD8⁺28^-57⁺ T cells (T cell clonal expansions (TCE)) (> 80% of the total CD8⁺ population), whose presence has been directly correlated with poor immune function. Anyway the age-associated alterations in naive CD8⁺ cell function are not found after primary stimulation, but may become apparent upon restimulation. This shift from naive to memory cells also causes a shift in the cytokine environment.
with increasing age, CD45RA⁺ naive cells are replaced by CD45RA^- memory CD4⁺ T cells.

in the CD8⁺ T-cell subset, there is an increased proportion of cells co-expressing CD57

in monocytes also, some alterations of the immunophenotype, for example the expression of the adhesion molecule CD54, are observed
a relative deficit of transendothelial migration with aging was found in T cells, whereas this function was not impaired in monocytes
the immunophenotype and the function of dendritic cells do no t appear to be affected by aging. Due to their capacity to present antigens to T cells and to induce T-cell proliferation, dendritic cells may provide a useful tool for immunotherapy^ref

antibody-mediated immunity : aging is accompanied by greatly reduced B cell production in the bone marrow, yet peripheral B cell numbers do not decline. This may reflect filling of the peripheral pool with B cells that are long-lived as a consequence of specifity for, and chronic stimulation by, environmental Ags (a novel form of receptor revision in which B cells are selected rather than deleted based on Ag reactivity). It has been suggested that the dimished ability to generate high-affinity protective Abs against infectious agents may be due to inefficient somatic hypermutation in the V gene segments of the Abs, inefficient help by aged T_h cells, and the altered cytokine environment. It is postulated that the Ab repertoire maturation in aged mice is delayed and may be notably improved by repeated immunizations. There is an increase in the asymmetric IgG : symmetric IgG ratio with aging.

Immune senescence is a factor in the increased susceptibility of the elderly to infectious diseases, such as pneumonias, urinary tract infections, and tuberculosis : decrease of immune surveillance could be a factor in the increasing incidence of cancer with increasin age. The age-associated increase in autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and glomerulonephritis, certainly results from deterioration of the immune system. Specifically, there is a loss in the ability to distinguish between self and non-self.
Web resources :

Institute for Advanced Studies in Aging & Geriatric Medicine (IASIA)

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