The document discusses how the immune system deteriorates with age, known as immunosenescence. Key points include:
- Innate immune cells like neutrophils and monocytes/macrophages show functional declines with aging, including altered receptor expression and signaling.
- The adaptive immune system also deteriorates with age. B cell and humoral immunity show reduced costimulatory molecule expression and defects in signaling. T cell immunity declines in naïve cell numbers, cytotoxic function, and proliferation ability. Memory CD8+ T cells lose co-stimulatory molecules like CD28 with age.
- These immune changes contribute to the chronic low-grade inflammation, or "inflamm-aging", seen in older individuals
2. WHAT’S THAT?
Immunosenescence refers to the gradual deterioration of the
immune system brought on by natural age advancement. It
involves both the host’s capacity to respond to infections and the
development of long-term immune memory, especially by
vaccination
5. JUST A MOMENT
On the contrary it has been recently shown that increased number
of neutrophils (neutrophilia) in elderly donors is associated to
increased risk of death in the following 2 years, a phenomenon that
is linked in other markers of inflammation as increased serum levels
of IL-6 or C-reactive protein
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6. NEUTROPHILS RECEPTORS AND SIGNALING PATHWAYS
PRRs ( TLR , RLR , NLR )
It has been shown that while the number of these receptors on neutrophils is
not significantly changed with aging, there is a significant alteration in the
trafficking of signaling molecules in and out of lipid rafts and alterations in the
signaling of TLRs leading to altered functions of neutrophils
Macroautophagy ,that activate by TLR’s signaling (TLR4 and TLR7), has been
shown to be defective with aging
FCγRIIIدرسطحنوتروفیلهاکاهشمیابدکهمیتواندیکیازدالیلکاهشتواناییفاگوسیتوز
نوتروفیلهاباشد.
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7. NEUTROPHIL INTERACTIONS WITH OTHER IMMUNE
CELLS
Neutrophil-macrophage interaction:
Neutrophils interact with macrophages by activating and recruiting them to the
site of infection or acute inflammation. This is occurring through the secretion
of various chemokines by neutrophils. In turn cytokines released by activated
macrophages prolong the life span of neutrophils. This mutually enhancing loop
has not been explored in aging. However, knowing that either the activation of
macrophages is altered or the apoptosis of neutrophils is not fulfilled it can be
assumed that this process is not functioning correctly.
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9. NUMBER AND SUBSETS OF CIRCULATING MONOCYTES
Recent studies have shown that different subpopulation of monocytes can be
defined by the differential expression of CD14 and CD16 :
1) CD14h , CD16- : CXCR1L , CCR2+ , CD64+ , CD62L+
2) CD14L , CD16+ : CX3CR1h , TNFαh
These latter are considered as pro-inflammatory as they produce high levels of
TNF-α in response to TLR2 and TLR4.
have recently found that CD16+ monocytes are increased with aging whereas
the proportion of CD16− is decreased compared to young subjects.
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10. RECEPTOR EXPRESSION AND FUNCTION
OF MONOCYTES/MACROPHAGES
phagocytosis and free radical production
Antigen presentation possibly due to diminished expression of MHC class II molecules
prostaglandin E2 which inhibits surface expression of MHC class II and IL-12 production
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11. RECEPTOR EXPRESSION AND …
Whereas the expression of some TLRs on monocytes, as TLR1 and TLR2,
increased with age, the function of other TLRs (TLR4 and TLR8) decreased.
expression of CD80/CD86 co-stimulatory receptors
clearing of apoptotic cells in an anti-inflammatory manner is one of the
important function of macrophages. The decrease in some PRRs as well as the
altered signaling leading to changes in chemotaxis and phagocytosis support
the hypothesis that the apoptotic cells are not cleared efficiently.
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14. NK CELL CYTOTOXICITY AND CYTOKINE
PRODUCTION
The overall NK cell cytotoxicity is not significantly affected
The production of IFN-γ by NK cells after activation is also maintained in the
elderly , with an increased production of IFN-γ by CD56bright cells, potentially
representing compensatory augmentation of cytokine production to maintain
the important immunoregulatory role of these cells in older individuals
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17. EFFECT ON DCS
There is still no agreement on how different types of DCs are changing with
aging in humans
DCs from the elderly contribute to the constant proinflammatory status
observed with aging by the increased IL-6 and TNF- production even in the
absence of stimulation.
Several virus-derived molecules, such as ssRNA or CpG, were unable to elicit
TLR7 or TLR9 activation
pDCs from the aged have a decreased capacity to secrete not only IFN-I but
also IFN-III
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18. A TINY CONCLUSION
Inflamm-aging
Is the imbalance of pro-inflammatory versus anti-inflammatory mediators and
cytokines that result low grade chronic inflammation.
It’s associated with many aging diseases, such as Alzheimer's disease,
atherosclerosis, heart disease, type II diabetes, and cancer.
You know In elderly people the level of pro-inflammatory cytokines such as IL-6
and TNF-α and inflammatory cells like CD6+ monocytes have been increased so
what’s that mean?
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20. EFFECT ON HUMORAL IMMUNITY
the numbers of B cells exported from the bone marrow is already reduced,
surpisingly peripheral B-cell numbers in peripheral blood remain relatively
constant.
Disrupt in T-cell/B-cell interactions result Increase T-cell independent
immunoglobulin production and production of low-affinity auto-antibodies
reduction of costimulatory molecules such as CD80 and CD86
defects in B-cell receptor signaling.
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22. CHANGES IN CELLULAR IMMUNITY
Surprisingly there is little change in the number of peripheral T cells with age.
The number of naïve T cells reduce otherwise the number of effector and
memory cells increase.
Decrease in CD4/CD8 ratio, even sometimes reverse
Defect in signaling of TCR and some other receptor’s like IL-2R
CD8+ T cell cytotoxicity and proliferation decline whereas expression of IFN-g
and TNF-a increase
Lose of co-stimulatory molecules particular CD28 in CD8+ T cells
gradually downregulating of CD28 as central memory CD8+ cells differentiate
into effector cells
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23. CHANGES IN CELLULAR IMMUNITY
These CD28- cells ,that so-called senescent cells, are proinflammatory , has
shorter telomeres and is less able to proliferate
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Editor's Notes
The relative and absolute number of elderly persons has significantly increased in the last century as a consequence of the worldwide improvement of socio-economical conditions. Subsequently the frequency of the diseases associated with aging including infections, cancer and neurodegenerative and cardiovascular diseases has dramatically augmented. Many of these diseases are linked to the age-associated deterioration of the immune system, a process termed immunosenescence.
Although immunosenescence affects primarily adaptive immunity cumulative evidences indicate that it also affects innate immunity. Thus age-associated alterations of cells of the innate immune system are involved in the increased susceptibility of elderly individuals to infectious diseases and the decreased
response to vaccination
Ferrando-Martinez S, Romero-Sanchez MC, Solana R, Delgado J, dela RR, Munoz-Fernandez MA, et al. Thymic function failure and C-reactive protein levels are independent predictors of all-cause mortality in healthy elderly humans. Age (Dordr) 2011 [PM:22095260]
The family of the PRRs includes three main types: Toll like receptors (TLRs), retinoic acid inducible gene 1 protein (RIG-1)-like helicases (RLRs) and nucleotide binding domain and leucine-rich-repeat-containing proteins (NLRs)
Macroautophagy that is to kill intracellular pathogens as bacteria, viruses and parasites ,has been shown to be defective with aging ,/ Engagement of different TLRs like TLR4 and TLR7 has been implicated in the activation of macroautophagy
Neutrophils interact with macrophages by activating and recruiting them to the site of infection or acute inflammation. This is occurring through the secretion of various chemokines by neutrophils. In turn cytokines released by activated macrophages prolong the life span of neutrophils. This mutually enhancing loop has not been explored in aging. However, knowing that either the activation of macrophages is altered or the apoptosis of neutrophils is not fulfilled it can be assumed that this process is not functioning correctly.
The percentage and absolute number of NK cells have been shown to be increased in healthy aging, associated with a decrease in the CD56bright NK cell subset and an expansion of CD56dim NK cells
CD57+ NK cells show an increased responsiveness to target cells and decreased responses to cytokines , are highly mature and display a mature phenotype, a higher cytotoxic capacity, a higher sensitivity to stimulation via CD16, a decreased responsiveness to cytokines and a decreased capacity to proliferate than the CD57 negative counterparts
possible explanation is that peripheral B cells in the mouse reflect a decreased B-cell generation and a fivefold increase in peripheral B-cell longevity
Despite the reduction in functional thymic area, the ageing thymus still demonstrates T-cell output, although at decreased rates