1
Q
what is the general thought behind the ageing of the immune system?
A
- with age, the adaptive and the innate immune system become less functional which results in the alreadly being unable to respond to infections or develop immunity following vaccination. This results in higher mortality
2
Q
what does immunosensece result in?
A
increased infection, neoplasia and autoimmune disease
3
Q
what percentage of the population is over 65 in the UK?
A
18%
4
Q
how are stem cells thought to affect immune ageing?
A
the HSC pool is thought to age- because all of the components of the immune system come form the HSCs, it is likely that ageing of this stem cell pool can affect the system
5
Q
how are HSCs thought to age and as a result of what processes?
A
- with time they are skewed towards myelin progenitor which differentiate into the innate immune system resulting in less T cells and B cells
- they show a decreased ability to engraft during transplantation (they have a reduced ability to reconstitute and divide)
- older HSCs my not decrease in number but there is increased frequency in the death of their progenitors- suggesting increase DNA damage that triggers the anti tumourr defences on asymmetric division
- they increase in ROS which can cause them to proliferate and not stay quiescent- exhaust the population
- they increase in p16 expression which has been linked to reduced repopulation potential- likely due to sen pathway activation
6
Q
how has increased inflammation disorders of ageing been attributed to a dysfunctional immune system?
A
macrophages have been shown to increase in their production in pro-inflammatory cytokines
7
Q
what sort of diseases does the increase in cytokines from macrophages stimulate?
A
atherosclerosis, diabetes, osteoporosis
8
Q
how and why does the function of granulocytes change with age?
A
- macorphages upregulate pro-inflammatory cytokines
- macorphages and neutrophils decline in their phagocytotic capabilities due to a reduced superoxide anion production
- reduced toll-like receptors on macrophages
9
Q
what are toll-like receptors?
A
Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single, membrane-spanning, non-catalytic receptors usually expressed in sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have breached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. receptors bind to structural shapes or patterns called PAMPs (pathogen-associated molecular patterns) that are present in whole groups of pathogens, but not the host - the ability oformyl-methionyl-leucyl-phenylalanine (fMLP)s to activate neutrophils decreases in old nueotrphils and it thought to occur as a result of a reduction in intracellular Ca2+ mobilisation
10
Q
what areormyl-methionyl-leucyl-phenylalanine (fMLP)s
A
they are cytokines which activate macrophages and neurtorphils by interaction with G-protein coupled receptor and activating an inflammatory response at the site of invasion
11
Q
how are hormones thought to affect the immune system?
A
- studies suggest that as we age, we gain more circulating cortisol and increase cortisol production. cortisol acts to suppress the immune system but is normally offset by DHEAS. However, the production of DHEAS decreases with age, meaning there is more immunosuppression in the elderly following injury
12
Q
how does the number and function of NK cells change with age?
A
increase in number but decrease in function as a result of decrease cytotoxicity
13
Q
why do NK cells decrease toxicity with time?
A
they express reduced production of cytokines and cheekiness- this is likely due to the expansion of different NK-cell subsets because there are reports that in the elderly there in an increased proportion of the CD 56- NK cells which exhibit lower cytolytic activity and have a reduced ability to secrete cytokines in comparison to the more abdunant CD56+ NK-cell subset.
14
Q
what is the decrease in NK cytoxicity attributed to?
A
the expansion of different NK-cell subsets because there are reports that in the elderly there in an increased proportion of the CD 56- NK cells which exhibit lower cytolytic activity and have a reduced ability to secrete cytokines in comparison to the more abdunant CD56+ NK-cell subset.
15
Q
what type of NK cell subset increases with age
A
CD56-
16
Q
how do B-cell mature in the bone marrow?
A
- the common lymphocyte precursors become Pro-B cells in the bone marrow by successful immunoglobulin heavy chain gene rearrangements and subsequently differentiated into Pre-B-cells which migrate to the periphery. Transition from the pro to the pre stages dependent the activity of recombination activating gene 1 and 2 (RAG-1/-2)
17
Q
what are the two main reasons y humour immunity in aged individuals is severely comprimised as a result of?
A
- decreased production go long-term immunoglobulin producing B-lymphocytes because of intrinsic and micro environmental defects
- the loss of immunoglobulin diversity and affinity as a result of disrupted germinal centre formation
18
Q
how do the numbers of pre-cells change over time?
A
they decrease
19
Q
what was the decline in pre-cells once attributed to and what is it now thought to also occur from?
A
- was thought to result from from the diminished capacity of pro-b cells to differentiate.
- but, the numbers of proB cells has also been found to decline and in the progenitor pols for the b-cell lineages. studies have found that there is a loss in RAG mRNA in the total bone marrow from old mice and it has been suggested that RAG expression in pro-B cells in controlled by the microenvironment itself rather than being an intrinsic defect of den b-cell progenitors
20
Q
what is VDJ recombination
A
the recombination of many teens carried out within the pro B and T cells by the RAG genes which recombine the genes of thegenes of immunoglobulin and T cell receptor molecules to allow millions of different antibodies to be expressed
21
Q
what gene are involved VDJ recombination?
A
RAG genes
22
Q
what are the rag genes involved in?
A
the maturation of pre T cells and B cells via VDJ recombination
23
Q
how does B cell migration form the bone marrow change in older mice?
A
recuced
24
Q
how does the thymus change over time?
A
reduces in size
25
where do T cells mature?
in the thymus
26
what happens when T cells mature in the thymus?
they undergo negative and positive selection in whichself-tolerant, self major histo- compatibility complex-restricted, immunocompetent T cells are produced
27
what type of cells int he thymus constitute a large proportion of the stroma involved in the regulation for eh microenvironment of t cell development
Highly keratinized thymic epithelial cells (TEC)
28
what are CD4 cells?
T helper cells
29
what are CD8 cells?
t killer cells
30
what is the general process of T cell maturation?
- rearrangement of T cell receptor genes
31
what is thymus involution?
decrease on thymic epithelial space and thymic cellularity which is replaced y adipose tissue in humans but in the mouse it just reduces in size
32
how does threat of T cells from the thymus with age change?
decrease
33
when is thymus growth thought to peak and decline and what argues against this ?
some claim that it peaks at puberty but others have found that in humans thymus cellularity decreases in 9 months old
34
what is the evidence that the reduction in thymus output stems from the HSC pool?
- purified HSC from old mice exhibit deceased differentiation potential towards lymphoid lineages in vivo and vitro
- decline in the ability of aged bone marrow to reconstitute T-cells populations in lethality irradiated hosts
- ealry thymic progenitors from older mice were inefficient at seeding metal thymus lobes
35
what is the evidence for the thymus playing a role in decreased T cel output?
- T cel progenitors form old mice were put in fetal thymus explant and they were able to develop normally
36
what is a key cytokine produced by the thymic epithelial cells that controls T cell maturation (thymocyte development?
IL-7
37
describe an experiment that demonstrates that IL-7 in thymus involution
IL-7 anitbody treatment of mice resulted in a similar phenotype to thymus involution
38
what happens when you inject aged mice with IL- 7?
increase thymus weight and cellularity and increased in CD8+ cells but not an overall increase in thymus output- so can rescue early defect in thymopoiesis of ageing mice but can't regenerate the thymus
39
give evidence for GH increases thymopoeisis and evidence against
- the decline in circulating levels of GH coincides with the assume onset of thymus atrophy
- administration of GH can increase thymus size and cellularity but can regenerate completely
- little mice with 90% deficiency in serum GH and IGF-1 do not display any changes in the rate of involution
40
as well as GH, what other hormones are thought to affect thymic involution and what is the evidence for this?
- sex hormones- castration or ovariectomy causes the regeneration of the thymus
- chimeric mice with androgen receptor-defective stroma but wild-type thymo- cytes did not undergo thymic atrophy, suggesting that the stroma is the target of androgen-induced regression
41
what is the evidence against sex hormones causing thymic involution?
there is evidence to suggest that testosterone is not the sole contributor to involution, including a recent examination of thymic atrophy in hypogonadal mice with diminished sex steroid produc- tion, which presented no changes in cellularity or cellular distribution compared to wild-type littermates.88 Corres- pondingly, this group showed that the effects of sex hor- mone removal are transient in the wild-type mouse, with positive effects lost after 20 weeks.
42
how are the TECs implicated n ageing?
- their proliferative abilities have been shown to decrease with age meaning they may decrease in number
- they decrease the expression of FoxNI which is needed for differentiation of the TECs
- they reduce in number and are replaced by adipose tissue
- they reduce their expression of IL-7
- it participates in a negative feedback loop in which it becomes deficient, causes perturbed T-cell development which then leads to further defective TECs because the maintenance of the htymic architecuture is dependent on the presence of functionally maturing thymocytes
43
who do the peripheral T -cells change?
- decrease reportoire of antigen recognition in older animals- 10^8 in young and 10^6 in older
- massive contrction in CD4 t cell diversity in very only
44
what is a proposed treatment for immunosensence and what are the problems with it
- bone marrow transplant
| - occurrence of fraft vs host disease
45
how cn hormone treatment improve immune ageing?
- application of IL-7- shown to greatly enhance B-cell lymphopoeisis
- IL-7 treatment in old mice has been shown to regenerate the thymus
- DHEAS treatment
46
what is the issue with IL-7 treatment?
P-STAT5 is a signal transducer of IL-7 signalling and has decreased expression in ageing T cells and B-cell precursors
- treatment in mice might not be reflective of humans because IL-7 has different properties in humans
47
how can thymic involution be treated?
thymus transplant to increase naive T cells
| - produce porgenitor multipotent TECs that can be transplanted
48
how do naive CD4 cells changed with time?
reduced responsiveness and [rpliferation linked to IL-2 decline in production
49
what is the reduction of CD4 proliferation and responsiveness liked to
decline in Il-2 production
50
how do b cells change in expression over time?
decrease in E47 and E12 expression and pax-5 expression
51
what are the age associated change in function in the HSCs?
- decline in function nd reduced ability to repopulate
52
what are the potential treatments for A-A decline in HSCs?
bone marrow transplant
53
what is the A-A decline in pro-B and pre-B cells?
- decreased number of pro and pre cells
- diminished RAG expression as result of defective bone marrow microenvironment
- reduced activity of transcription factors E2A and Pax-5
54
what is pax-5
PAX5 gene encodes the B-cell lineage specific activator protein (BSAP) that is expressed at early, but not late stages of B-cell differentiation
55
what is E2A?
gene involved in b cell development
56
what are the potential therapies for A-A changed b-cell ?
bone marrow transplant or gene therapy to induce the expression of E2A and pax-5
57
what are the age associated defects with T cell development int he thymus?
- reduced number of early thymic progenitors
- thymus regresses with age along with a decline in thymic output
- tese both may occur as a result of changed in soluble factors, hormones and alterations in thymic microenvironment
58
what can the thymus be treated in ageing?
thymic tissue transplant
| - GH replacement, sex steroid ablastion, IL-7 treatment
59
what is the A-A decline of memory CD4+ T cells?
- those memory cells developed from young respond well into age but those derived from older naive T cells respond poorly
60
how is the early lymphoid progeniotr production affected with age?
reduced from the bone marrow
61
how are memory cells thought to age?
when memory lymphocyte clones are activated by the adaptive immune response, they must proliferate a lot. When this occurs over and over again the proliferation can cause them to exhaust and become disfunctional. This results in memory cells for common infections becoming exhausted Those clones that are relevant for theCMV virus but have low affinity, so they will not get exhausted and will take up space in the T cell pool which is ignites. This occurs over andover again until 25% are used up by the CMV virus clones will low affinity. This means that the memory lymphocyte pool become taken up with low affinity or irrelevant clones- in the space of other clonal t -cells
62
what is the proof for increased proliferation of b cells or t cells causing ageing?
the length of telomeres for clones for common diseases such as CMV have shorter telomeres- short telomeres links to dysfunction
63
how can the exhaustion of T cell pools by Cmv be treated?
- headr immunity- try to stop people becoming repeatedly infected by making sure no one has this virus- this way the cells do not build up in number an take up space
64
what is the ratio of CD4 to CD8 cells with time?
less CD 4 cells - lose the memory cells due to over stimulation
65
what does reduced CD4 cells mean for the adaptive respons ?
CD4 cells are need to activate killer cells and activate the recruitment of B cells- this means there is less killing of the infected cell, and less of an antibody response from B cells which means a lower phagocyte response because macrophages are attracted by the antibodies bound to the antigens. (opsonisation)
66
what re T helper cells need for?
- activation of B-cells that have presented the relevant antigen which then allows body antibodies to be made to attract macrophages. b cells also produced memory b cells when activated
- activation of CD8 killer cells which can then become long lived memory cells .
67
what happens with latent viruses in elderly?
latent viruses such as herpes can reactive
68
what is the increased incidence of influenza in people over 65?
89-fold §
69
how can telomerase aid ageing? what has already been done?
can induce telomerase expression to prevent telomere shorting and prevent exhaustion of memory T and B cell pools - this has been carried out in virus speciifc T cells from people suffering from HIV - they showed that Telomerase induction could prevent the loss of CD28 and defer senescence via viral infection- CD28 expression is required for telomerase activation so methods to prevent this downreg could also help. they found it wasn't definite thought- eventually senesced
70
what type of hormones induce thymic involution and what sex does this particularly effect?
androgens- males
71
how might malnutirition contribute to immune sen?
not enough energyy to meet the demands associate with the immune response
72
what vitamin can be used to treat immunosen and why?
vitamin D- enhances activation of toll-like receptors of the granulocytes.
73
why is zinc important in the immune response?
it is important to the functioning of 300 enzymes including those in phagocytes and natural killer cells
74
how does the lipid environment alter T cell functioning?
- human high density lipoprotein has an anti-inflammatory and anti-oxidative effect- HDL-extracts accumulated cholesterol in lipid rafts, resulting in increased T cell receptor activity
75
how does caloric restriction improve the immune response?
- was shown to improve immune responsiveness in rodents and delay T lymphocyte immunosenescence
76
what do macrophages lose the ability to secrete over time? what is thiscytokine needed for?
tumour necorsis factor- essential for the secretion of other cytokines critical for bone marrow stream integrity such as IL-6, IL-11, monocyte colony stimulating factor etc
77
what is reduced in the bone marrow stromal cells over time?
IL-7
78
how does TLR expression and function change? what is the result of this?
decline with age- reduced production go pro-inflammatory cytokines and cheekiness as well as in the deregulation of the adaptive immune system
79
what is the production rate of Nk cells affected by and why?
ageing- halves, reduction in IL-2 production
80
how do b cells change in their responsiveness to IL-7 with age?
decline
81
how does V-DL recombination of Ig genes changes in B cells with age?
declines
82
how is the progression to pro- b cells to pre-b cells changed and why?
reduced
- decrease responsiveness to IL-7
- decreased V-DJ recombination of Ig genes, decreased expression go the TFs E12 and E47
83
how does the level of naive b cells change? what has implicated this in age?
decreases- many children of centenarians in a study has increased naive B cell levels compared to normal children
84
where do B cells undergo their maturation?
in the secondary lymphoid tissues such as the spleen and the lymph nodes- germinal centres.
85
what are the germinal centres?
areas in the spleen and lymph nodes which are structure for the interaction between T and B cells and APCs to stimulate B cell maturation and T cell maturation
86
how is the interaction between the B and T cells with APCs reduced with age and how does this affect the immune system?
the germinal centres are reduced in size- this means a reduced environment for immune reactions to take place - this may result in less somatic hyper mutation and impair the selection process of b cells and ineffective interaction between the lymphoctytes- result in ineffective differentiation o
- ineffetive selection- not selecting high affinity
- or not allow b cells through that should nomrallyhav been negatively selected for
87
what occurs int he germinal centre?
somatic hypermutation
- hypermutation, followed by Tfh-mediated selection of B-cell clones with increased affinity for antigen enables B cells to increase their affinity for foreign antigen
88
what happens to the thymus over time?
Both the thymic epithelial space, in which thymopoiesis occurs, and the non-epithelial, non-thymopoietic perivascular space show morphological and functional alterations. The expansion of the perivascular space (adi- pocytes, peripheral lymphocytes, stroma) with age results in a shift in the ratio of true thymic epithelial space to perivascular space. On the contrary, the thymic epithelial space shrinks to less than 10% of the total thymus tissue by 70 years of age.
89
when is it predicted that a person would not be able to produce new t cells due to thymus shrinkage?
105 years
90
which cytokines from the thymus are crucial for thymopoiesis? which of these are thymosuppresive?
Thymic epithelial cells produce a num- ber of colony-stimulating factors and haemopoietic cytokines such as IL-1, IL-3, IL-6, IL-7, transforming growth factor (TGF)-β, oncostatin M (OSM) and leukae- mia inhibitory factor (LIF).
- Il-6, LIF and OSM
91
what is IL-7 needed for in the thymus?
IL-7 is necessary for thy- mopoiesis, promoting cell survival by maintaining the anti-apoptotic protein Bcl-2 and inducing V-DJ recombi- nation
92
what does thymic involution general result in?
decreased output of naive t cells- shift in the ratio of T cells less naive and more memoryy
93
give an example of a thymus being transplanted?
It was reported that in mice transplantation of aged thymuses into juvenile recipients led to reconstruction of the struc- ture and function of the thymus [74]. Moreover, trans- plantation of cultured thymic fragments to patients with DiGeorge syndrome who lack a functional thymus has been carried out successfully [74] and may also be a con- ceivable approach to restore naive T lymphocyte num- bers in the elderly
94
how are sen cells relevat to immune sen?
treatment could involve removing sen cells these cells and permitting their replacement with naive lymphocytes through the thymic output.
95
give evidence for IL-7 being used as a treatment
or therapeutic interven- tions to rejuvenate thymopoiesis. It has been shown that IL-7 can reverse thymic atrophy in old animals, ensuring increased thymic output to replenish the peripheral T lymphocyte pool and improving immune responses [78]. Human IL-7 administration to young mice (aged 6-8 weeks) minimally increased thymopoiesis and peripheral T cell expansion [
96
how has IL-10 treatment been used?
intrathymic injection of an IL-10 expressing adenovirus can prevent thymocyte apoptosis and the thymic atrophy induced by sepsis in mice
97
what are hormones that can be applied to stimulate thymal stroma ?
Keratinocyte growth factor (KGF) and thymic stromal lymphopoietin (TSLP), which is known to stimulate thymus stromal cells, can promote thymopoie- sis in mice following chemotherapy-induced thymic atro- phy [83]. The growth hormone has also been shown to have a stimulatory effect on thymopoiesis in old mice and ablative/bone marrow transplant mice [84]. Together, these studies suggest that coupling thymostimulatory regimens such as IL-10, leptin, KGF and TSLP with inhi- bition of thymosuppressive cytokines
98
how can you address the sex hormone problem
Sex steroid ablation in men undergoing therapy for prostate cancer is reported to result in increased numbers of circulating naive T lymphocytes, but this approach is obviously not generally applicable to the majority of elderly people
99
how do natural killer cells work?
they do not nee antigens to bind- instead they can sense virally infected or cancerous cells and kill them by injecting porforin
100
how do T killer cells work?
TC cells release the cytotoxins perforin, granzymes, and granulysin. Through the action of perforin, granzymes enter the cytoplasm of the target cell and their serine protease function triggers the caspase cascade, which is a series of cysteine proteases that eventually lead to apoptosis (programmed cell death).
101
what are the general consequences of a reduction in the adaptive immune response in the elderly?
- reduced antibodies to attract macrophages- opsinisation
- reduced killer cells due to reduced activation by CD4 cells
- reduced activation of B cells which occurs via CD4 cells,
- increased autoimmunity due to faulty negative selction in the germinal centre
- memory secondary response in blunted
102
what two growth factors have already been used to treat thymic involution?
keratonicyte growth factor and FGF
103
what have keratonicyte growth factor and FGF treatment been used for so far?
used to support therapy during irradiation chemotherapy to supportt thymus growth by inducing IL-7 production
104
how do the peripheral B cells change with age?
- they decrease in their repertoire, this is due to decreased RAG expression and due to the consistent stimulation of the memory pools over and over again- same as T cells- and also due to deficient somatic hypermutation so less choice selection
- also due to faulty germinal centres- there can be faulty negative and positive selection -decreases affinity and also select for those that have affinity for self antigens
105
how are T reg cells implicated in the ageing of the immune system?
- in the elderly there is increased tissue damage which results in an increase of autoantibodies in the blood- as a result T reg cells are unregulated in an attempt to suppress the response of the CD4 and CD8 cells- but this can also allow increased infection and increased cancer cells
106
where is the IL-2 expressed for T cell and B cell proliferation?
in the cells themselves
107
do memory T and B cells express telomerase and what is the level or telomerase expression?
yes but it is not high- less than in HSCs
108
why would use telomerase treatment on lymphocytes be a good idea?
- if would prevent sensence and apoptosis of over proliferating B and T memory cells- this would increase reporotie etc
109
what do CD8 cells release?
anti viral cytokines
110
give a study which actually used constituitively active telomerase in a study and what did they find?
they induced the express of CA telomerase in the CD8+ cells of HIV patietns- this resulted in decreased levels of CD8+ cells sen via decreases expression of p21 and p16
111
what is the sequence of events for activation of the adaptive immune response?
T helper cells bind to APC such as dendritic cell- they they activate T memory cells and T killer cells and also activate B cells
112
how does the variation in thymus receptors occur?
- it occurs in a similar way to the immunoglobulin rearrangement in the B cells in the bone marrows- the genes for the T cell receptors recombine in the thymus VDJ recombination using RAG genes
113
How is it that CD4 cells helper CD 8 cells?
- they release IL-2 which stimulate proliferation of the CD 8 cells0 CD8 cells can be activated alone but htishelp fro the CD4 cells increases the response dramatically
Biology Of Ageing
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