Ageing immune system

Question 1

With age what happens to infection susceptibility and vaccine responses?

Answer 1

Infection susceptibility increases whilst vaccine responses decrease in efficacy and longevity.

Question 2

What results from immune senescence?

Answer 2

More likely to get hospital acquired infections.
Susceptibility to infections increases with age.
Reduced vaccine efficacy and longevity requiring more frequent boosters.
Cancer incidence increases with age.
AI disease increases with age as immunotolerance mechanism less effective.

Question 3

What happens to haematopoiesis with age?

Answer 3

Haematopoietic stem cells are reduced. Those that do develop are biased to myeloid lineage, reducing lymphoid cell population.

Question 4

What is inflammageing?

Answer 4

Pro-inflammatory cytokine levels increase (IL-1beta, IL-6, CRP, TNFalpha)
Anti-inflammatory cytokine levels decrease (TGFbeta , IL-10)
The levels remain high even without infection.

Question 5

What are the consequences of inflammageing cytokine levels?

Answer 5

Persistance of high cytokine levels contributes to CVD, insulin resistance, sarcopenia (loss of muscle mass and strength) and dementia.

Question 6

What causes inflammageing with age?

Answer 6

Reduced sex hormones and their anti-inflammatory effects.
Cells become senescent and have no function but can produce pro-inflammatory cytokines.
Increased adipose tissue produces inflammatory cytokines.
low production of macrophages

Question 7

What happens to neutrophils with age?

Answer 7

Numbers still rise rapidly in response to infection = neutrophilia. However, their bactericidal functions are reduced:
Chemotaxis/ migration
phagocytosis
ability to generate ROS
NET generation 
Degranulation

Question 8

How is neutrophil migration affected with age?

Answer 8

The time to reach the site increases as migration is less persistent and has more diversions. This increases tissue damage by 40% due to the proteases released to move through the tissue, causing a slower recovery from infection.

Question 9

What happens to monocytes with age?

Answer 9

Circulating levels increase but function decreases. They produce cytokines whilst in a resting state but when stimulated their production is reduced. Prevents ability to promote inflammatory resonse and act as APCs. Decreased IL-6, TNFalpha, ROS, CD80 costimulatory molecule, phagocytosis.

Question 10

What happens to NK cells with age?

Answer 10

Increase in number but have reduced toxicity by 50%. Reduced perforin and IFNgamma release for apoptosis. Linked with increased infections rates and mortality.

Question 11

What happens to T lymphocytes with age? When does it begin?

Answer 11

As the thymus atrophies in childhood, T cell producing capacity decreases with age, with only 5% remaining at 70 years old. Less production of naive T cells means the body is less responsive to new pathogens or vaccinations. However memory T cells continue to expand, decreasing the naive:memory ratio.

Question 12

Where do memory T cells have limited number of replications?

Answer 12

With each replication their telomeres shorten and reduces proliferation capacity.

Question 13

What happens to Treg function with age?

Answer 13

Declines

Question 14

What happens to CD4 Th cells and there receptors?

Answer 14

They change their surface receptors to ones normally restricted to NK cells, so they acquire the ability to induce apoptosis and lose helper function. They also lose costimulatory molecule CD28.

Question 15

What is the problem with the change in CD4 Th cells?

Answer 15

The have an increased tendency to become autoreactive as Treg cell activity is reduced.

Question 16

What happens to the pool of T cells in a Pt who has been infected with persistent CMV?

Answer 16

CMV specific T cells develop in large numbers and can make up 10-15% of the T cell pool. This limits the ability to expand T cells in response to other infections.

Question 17

What happens to B lymphocytes with age?

Answer 17

BM produces less B cells but memory increases. Their telomeres shorten with proliferation. Lack of T cell help means reduced ability to produce high affinity Ig in the germinal centre and diversity of Ig is narrow. Reduced response to new pathogens and vaccines and reduced memory to previously immune pathogens.

Question 18

Why does the number of autoantibodies rise?

Answer 18

Reduced peripheral tolerance

Question 19

What are the 3 main consequences of immunosenescence?

Answer 19

Increased susceptibility to infection, particularly respiratory. Reactivation of infections is increased and ability to control previously immune infections decreases as less proliferation of memory cells.

Vaccinations - reduced naive T cells and reduced adaptive immunity reduces longevity and efficacy.

AI - Peripheral tolerance declines due to altered T cell phenotype and reduced Treg function. Increase in autoantibodies e.g. rheumatoid factor, anti-ssDNA

Question 20

Summarise 4 key consequences of the ageing immune system?

Answer 20

Reduced ability to detect and kill pathogens.
Memory decreases.
Ability to remove damaged cells decreases.
Self damage increases.

Question 21

What drug has been found to improve neutrophil migration and can reduce inflammageing?

Answer 21

Statins