Immune Senescence and Inflammation

Question 1

What is immune senescence?

Answer 1

Deterioration of immune system with age - not immune cells in senescent state

Question 2

Which factors cause different ageing rates in different individuals?

Answer 2

Genetic - weak link - importance decreases with age
Environmental - toxin and infectious agent exposure, diet, exercise, microbiota composition - importance increases with age

Question 3

What is innate immunity and which cell types does it involve?

Answer 3

Fast non-specific response

Neutrophils, macrophages, dendritic cells

Question 4

What is adaptive immunity and which cell types does it involve?

Answer 4

Very specific response - long-term memory

T-cells, B-cells

Question 5

Which aspects of the immune system change with age?

Answer 5

Innate immunity
Adaptive immunity
Immune environment (cytokines, hormones)

Question 6

What are the 2 key features of immune senescence?

Answer 6

Loss of antigen-specific immunity and memory

Increased inflammation

Question 7

Why is a balance between immune action and regulation needed?

Answer 7

Immune action protects against cancer and pathogens

Immune regulation needed so no reaction to non-pathogens

Question 8

How does age affect immune action and regulation and what is the effect of this?

Answer 8

Decreased immune action - more prone to infections and cancer
Decreased immune regulation - more prone to autoimmune and inflammatory disease

Question 9

What does the loss of antigen-specific memory with age involve?

Answer 9

Impaired ability to respond to new antigens

Increased frequency and severity of infections from established pathogens

Question 10

What does the increased inflammation with age involve?

Answer 10

Chronic immune cell activation

Increased senescence in non-immune cells - SASP

Question 11

How does the normal antigen-specific immune response affect pathogen antigen levels?

Answer 11

Initial exposure - primary immune response - decreases antigen level
Secondary exposure - faster and stronger immune response - pathogen does not have time to replicate to same level as before - smaller increase in antigen level

Question 12

How does the aged antigen-specific immune response affect pathogen antigen levels?

Answer 12

Initial exposure - primary immune response slow and smaller magnitude - more time for pathogen replication - higher antigen level
Secondary exposure - slower and smaller magnitude response - impaired immune memory

Question 13

How is the ability to respond to a new antigen (vaccine) changed in older people?

Answer 13

Impaired
Smaller increase in T-cells after vaccination - loss of T-cell proliferation (cellular response)
Smaller increase in antibody after vaccination - loss of humoral response

Question 14

What is the effect of the loss of T-cell memory with age?

Answer 14

Loss of control of established virus - reactivation

Increases incidence of established infections

Question 15

Name a common virus that becomes reactivated in older people

Answer 15

VZV (chickenpox/shingles)

Question 16

What is required for a positive skin test response to VZV?

Answer 16

Prior exposure and memory of VZV

Question 17

What is the difference between the response to the VZV skin test in old and young people and what does this show?

Answer 17

Young have positive response - old do not

T-cells do not proliferate in older people - memory lost

Question 18

How do innate immune cells detect danger?

Answer 18

Pathogen-associated molecular patterns (PAMPs) -patterns not found on own cells

Question 19

How do innate immune cells detect damage of own cells?

Answer 19

Host damage-associated molecular patterns (DAMPs)

Question 20

How do innate immune cells detect PAMPs and DAMPs?

Answer 20

Via pattern recognition receptors (PRRs)

Question 21

How do innate immune cells respond to PAMP/DAMP detection?

Answer 21

Cytokine secretion
Phagocytosis
Communication to other immune cells

Question 22

How is an antigen-specific response generated?

Answer 22

Dendritic cell activation by danger signals - become mature
Picks up antigen - breaks down
Moves into lymph nodes
Costimulatory molecule between dendritic cell and naive T-cell - immunological synapse
Activated T-cells proliferate, secrete cytokines - kill infected cells, help B-cells make antibodies

Question 23

What is the expansion and retraction of adaptive immunity?

Answer 23

Expansion - proliferation of specific cells in response to infection
Retraction - once infection resolved most cells die via apoptosis - few remain for memory

Question 24

What are the types of T-cell and the differences between them?

Answer 24

Naive T-cells - never detected antigen - slower activation than memory T-cells
Memory T-cells - detected antigen
End-of-life T-cells - may not activate

Question 25

When does T-cell differentiation occur?

Answer 25

In response to antigen detection

Question 26

What happens to the innate immune system with age?

Answer 26

Impaired phagocytosis, movement, cytokine release, antigen presentation Preserved numbers

Question 27

What happens to the adaptive immune system with age?

Answer 27

Changes at population level - relative proportions of each T-cell type Intrinsic cellular changes - reduced activation of naive T-cell

Question 28

How does the T-cell population change with age?

Answer 28

Numbers stable overall More end-stage than naive T-cells More oligoclonal T-cells - from clonal expansion - more cells recognising same antigen - but fewer specificities Decreased T-cell repertoire Decreased proliferative response to antigen

Question 29

How does the B-cell population change with age?

Answer 29

Decreased number Decreased antibody production Decreased antibody affinity Increased B-cell clonal expansion

Question 30

Where are naive T-cells produced in young people?

Answer 30

Thymus

Question 31

Where are naive B-cells produced?

Answer 31

Bone marrow

Question 32

What process decreases the number of naive T-cells produced with age?

Answer 32

Thymic involution

Question 33

How is the total lymphocyte number kept constant in older people despite thymic involution?

Answer 33

Local environment cues promote proliferation of existing cells Not all cells equally responsive - homeostatic competition favours some clones - over-representation to some specificities - decreases repertoire diversity Clones not naive Clones nearer to end-stage - defective

Question 34

How does telomere shortening affect T-cells?

Answer 34

Limits number of T-cell divisions

Question 35

The levels of which factors are increased in inflammageing?

Answer 35

IL-6 TNF-alpha CRP

Question 36

What causes inflammageing?

Answer 36

Chronic activation of immune cells (macrophages) | Accumulation of senescent immune and non-immune cells (e.g. adipose, fibroblasts)

Question 37

What are the factors contributing to inflammation?

Answer 37

Long-term exposure to persistent viruses - keep activating immune system Obesity - visceral fat inflammatory - accumulates with age Gut microbiota - in old age gut leakier - microbiota move into blood - activates immune system Cellular debris and misfolded/misplaced DAMPs - in olde ages cells more likely to malfunction Senescent cell accumulation - SASP

Question 38

Why do senescent cells accumulate with age?

Answer 38

Increased rate of accumulation - due to damage accumulation | Decreased efficacy of senescent cell clearance

Question 39

Which pathways contribute to senescent cell accumulation with age?

Answer 39

``` Telomere erosion DNA damage ROS SASP from other senescent cells Activated oncogenes ```

Question 40

What is the effect of caloric restriction in mice and monkeys?

Answer 40

Decreased inflammation Increased anti-inflammatory molecules Increased T-cell and innate responses Increased lifespan

Question 41

How could microbiota composition be manipulated to decrease inflammageing?

Answer 41

Diet/prebiotics - to change cell environment

Question 42

What are the effects of a healthy gut microbiota?

Answer 42

Decreased systemic inflammation | Increased blood phagocytosis

Question 43

Name 5 potential immune senescence treatments

Answer 43

``` Thymic regeneration - increase naive T-cell numbers Cytomegalovirus vaccination Exercise and stress management Senescent cell removal Blocking SASP-related pathways ```

Question 44

What is a problem with thymic regeneration as a treatment for immune senescence?

Answer 44

Ineffective

Question 45

What is the rationale behind the cytomegalovirus vaccination as a treatment for immune senescence?

Answer 45

In older people many cells specific for cytomegalovirus - waste of cells - aim to prevent

Question 46

What is the effect of exercise and stress management as a treatment for immune senescence?

Answer 46

Exercise decreases systemic inflammation, increases telomerase activity Chronic stress increases immunosenescence

Question 47

Which of the potential immune senescence treatments are most promising?

Answer 47

Senescent cell removal | Blocking SASP-related pathways

Question 48

How can SASP-related pathways be blocked?

Answer 48

Metformin | Rapamycin