Immune Senescence and Inflammation Flashcards
What is immune senescence?
Deterioration of immune system with age - not immune cells in senescent state
Which factors cause different ageing rates in different individuals?
Genetic - weak link - importance decreases with age
Environmental - toxin and infectious agent exposure, diet, exercise, microbiota composition - importance increases with age
What is innate immunity and which cell types does it involve?
Fast non-specific response
Neutrophils, macrophages, dendritic cells
What is adaptive immunity and which cell types does it involve?
Very specific response - long-term memory
T-cells, B-cells
Which aspects of the immune system change with age?
Innate immunity
Adaptive immunity
Immune environment (cytokines, hormones)
What are the 2 key features of immune senescence?
Loss of antigen-specific immunity and memory
Increased inflammation
Why is a balance between immune action and regulation needed?
Immune action protects against cancer and pathogens
Immune regulation needed so no reaction to non-pathogens
How does age affect immune action and regulation and what is the effect of this?
Decreased immune action - more prone to infections and cancer
Decreased immune regulation - more prone to autoimmune and inflammatory disease
What does the loss of antigen-specific memory with age involve?
Impaired ability to respond to new antigens
Increased frequency and severity of infections from established pathogens
What does the increased inflammation with age involve?
Chronic immune cell activation
Increased senescence in non-immune cells - SASP
How does the normal antigen-specific immune response affect pathogen antigen levels?
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
How does the aged antigen-specific immune response affect pathogen antigen levels?
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
How is the ability to respond to a new antigen (vaccine) changed in older people?
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
What is the effect of the loss of T-cell memory with age?
Loss of control of established virus - reactivation
Increases incidence of established infections
Name a common virus that becomes reactivated in older people
VZV (chickenpox/shingles)
What is required for a positive skin test response to VZV?
Prior exposure and memory of VZV
What is the difference between the response to the VZV skin test in old and young people and what does this show?
Young have positive response - old do not
T-cells do not proliferate in older people - memory lost
How do innate immune cells detect danger?
Pathogen-associated molecular patterns (PAMPs) -patterns not found on own cells
How do innate immune cells detect damage of own cells?
Host damage-associated molecular patterns (DAMPs)
How do innate immune cells detect PAMPs and DAMPs?
Via pattern recognition receptors (PRRs)
How do innate immune cells respond to PAMP/DAMP detection?
Cytokine secretion
Phagocytosis
Communication to other immune cells
How is an antigen-specific response generated?
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
What is the expansion and retraction of adaptive immunity?
Expansion - proliferation of specific cells in response to infection
Retraction - once infection resolved most cells die via apoptosis - few remain for memory
What are the types of T-cell and the differences between them?
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
When does T-cell differentiation occur?
In response to antigen detection
What happens to the innate immune system with age?
Impaired phagocytosis, movement, cytokine release, antigen presentation
Preserved numbers
What happens to the adaptive immune system with age?
Changes at population level - relative proportions of each T-cell type
Intrinsic cellular changes - reduced activation of naive T-cell
How does the T-cell population change with age?
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
How does the B-cell population change with age?
Decreased number
Decreased antibody production
Decreased antibody affinity
Increased B-cell clonal expansion
Where are naive T-cells produced in young people?
Thymus
Where are naive B-cells produced?
Bone marrow
What process decreases the number of naive T-cells produced with age?
Thymic involution
How is the total lymphocyte number kept constant in older people despite thymic involution?
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
How does telomere shortening affect T-cells?
Limits number of T-cell divisions
The levels of which factors are increased in inflammageing?
IL-6
TNF-alpha
CRP
What causes inflammageing?
Chronic activation of immune cells (macrophages)
Accumulation of senescent immune and non-immune cells (e.g. adipose, fibroblasts)
What are the factors contributing to inflammation?
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
Why do senescent cells accumulate with age?
Increased rate of accumulation - due to damage accumulation
Decreased efficacy of senescent cell clearance
Which pathways contribute to senescent cell accumulation with age?
Telomere erosion DNA damage ROS SASP from other senescent cells Activated oncogenes
What is the effect of caloric restriction in mice and monkeys?
Decreased inflammation
Increased anti-inflammatory molecules
Increased T-cell and innate responses
Increased lifespan
How could microbiota composition be manipulated to decrease inflammageing?
Diet/prebiotics - to change cell environment
What are the effects of a healthy gut microbiota?
Decreased systemic inflammation
Increased blood phagocytosis
Name 5 potential immune senescence treatments
Thymic regeneration - increase naive T-cell numbers Cytomegalovirus vaccination Exercise and stress management Senescent cell removal Blocking SASP-related pathways
What is a problem with thymic regeneration as a treatment for immune senescence?
Ineffective
What is the rationale behind the cytomegalovirus vaccination as a treatment for immune senescence?
In older people many cells specific for cytomegalovirus - waste of cells - aim to prevent
What is the effect of exercise and stress management as a treatment for immune senescence?
Exercise decreases systemic inflammation, increases telomerase activity
Chronic stress increases immunosenescence
Which of the potential immune senescence treatments are most promising?
Senescent cell removal
Blocking SASP-related pathways
How can SASP-related pathways be blocked?
Metformin
Rapamycin
