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Phase 2a - ICS > Ageing and immunology > Flashcards

Ageing and immunology Flashcards

1
Q

Examples of diseases associated with ageing.

A

Neurodegenerative disorders
Cardiovascular diseases
CAs
Autoimmune diseases
COVID-19

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2
Q

Intersection of ageing biology and chronic disease

A

Ageing biology (changes in signalling, epigenome etc) leads to disease and less function -> CA, Neurodegeneration.

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3
Q

What are the three levels of hallmarks of ageing?

A

Systematic level (nutritional dysregulation)

Cellular level (cellular senescence, stem cell exhaustion, altered intracellular signalling)

Molecular level (genomic instability, telomere shortening, epigenetic alteration, loss of proteostasis, compromised autophagy, mitochondrial dysfucntion).

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4
Q

What immunological alteration take place in the innate response during immunosenecense?

A

DC decreases the expression of CD80, MHC II and IFN-I

Neutrophils decrease their activity - reduced phagocytosis.

NK cells produce less IFN-gamma.

Inflammatory CK production goes up!

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5
Q

What immunological alteration take place in the adaptive response during immunosenecense?

A

AB production and the levels go down.

Naive memory cells exhausted.

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6
Q

Inflammaging

A

Stimuli to NFkB -> increased production of inflammatory cytokines.

This leads to:
Impaired autophagy
Changes in proteostasis
Mitochondrial dysfunction
Microbiota dysbiosis
Cell senescence

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7
Q

T cells during immunosenescence

A

Naive T cell decreases
Memory T cell increases
TCR diversity decreases
Effector T cell decreases
Virtual memory cell increases
AG recognition decreases

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8
Q

NK cells during immunosenescence

A

Cytokine production decreases
CD56 dim and NKG2C increases.

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9
Q

Dendritic cells during immunosenescence

A

Everything drops (AG presentation, endocytosis, IFN production)

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10
Q

Macrophages during immunosenescence

A

Everything decreases (number and function, AG presentation, phagocytosis)

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11
Q

B cells during immunosenescence

A

Naive decrease
Memory increase

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12
Q

MDSCs during immunosenescence

A

Stands for myeloid derived suppressor cell - number and function increases.

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13
Q

Efferocytosis

A

Efferocytosis is the effective clearance of apoptotic cells by professional and non-professional phagocytes.

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14
Q

Macrophage efferocytosis

A

Apoptosis -> recognition and clearing -> macrophage secretion of pro-resolution CKs

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15
Q

Macrophage impaired efferocytosis

A

Necrosis - release of histotoxic neutrophil contents -> macrophage secretes pro-inflammatory CKs.

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16
Q

Age related changes to macrophages during MSK repair and CA.

A

Become impaired and altered -> pro-inflammatory

The transition to reparative macrophages is altered?

17
Q

SASP

A

Senescence-Associated Secretory Phenotype

It can be transient (beneficial) or persistent (detrimental).

Over time becomes persistent.

18
Q

What are transients SASPs?

A

Anti-fibrotic
Anti-inflammatory
SC clearance
Tissue Patterning

19
Q

What are persistent SASPs?

A

Pro-fibrotic
Pro-inflammatory
SC accumulation
Stem Cell Exhaustion
Tissue dysfunction

20
Q

What is the scale of SASP?

A

Development - repair - regeneration - tumour suppression - tumour progression - chronic inflammation - age-related diseases

21
Q

What are the effects of SASPs on the microenvironment?

A

Matrix remodelling
Mitogenic Signals
Clearance regulation
Inflammation
Immune modulation
Cell proliferation
Cell migration
Cell differentiation
Cell plasticity
Vascularisation

22
Q

Examples of SASP related age-related diseases?

A

They accumulate and arrest proliferation:

NAFLD
T2DM
OA,OP
BPH
Presbycusis
Age-related macular degeneration
PD, AD
COPD
HF

23
Q

Senescence

A

Senescence is a cellular response characterized by a stable growth arrest and other phenotypic alterations that include a proinflammatory secretome

24
Q

Senescence leads to

A

Metabolic changes (lysosomal and mitochondrial expansion)

Reinforcement of growth arrest

Resistance to apoptosis

Autophagy (increased early, decreased late)

25
Q

Assessing senescence in vitro and in vivo

A

Cell surface markers
Chromatin reorganisation
Cell cycle arrest
Metabolic adaptations
Morphological changes
Lysosomal compartment
Secretory phenotype

26
Q

How is altered redox balance accelerates ageing?

A

Inflammatory condition favour redox state (NOX, TNF-alpha, IL-1B, COX, XO, MPO).

Leads to increased oxidative stress, tissue damage which results in increased ROS and decreased antioxidants -> chronic inflammation.

27
Q

Thymus in ageing

A

Thymus - involution (decreased output of mature T cells)

28
Q

Bone marrow in ageing

A

Decreased B cell maturation. Impaired haematopoiesis due to increased adiposity of bone marrow.

29
Q

Spleen and lymph nodes in ageing

A

Reduced number and size of follicles.
Decreased CXCL 13 expression in follicles.
Reduced B cell migration into follicles.

30
Q

Lungs in ageing

A

Increased infiltration of pro-inflammatory cells and lung tissue damage.

31
Q

Changes in T and B cells during immunosenescence

A

Decrease:
Naive lymphocyte production
Lymphocyte repertoire diversity
Effector cell functionality
Lymphocyte proliferation
Post-vaccination AB titers

Increase:
Terminally-differentiated memory lymphocytes
Dysregulated CK production
Lymph node fibrosis
Susceptibility to infectious disease

32
Q

Successful aging - elderly

A

Elderly: increased subtypes from naive to exhausted, cytotoxic and regulatory T cells.

Decrease in proliferation ability and cytotoxicity of CD8 T cells

Decrease in naive B cells and high-affinity AB.

NK: decreased CD56 bright immunoregulatory cells
Increased CD56dim cytotoxic cells

Decreases neutrophil phagocytic ability, adhesion and chemotaxis

Increased inflammatory molecules.

Susceptible to age-related diseases.

33
Q

Successful ageing - centenarians

A

Expansion of cytotoxic cells

Highly differentiated CD8 +

Decrease in the number of B cells (Increase in naive B cells and IgM)

Increased cytotoxic capacity of NK cells

Increased IFN-gamma prod.

Increased neutrophil chemotaxis and microbicidal capacity.

Decrease in neutrophil adherence.

Increased anti-inflammatory molecules.

Avoid or delay susceptibility to age-related diseases.

34
Q

What lifestyle modification slows ageing related diseases?

A

Physical activity
Calorie restriction
Maintaining optimal nutrition

35
Q

What pharmacological interventions reduce inflammaging?

A

Caloric restriction mimics
Reversal of thymic atrophy (IL7 therapy)
Statins
PI3Kinase inhibitors
P38 MAPK inhibition

36
Q

Vaccination

A

Adjuvants should work with the ageing immune system.

37
Q

Innate immune response to vaccination (muscle) in ageing.

A

Increased haematopoetic stem cell differentiation skewed towards myeloid lineage.

Decreased:
migratory capacity
chemotaxis
phagocytosis

38
Q

Adaptive immune response to vaccination (lymph node) during ageing.

A

Increased: pre-existing memory T and B cells
Exhausted T cells and pro-inflammatory B cells

Decreased: T and B cell repertoire diversity
Naive T and B cell pool
New memory cell formation
AB quality, quantity and durability

39
Q

Clinical approaches in immunomodulatory interventions

A

Checkpoint inhibitors
Anti-PD-L1

MAPK inhibitors (Spermidine)

mTOR inhibitors (Rapamycin)

Phase 2a - ICS (43 decks)

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