L20- Ageing and Immunity

Question 1

What are a few consequences of ageing that effect the population?

Answer 1

 Increased morbidity and mortality from infections (e.g. pneumococci, influenza)

 Vaccinations are less effective in older individuals

 Acceleration of degenerative diseases as a result of the production of inflammatory mediators (e.g., atherosclerotic disease, Alzheimer disease, osteoarthritis)

 Increased incidence of autoimmune disease (e.g., polymyalgia rheumatica, giant cell arteritis, rheumatoid arthritis)

 Increased propensity to develop cancer.

Question 2

What are 9 Hallmarks of ageing?

Answer 2

1. Altered intercellular communication
2. Genomic instability
3. Telemere attrition
4. Epigenetic alterations
5. Loss of proteostatis
6. Deregulated nutrient-sensing
7. Mitochondrial dysfunction
8. Cellular senescence
9. Stem cell exhaustion

Question 3

What’s the immune system function in the ageing individual during immunosenescence?

Answer 3

Thymus atrophy, reductions in neutrophil function, naïve T cell number, and the cytotoxic capacity of natural killer cells, and lowered B-cell antibody production in response to antigen

Question 4

What’s the immune system function in the ageing individual during Inflammaging?

Answer 4

Chronic, sterile, systemic, low-grade inflammation - increase pro-inflammatory mediators (IL-1, IL-6, IL-8, C-reactive protein (CRP) and TNF-α)

Question 5

How does ageing effect physical barriers?

Answer 5

 Decline in skin cell replacement, flattening of the dermo-epithelial junctions and dermal and subcutaneous atrophy -skin becomes thinner, collagen becomes disorganised, and tensile strength is reduced

 Decreased production of sweat and sebum

 Depletion of Langerhans cells and melanocytes

 Reduced ciliary beat frequency (controversial)

 Increases in salivary secretory IgA up to 60 years and thereafter slight decrease

 Increased microbial translocation

Question 6

What happens to our haematopoietic stem cells as we age?

Answer 6

 The proliferative capacity of HSCs diminishes with age

 A shift towards production of myeloid progenitors

 Cell-intrinsic mechanisms: Pro-inflammatory status (upregulation of P-selectin, ICAM1 and NF-κB) Protein integrity compromised (increased expression of heat shock protein 8 and 40) mtDNA mutations and oxidative damage DNA damage and telomere shortening

 Results: onset of anaemia, decreased competence of the adaptive and immune system and an expansion of myeloid cells

Question 7

What happens to DCs as we age?

Answer 7

 Reduced number and function of plasmacytoid DCs

 Altered maturation and migration in some subsets

 Altered TLR expression and signaling (e.g. increased response to LPS/ impaired response to TLR7/9 ligands)

 Altered CD80 and CD86 expression retained or increased (concomitantly, decreased CD28 expression and increased CTLA-4 in T cells)

Question 8

What are the negative crosstalk between DCs and T cells as we age?

Answer 8

Inhibition of activation of both T cells and DCs

Increased IL-10 but reduced IL-2, IFNy, TNFa

Decreased cytotoxicity, increased apoptosis and promotes anergy

Increased IDO production leading to tryptophan depletion and inhibition of effector T cells and promotion of Tregs.

Question 9

What happens to macrophages as we age?

Answer 9

 Number of macrophages

 TLR response is not uniform - M1 and M2

 Increased M2 polarization *but with unusual proinflammatory profile (?)

 Polarization, metabolism and inflammation

Question 10

What happens to NK cells as we age?

Answer 10

 Increase in overall NK frequency and number – increased mature NK (CD16+ CD56dim ) and decrease of immature CD56bright

 Increased expression of CD57, which is marker of replicative senescence and lack of proliferation

 Function changes from immature and naïve mature that produce high amounts of cytokines to experienced and terminally differentiated NK cells, with strong target cell cytotoxicity and ADCC

Question 11

What happens to T cells as we age?

Answer 11

 HSC and progenitors to shift away from lymphoid lineages and toward myeloid lineage

 Thymic aging/ involution - age-related thymic atrophy or involution

 Absolute T cell numbers decrease with age particularly naïve subset (more CD8 than CD4)

 CD28 expression by CD4 and CD8 cells decreases

Question 12

What happens to B cels as we age?

Answer 12

 Decline in B cell production in the bone marrow

 Reduced clonal expansion capability of memory B cells

 Functionally impaired antibodies with lower affinities and decreased opsonising abilities

 Increase of age-associated B cells associated with autoimmunity

 Persistent latent CMV infection (prevalent in the elderly) and decreased antibody titres after vaccination