The Innate Immune System Part II – Inflammation

Question 1

What is Inflammation ?

Answer 1

• Affects on both innate & adaptive
• A local response to injury or trauma
• Important in the recruitment of immune cells & molecules to kill infection and initiate repair at the site of injury or infection.
• Largely co-ordinated by leukocytes & leukocyte traffic
• Gross characteristics are redness, swelling, heat and pain

Question 2

Process of Inflammation ?

Answer 2

1. Tissue damage and bacteria cause resident sentinel cells to release chemoattractants and vasoactive factors that trigger a local increase in blood flow
2. Permeable capillaries allow an influx of fluid (exudate) and cells
3. Neutrophils and other phagocytes migrate to site of inflammation (chemotaxis)
4. Phagocytes and antibacterial substances destroy bacteria

Question 3

What do cells of the innate immune system have to enable them to respond to infection ?

Answer 3

They have PRR that enable them to respond to infection (PAMPs) or damage (DAMPs) by initiating inflammation

Question 4

Define Inflammation ?

Answer 4

This is a general term for local accumulation of fluid, plasma proteins & leukocytes initiated by physical injury or infection

Question 5

What are the characteristics of an Inflammation ?

Answer 5

Redness, heat, pain, swelling & loss of function

Question 6

At the site of infection, what us activated so then produced ?

Answer 6

At the site of infection, resident macrophages are activated by PRR to produce cytokines

Question 7

What do both IL-1β and TNF-α ?

Answer 7

Induce blood vessels to become more permeable, enabling effector cells and fluid containing soluble effector molecules to enter the infected tissue

Question 8

What does IL-6 induce ?

Answer 8

Induces fat and muscle cells to metabolise, make heat and raise the the temperature in the infected tissue

Question 9

What does CXCL8 recruit ?

Answer 9

Recruits neutrophils from the blood and guides them to the infected tissue

Question 10

What does IL-12 recruit and activate ?

Answer 10

Recruits and activates natural killer (NK) cells that in turn secrete cytokines that strengthen the macrophages’ response to infection

Question 11

Inflammation at one site can have systemic effects. What is this due to ?

Answer 11

This is due to production of cytokines by innate cells as the result of PRR

Question 12

What are the key cytokines that help establish inflammation ?

Answer 12

IL-1β, IL-6 & TNFα

Question 13

What kind of response do these cytokines induce ?

Answer 13

Acute Phase Response

Question 14

What property do these cytokines have ?

Answer 14

These cytokines are Pyrogens (temperature rising) causing fever (lethargy, somnolence etc), a tactic for fighting infection

Question 15

What is the Acute Phase Proteins made and secreted by ?

Answer 15

By the liver into blood
rapidly in response to inflammatory cytokines IL-6, TNFα & IL-1β
- One example is C-Reactive Protein but there are many

Question 16

What kind of local effect does cytokines have ? and responsible for ?

Answer 16

Cytokines have LOCAL effects at the site of injury or infection
- This is responsible for cardinal features of inflammation and recruitment of other immune cells

Question 17

What do cell-adhesion molecules control ?

Answer 17

The interactions between immune cells and endothelium (blood vessels) during inflammation

Question 18

What is the Extravasation ?

Answer 18

This is the passage of immune cells from blood into tissue and is driven by sequential activation of surface molecules on the cell and
endothelium

Question 19

What are the steps of Extravasation ?

Answer 19

1. Chemoattraction
2. Rolling adhesion
3. Arrest and tight adhesion
4. Diapedesis - transendothelial migration

Question 20

Explain Chemoattraction ?

Answer 20

• Upon recognition of and activation by pathogens, resident macrophages in the
  affected tissue release acute phase cytokines
• These cause the endothelial cells of blood vessels near the site of infection to express cellular adhesion molecules
• Circulating immune cells are localised towards the site of injury or infection

Question 21

Explain Rolling adhesion ?

Answer 21

• Like velcro, ligands on the circulating immune cells bind to selectin molecules on the inner wall of the vessel
• This causes the immune cells to slow down and begin rolling along the inner surface of the vessel wall

Question 22

Explain Tight adhesion and diapedesis ?

Answer 22

• Chemokines released by macrophages activate the rolling cells and cause
  activation of surface integrin molecules on immune cells which bind to complementary receptors on endothelial cells with high affinity
• This causes the immobilisation of the leukocytes and allows for transmigration through the endothelium - diapedesis

Question 23

What is Phagocytosis ?

Answer 23

Inflammatory cells kills invading germs and help repair tissue

Question 24

Steps of Phagocytosis ?

Answer 24

1. Bacterium binds to PRRs on membrane evaginations called pseudopodia
2. Bacterium is ingested, forming phagosome (pH 6.2)
3. Phagosome fuses with lysosome (pH 4.5-5)
4. Bacterium is killed and then digested by low pH-activated lysosomal enzymes (pH 4.5)
5. Digestion products are released from cell

Question 25

What can Phagocytosis also be defined as ?

Answer 25

Defined as engulfment and

internalisation of materials such as microbes for their clearance and destruction

Question 26

What are Microbes recognised by ?

Answer 26

• By PRR on macrophages and neutrophils (the phagocytes)

- Also results in further inflammatory cytokine release

Question 27

Where do ingested materials get taken into ?

Answer 27

Taken into phagosomes

which are fused with lysosomes or granules

Question 28

How does destruction occur in Phagocytosis ?

Answer 28

• Enzyme degradation e.g., lysozyme
• Antimicrobial peptides e.g., cathelicidin, defensins
• Acidification pH of around
  3. 5-4
• Toxic effects of reactive oxygen and reactive nitrogen species (ROS and RNS)

Question 29

In the cytoplasm of neutrophils, macrophages and dendritic cells several enzymes including NADPH oxidase transform ?

Answer 29

Oxygen into highly Reactive Oxygen Species (ROS)

Question 30

One of the products of this pathway, superoxide anion can interact with ? and what is the result ?

Answer 30

• Reactive Nitrogen Species called Nitric Oxide (NO) to generate inducible Nitric Oxide Synthase (iNOS)
• The result is peroxynitrite (ONOO-), another RNS. NO can also undergo oxidation to become Nitrogen Dioxide (NO2)

Question 31

What is Cell death induced by?

Answer 31

By receptor-activated signal pathways

Question 32

What is Apoptosis induced by?

Answer 32

Apoptosis induced by TNF binding to TNFR, NK cells, and T cytotoxic cells

Question 33

What is Pyroptosis induced by?

Answer 33

Pyroptosis induced by inflammasome activation eliminates infected
macrophages allowing release of IL-1β and IL-18

Question 34

What is Neutrophil extracellular traps (NETs) induced by ?

Answer 34

Neutrophil extracellular traps (NETs) activation requires NADPH oxidase and generation of ROS

Question 35

Dendritic cells are a key bridge. They bring antigens ?

Answer 35

• From the site of infection and present them to T cells in lymph nodes
• This activates the T cells, allowing them to differentiate into particular pathogen-specific subsets for the best antigen clearance. T cells help β cells produce antibodies