Innate Immunology II

Question 1

Describe the steps of the inflammatory response

Answer 1

1. Chemical signals from tissue-resident cells act to attract more cells to the site of injury or infection
2. Neutrophils enter blood from the bone marrow
3. Neutrophils cling to the capillary wall
4. Chemical signals from tissue-resident cells dilate blood vessels and make capillaries ‘leakier’
5. Neutrophils squeeze through the ‘leaky’ capillary wall and follow the chemical trail to the injury site
   They then undergo phagocytosis

Question 2

Describe the discovery of myeloid cells being phagocytic

Answer 2

In 1886-87 Elie Metchnikoff discovered the cells in the blood could inject and destroy microbes - a process called phagocytosis
Phagein = Ancient Greek “to devour”

Question 3

Describe the phases of phagocytosis

Answer 3

1. Phagocyte adheres to pathogens or debris
2. Phagocyte forms pseudopods that eventually engulf the particles, forming a phagosome (phagocytic vesicle)
3. Lysosome fuses with the phagocytic vesicle, forming a phagolysosome
4. Toxic compounds and lysosomal enzymes destroy pathogens
5. Sometimes exocytosis of the vesicle removes indigestible and residual material

Question 4

Describe the features of lysosomes that allow them to kill and digest phagocytose microbes

Answer 4

• Low pH - acid environment
• Reactive oxygen (hydrogen peroxide) and reactive nitrogen intermediates (nitric oxide) [basically creates bleaches the lysosome, which chemically kills the microbes]
• Enzymes - proteases, lipases, nucleases

Question 5

Describe the Compliment Cascade

Answer 5

• Compliment - 9 major proteins/protein complexes (C1-9) act in sequence to clear pathogens form blood and tissues
• The compliment cascade is like a waterfall, start at the top with lots of potential, end at the bottom with a force much larger than what you started with
• At the end it does three things:
  - Label pathogens (opsonisation)
  - Recruit phagocytes (chemotaxis)
  - Destroy pathogens (lysis)

Question 6

What are the three compliment pathways and their ‘trigger’?

Answer 6

• Classical: antibody bound to pathogen binds compliment
• Alternative: pathogen binds compliment to surface/pathogen component
• Lectin: carbohydrate components of microbes bind compliment
  The compliment molecules circulate in the blood, ready to get started if they get any one of these signals.

Question 7

Describe how the compliment pathways converge

Answer 7

• Triggers: classical, alternative (properdin), lectin
• Amplification (where they converge): C3 Convertase (enzyme complex)
• Outcomes: label, destroy, recruit

Question 8

What is the outcome of compliment cascade called: Label (opsonisation)?

Answer 8

Opsonisation = coating of a microbe with:
- Antibody and/or
- Compliment fragment of C3
These are two ways that the bacterium can be labelled for uptake into phagocytic cell.

Innate immunity: rapid destruction and restoration of blood sterility, and immediate protection

Question 9

What is the outcome of compliment cascade called: Recruit?

Answer 9

• Phagocytes attracted into site
• Mast cells degranulated by C3a and C5a (which are fragments of C3)
• Inflammatory mediators release, including proteins that attract phagocytes

Question 10

What is the outcome of compliment cascade called: Destroy?

Answer 10

• microbes coated with C3b are phagocytosed
• assembly of the membrane attack complex (MAC) causes lysis
  MACs form from activated compliment components (C5b to C9) that insert into the target cell membrane, creating pored that can lyse the target cell.