Immunology 4

Question 1

Examples of pro-inflammatory mediators? Functions?

Answer 1

Nitric oxide, prostaglandins/leukotrienes,histamines - cause vasodilation, increased vascular permeability, smooth muscle contraction and pain

Cytokines (TNFα, IL-1, IL-6, IFNγ) - increase vascular permeability and cause endothelial cell activation

Chemokines - recruit and activate wbcs by chemotaxis

Question 2

What is it called when neutrophils squeeze between endothelial cells?

Answer 2

Diapedesis

Question 3

What are neutrophils?

Answer 3

Short-lived phagocytic cells circulating in blood that have intracellular granules and multi-lobed nuclei

Question 4

Function of neutrophils?

Answer 4

Recruited into inflamed sites by cytokines/ other pro-inflammatory mediators

Kill extracellular pathogens
Produce pro-inflammatory cytokine (like TNFα)

Question 5

What are the killing mechanisms of neutrophils?

Answer 5

Phagocytosis
Degranulation
NETs

Question 6

How do neutrophils phagocytose pathogens?

Answer 6

Pathogens release chemokine-like signals that attract neutrophils

Neutrophils use PRRs to bind to PAMPs on pathogens

Phagocytosis via anti-microbial proteins OR NADPH oxidase-dependent mechanisms

Question 7

Anti-microbial protein mechanisms in phagocytosis?

Answer 7

Granules with anti-microbial proteins:

Acidification - makes pH of phagolysosome 3.5-4.0 and makes bacteriostatic and bactericial products

Anti-microbial peptides - defension and cationic proteins

Enzymes - lysozyme and acid hydrolases

Competitors - lactoferrin (binds Fe) and vitamin-B12 binding protein

Question 8

NADPH oxidase-dependent mechanism in phagocytosis?

Answer 8

AKA respiratory burst produces toxic Reactive Oxygen Species (ROS), like superoxides and nitric oxide

Neutrophil activation
Aseembly of NADPH oxidase complex
Production and release of ROS into phagolysosome

Question 9

What does neutrophil degranulation involve?

Answer 9

Release of anti-bacterial proteins from neutrophil granules into EC environment

Question 10

What are the outcomes of neutrophil degranulation?

Answer 10

Direct killing of EC pathogens

Kill ‘self’ cells causing tissue damage and potentially systemic inflammation

Question 11

What are NETs?

Answer 11

Neutrophil Extracellular Traps

Activated neutrophils release intracellular structures (NETs) into EC environment

Question 12

How do NETs work?

Answer 12

Immobilise pathogens and prevent them from spreading, facilitates phagocytosis

Question 13

How is it known that neutrophils are important in killing bacteria and fungi?

Answer 13

Patients suffering from immunodeficiency disease affecting neutrophils get recurrent bacterial/fungal infection

Question 14

Examples of immunodeficiency diseases affecting neutrophils?

Answer 14

Chédiak–Higashi syndrome - defective phagocytosis

Chronic granulomatous disease - deficiency in NADPH oxidase

Leukocyte adhesion deficiency - defective integrin expression

Question 15

Pathological consequences of neutrophils producing excess TNFα?

Answer 15

Inflammatory bowl disease, psoriasis, rheumatoid arthritis, asthma, cancer, infectious disease, auto-immune pathologies

Question 16

How are these pathological consequence of excess TNFα treated?

Answer 16

Some are co-treated with monoclonal antibodies or other molecules that neutralise TNFα (highly inflammatory cytokine)

Question 17

Examples of complement proteins?

Answer 17

Kinins
Coagulation factors
Fibrinolytic system

Question 18

What is the complement system?

Answer 18

Family of approx. 30 proteins circulating in blood
Produced in liver

Enter infected/inflamed tisses

Question 19

How are complement proteins activated?

Answer 19

Activated directly OR indirectly by pathogens.

When triggered, specific complement proteins can enzymatically activate other complement proteins in a CASCADE reaction

Question 20

Briefly describe mannose-binding lectin pathway

Answer 20

Inactive C3 (acute phase protein) cleaved by upstream complement protein to from ACTIVE C3a and ACTIVE C3b

Question 21

Explain the mannose-binding lectin (MBL) pathway

Answer 21

Pathogens express mannose sugars on cell surface - ligand for MBL; human cells do not express mannose

Produced complex of C4b + C2a which cleaves C3 into C3b and C3a - both trigger downstream events

Question 22

Explain the alternative to the MBL pathway

Answer 22

C3 is unstable so spontaneous degradation into C3b and C3a occurs
C3b rapidly degrades if not attached to a pathogen
If attached to pathogen, factor B attached to C3b
Factor D converts factor B into factor Bb
The factor Bb attached to C3b reproduce C3b

Question 23

What do C3a, C5a and the membrane-attack complex all do?

Answer 23

Kill pathogen
Pathogen opsonisation
Wbc recruitment and inflammation

Question 24

Describe complement mediated killing

Answer 24

C5b binds to pathogen surface

C6, C7, C8, C9 assemble with C5b to form MEMBRANE ATTACK COMPLEX

Inserted into target cell wall causing osmotic lysis of cell

Question 25

What is complement-mediated opsonisation?

Answer 25

Coating of pathogens with humoral factors (opsonins) to faciliate phagocytosis

Opsonin example is C3b

Question 26

Describe complement-mediated inflammation and wbc recruitment

Answer 26

C3a and C5a are ANAPHYLATOXINS - promote inflammation by acting directly on blood cells

OR by stimulating mast cells to produce pro-inflammatory mediators and chemokines

Question 27

Complement system regulation?

Answer 27

Only cleaved complement proteins are active
Active complement proteins have short half-life
Some complement proteins only produced during APR
Some complement proteins do not bind to human cells
Complement inhibitors/ regulatory protein limit activation of the system

Question 28

What are dendtritic cells?

Answer 28

The bridge between the innate and adaptive immune system

“Professional” antigen presenting cells

Question 29

How do dendritic cells work?

Answer 29

Present in peripheral tissues in immature state
Phagocytose antigens, cell debris, particles, etc
Mature and migrate into secondary lymphoid tissues - play key role in antigen presentation