Alpha 1 Antitrypsin

Question 1

Describe innate immunity in the airways

Answer 1

1. Physical - ciliates cells + mucocilliary clearance
2. Chemical - secretions of antimicrobial peptides
3. Cellular - inflammation leads to recruitment of phagocytic cells (neutrophils and macrophages)

Question 2

Describe a neutrophil

Answer 2

Most common type of white blood cells
Have lobular granules which are filled with destructive enzymes

Question 3

Describe the action of neutrophils

Answer 3

Arrive to site of injection fast
Engulf and digest microorganisms
Use reactive oxygen species (ROS), antimicrobial peptides and proteases
Die immediately after ingesting a pathogen

Question 4

List the 3 main serine proteases

Answer 4

Neutrophil Elastase (NE)
Cathepsin G (CatG)
Proteinase-3 (PRT3)

Question 5

Which serine proteases is essential for resistance against Staphylococcus aureus infection?

Answer 5

Cathepsin G

Question 6

What are the functions of Cathepsin G?

Answer 6

1. Contributes to killing and digestion of engulfed pathogens
2. Connective tissue remodelling at sites of inflammation
3. Resistance to Staphylococcus Aureus

Question 7

What is the function of Proteinase-3?

Answer 7

Generation of antimicrobial peptides

Question 8

What is Neutrophil Elastase (NE)?

Answer 8

NE is a neutrophil serine protease in the innate immune response
It is a bio marker for infection and inflammation

Question 9

What can excessive Neutrophil Elastase cause?

Answer 9

Lung tissue damage
Perpetuates cycle of infection and inflammation

Question 10

What are the functions of neutrophil elastase? (4)

Answer 10

1. Intracellular clearance of gram negative bacteria
2. Degrade structural proteins e.g. elastin, collagen
3. Cleave immunoglobulins
4. Act as a chemoattractant for neutrophils (+ induce IL-8 production)

Question 11

What are the SERPINs?

Answer 11

The SERine Protease INhibitor family

Question 12

What is AAT?

Answer 12

Alpha 1 Antitrypsin
A glycoprotein containing 394 amino acid residues
Functions as an anti protease

Question 13

What is the major role of AAT?

Answer 13

Protecting alveolar tissue from damage due to action of neutrophil elastase

Question 14

Describe AAT’s effect on innate immunity

Answer 14

Production of pro- and anti-inflammatory cytokines mediated by neutrophils

Question 15

Describe AAT’s effect on active immunity

Answer 15

Reduce the activation of B cells

Question 16

Describe AAT’s anti-apoptotic effect

Answer 16

Inhibits TNF-induced apoptosis

Question 17

What is the result of a protease/anti protease imbalance? (In the lungs)

Answer 17

If there are more proteases than protease inhibitors it will result in a diseased lung

Question 18

What is AAT deficiency?

Answer 18

AATD is a rare, inherited (autosomal recessive) disorder that can cause lung and liver disease

Question 19

What are the symptoms of AATD?

Answer 19

SOB
Reduced exercise capacity
Wheezing

Question 20

Describe the genes and mutations which are responsible form AAT production

Answer 20

M - normal function
S - abnormal function
Z - abnormal function

MM normal, MS/MZ mild & ZZ severe

Question 21

Which AAT production genotype is most commonly associated with COPD and liver disease?

Answer 21

Homozygous genotype ZZ (aka PIZZ)

Question 22

How does AAT deficiency occur?

Answer 22

AAT is produced in the liver
Mutant protein fold improperly
These molecules are retained in the liver and not secreted appropriately

Question 23

How does AAT deficiency cause injury to the lungs?

Answer 23

Low serum levels of AAT
Levels not high enough to inhibit NSP’s
Leaves lungs vulnerable to injury from uninhibited NSP’s

Question 24

What type of disorder is Cystic Fibrosis? (In terms of genetics)

Answer 24

Autosomal Recessive Disorder

Question 25

What protein encoding gene mutation causes Cystic Fibrosis

Answer 25

CFTR - Cystic Fibrosis Transmembrane Regulator

Question 26

What type of protein does CFTR function as?

Answer 26

cAMP chloride channel

Question 27

Describe Cystic Fibrosis

Answer 27

Multi-Organ disease
Characterised by chronic bacterial infection and inflammation in the airway

Question 28

Describe the cycle of inflammation in cystic fibrosis

Answer 28

Airway epithelium exposed to bacteria
‘Overshooting’ inflammatory reaction
Epithelium becomes damaged
Bacteria are allowed to proliferate in the damaged epithelium
Results in lung injury

Question 29

List 4 inflammatory markers involved in CF

Answer 29

IL-8 (cytokines)
Free Radicals
Immune complexes
Proteases

Question 30

Describe the protease-antiprotease imbalance in CF & AATD

Answer 30

Excess NE in diseased lung overwhelms the natural inhibitors

Question 31

Describe the protease-antiprotease imbalance in COPD

Answer 31

Imbalance is due to a combination of excess NE and oxidised AAT
Oxidation caused by cigarette smoking