Alpha 1 Antitrypsin Flashcards
Describe innate immunity in the airways
- Physical - ciliates cells + mucocilliary clearance
- Chemical - secretions of antimicrobial peptides
- Cellular - inflammation leads to recruitment of phagocytic cells (neutrophils and macrophages)
Describe a neutrophil
Most common type of white blood cells
Have lobular granules which are filled with destructive enzymes
Describe the action of neutrophils
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
List the 3 main serine proteases
Neutrophil Elastase (NE)
Cathepsin G (CatG)
Proteinase-3 (PRT3)
Which serine proteases is essential for resistance against Staphylococcus aureus infection?
Cathepsin G
What are the functions of Cathepsin G?
- Contributes to killing and digestion of engulfed pathogens
- Connective tissue remodelling at sites of inflammation
- Resistance to Staphylococcus Aureus
What is the function of Proteinase-3?
Generation of antimicrobial peptides
What is Neutrophil Elastase (NE)?
NE is a neutrophil serine protease in the innate immune response
It is a bio marker for infection and inflammation
What can excessive Neutrophil Elastase cause?
Lung tissue damage
Perpetuates cycle of infection and inflammation
What are the functions of neutrophil elastase? (4)
- Intracellular clearance of gram negative bacteria
- Degrade structural proteins e.g. elastin, collagen
- Cleave immunoglobulins
- Act as a chemoattractant for neutrophils (+ induce IL-8 production)
What are the SERPINs?
The SERine Protease INhibitor family
What is AAT?
Alpha 1 Antitrypsin
A glycoprotein containing 394 amino acid residues
Functions as an anti protease
What is the major role of AAT?
Protecting alveolar tissue from damage due to action of neutrophil elastase
Describe AAT’s effect on innate immunity
Production of pro- and anti-inflammatory cytokines mediated by neutrophils
Describe AAT’s effect on active immunity
Reduce the activation of B cells
Describe AAT’s anti-apoptotic effect
Inhibits TNF-induced apoptosis
What is the result of a protease/anti protease imbalance? (In the lungs)
If there are more proteases than protease inhibitors it will result in a diseased lung
What is AAT deficiency?
AATD is a rare, inherited (autosomal recessive) disorder that can cause lung and liver disease
What are the symptoms of AATD?
SOB
Reduced exercise capacity
Wheezing
Describe the genes and mutations which are responsible form AAT production
M - normal function
S - abnormal function
Z - abnormal function
MM normal, MS/MZ mild & ZZ severe
Which AAT production genotype is most commonly associated with COPD and liver disease?
Homozygous genotype ZZ (aka PIZZ)
How does AAT deficiency occur?
AAT is produced in the liver
Mutant protein fold improperly
These molecules are retained in the liver and not secreted appropriately
How does AAT deficiency cause injury to the lungs?
Low serum levels of AAT
Levels not high enough to inhibit NSP’s
Leaves lungs vulnerable to injury from uninhibited NSP’s
What type of disorder is Cystic Fibrosis? (In terms of genetics)
Autosomal Recessive Disorder
What protein encoding gene mutation causes Cystic Fibrosis
CFTR - Cystic Fibrosis Transmembrane Regulator
What type of protein does CFTR function as?
cAMP chloride channel
Describe Cystic Fibrosis
Multi-Organ disease
Characterised by chronic bacterial infection and inflammation in the airway
Describe the cycle of inflammation in cystic fibrosis
Airway epithelium exposed to bacteria
‘Overshooting’ inflammatory reaction
Epithelium becomes damaged
Bacteria are allowed to proliferate in the damaged epithelium
Results in lung injury
List 4 inflammatory markers involved in CF
IL-8 (cytokines)
Free Radicals
Immune complexes
Proteases
Describe the protease-antiprotease imbalance in CF & AATD
Excess NE in diseased lung overwhelms the natural inhibitors
Describe the protease-antiprotease imbalance in COPD
Imbalance is due to a combination of excess NE and oxidised AAT
Oxidation caused by cigarette smoking
