Innate immunity: barriers and pre-formed mediators

Question 1

Examples of mechanical barriers

Answer 1

-epithelium tight cell junctions (skin, gut, etc)
-flow -of air (eg. skin) or fluid (eg. gut, urine in urogenital tract)

Question 2

Examples of chemical barriers

Answer 2

-fatty acids (eg. skin)
-mucins (component of mucous; eg. gut, lungs, nose, etc)
-enzymes (eg. lysozymes in skin, eyes, etc; pepsins in gut)
-low pH (eg. gut, vagina)
-antimicrobial peptides (eg. defensins)

Question 3

Examples of microbiological barriers

Answer 3

commensals (microbiota everywhere!)

Question 4

How does skin act as barrier?

Answer 4

-keratinocytes produce keratin (provides strength) and sebum (containing fatty acids, low pH)
-skin shedding (removes pathogens)
-covered in commensals
-generally impermeable

Question 5

How do mucousal membranes act as barriers?

Answer 5

-mucous (traps pathogens) and cilia (in resp tract) to move the mucous
-secreted enzymes eg. lysozymes
-low pH
-peristalsis in gut (movement of food by contractions)
-shedding of epithelium
-commensals present

Question 6

What are pre-formed mediators?

Answer 6

proteins with broad specificity which damage pathogens, induce inflammation or help recruit/activate innate immune cells
eg. lysozymes, complement, antimicrobial peptides like defensins

Question 7

What are lysozymes?

Answer 7

enzyme present in secretions (mucous, tears, saliva) which breaks bond in peptidoglycan
-targets gram +ve bact

Question 8

What are defensins?

Answer 8

antimicrobial short peptide produced by epithelial cells and neutrophils
cationic so disrupts membranes when inserted into them
-targets bacteria, fungi, enveloped viruses

Question 9

What is complement?

Answer 9

20+ soluble proteins found in bodily fluids (eg. blood)
-inert but activated by presence of pathogen or binding of an antibody
-work in an enzyme cascade (amplifies response)

Question 10

What are the three pathways of complement activation?

Answer 10

-classical (antibody binding)
-alternative (spontaneous C3 cleavage)
-mannose-binding lectin (MBL) (binding to mannose on pathogen)

Question 11

What is the role of C3 convertase?

Answer 11

cleave C3 into C3b and C3a
-exposing thioester bond on C3b that can bind to carbs and prots (eg. on pathogen surface)
N/B: thioester bond hydrolysed vert rapidly in fluid phase to prevent inappropriate activation

Question 12

What is the C3 convertase in the classical and MBL pathways?

Answer 12

C4bC2a

Question 13

What is the C3 convertase in the alternative pathway?

Answer 13

C3bBb

Question 14

What happens in the alternative pathway of complement activation?

Answer 14

-C3b spontaneously generated
-C3b binding to LPS on pathogen surface, causing factor B to bind
-factor D cleaves factor B, generating C3bBb (the C3 convertase)
-C3bBb is stabilised by factor P (properdin)

Question 15

What happens after complement activation (in all three pathways)?

Answer 15

-C3b and C3 convertase combine to generate a C5 convertase
-C5 convertase cleaves C5, generating C5b
-C5b triggers the membrane attack complex to be formed

Question 16

What biological activity can occur as a response to complement activation?

Answer 16

-recruitment of phagocytes (by chemotaxis) and mast cells (releasing infammatory mediators) by C5a and C3a
-opsonisation (phagocytes more attracted to bacteria) promoted by C3b
-C5b-9 activation causes C9s to polymerise into a membrane attack complex, which forms a pore in pathogen membrane causing lysis

Question 17

How is inappropriate complement activation prevented?

Answer 17

by soluble and membrane-bound regulatory proteins
soluble:
-carboxypeptidase N (inactivates C5a and C3a in fluid phase)
-Factor I protease (cleaves C3b)
membrane-bound:
-CD59 (on healthy host cell surface, binds C9 to prevent MAC forming)
-decay-accelerating factor (on host membranes, prevents C3 and C5 convertases forming)

Question 18

What can deficiencies in complement inhibitors cause?

Answer 18

increased risk of diseases
eg. lack factor H: increased risk of age-related macular degeneration
lack CD59: increased risk of paroxysmal nocturnal hemoglobinuria
deficiency in factor I: increased risk of infections and autoimmune diseases

Question 19

Which infections is complement important in?

Answer 19

extracellular bacteria and fungal infections