molecular interactions of innate immunity

Question 1

TLR signalling

Answer 1

• conserved
• TLR stimulation → IkB phosphorylation
  
  • inhibitor of NFkB
  • sequesters it in cytoplasms
• IkB now dissociates from NFkB
• translocates to nucleus → cytokine transcription
• immune response genes all have NFkB binding sites

Question 2

complement system

Answer 2

• 30 serum proteins
• combine to form MAC when activated by immune complexes or walls of microorganisms
  
  • destroys target cells by punching holes
• produced in liver by macrophages or fibroblasts
• found in plasma or bound to cell membranes

Question 3

C3

Answer 3

• first complement protein involved
• undergoes autocatalytic cleavage yielding C3a and C3b
• homolog in insects

Question 4

C3b

Answer 4

• highly adhesive
• binds bacterial surface and accumulates
• recruits factor B, followed by D
  
  • forms C3-activated Bb
    
    • potent enzyme attached to C3b
    • amplifies decay of C3 inducing further catalytic activation

Question 5

mannose binding proteins

Answer 5

• can activate C3
• high mannose microbe surface binds MBP
• MBP binds mamman-activated serum protein (MASP)
• also activates C3 by stimulating convertase
• increased C3a and b production

Question 6

C5

Answer 6

• cleaved by C3b stimulation
• cleaves to C5a and C5b
• recruits other complement proteins to form MAC
• also potent activator of endothelial cells

Question 7

regulation of complement

Answer 7

• important to protect self
• mammalian cells have surface molecules to degrade C3b
• delay acelerating factor (DAF) accelerates C3bBb breakdown
• CD59 protectin binds MAC complexes

Question 8

functions of complement

Answer 8

• membrane damage by MAC
• opsonisation
  
  • C3b coating recongised by phagocytes
• chemotaxis
  
  • fragments recruit inflammatory cells
• inflammation
  
  • complement increases vascular permeability in particular

Question 9

types of leukocytes

Answer 9

• neutrophils
• mononuclear phagocytes

Question 10

neutrophils (PMNs)

Answer 10

• polymorphonculeates (multi-lobed nucleus)
• 75% of leukocytes
• mature from committed granulocyte-monocyte progenitor in bone marrow
• migrate to regions of tissue damage
• first cells to arrive at site of infection
• 3 day turnaround

Question 11

mononuclear phagocytes

Answer 11

• includes circualting monocytes and tissue macrophages
• differentiate from granulocyte-monocyte progenitor
• fully mature after 8 hours and enter tissues
• 4-15 day lifespan
• can form residential macrophages
• cytokine production

Question 12

extravasation

Answer 12

• process by which leukocytes leave the cirulation and enter tissues at the site of infection
• rolling → slows down → tight adhesion → diapedesis into endothelium
• each stage requires specific interactions between leukocyte receptors and endothelial ligands
  
  • varying expression of endothelium intissues results in different adhesion
• made easier by apoptosis of endothelium triggered by infalmmation - regions of blood vessel left uncovered

Question 13

leukocyte control

Answer 13

• leukocyte subset and tissue specific expression of adheson molecules and chemoattractants
• combinatorial control of what leukocytes go where and when

Question 14

leukocyte rolling

Answer 14

• occurs in small venular endothelium
  
  • overlies site of inflammation
• requires P-selectin on endothelium
  
  • preformed in vesicles
  • released upon signalling and exposed on cell surface
• interacts with L-selectin on leukocyte surface

Question 15

leukocyte sampling

Answer 15

• leukocyte samples endothelium for chemokines present on endothelial glycocalyx
• leukocyte expresses C5a receptors
  
  • allows tight junction formation so rolling ceases

Question 16

integrins

Answer 16

• mediate extravasation
• adhesion molecules expressed on both endothelial and leukocyte surface
• reversible adhesion
• bind ICAM-1 on opposing surface