Innate Immunity 2

Question 1

Phagocytes

Answer 1

• always present in tissues (macrophages and dendritic cells), act early in an infection
• additional phagocytes are recruited (neutrophils) as part of induced immune response
• -> macrophages and neutrophils are very good at killing pathogens
• -> dendritic cells will phagocytose pathogens, but are mainly important for presenting antigens to lymphocytes - not very good at killing pathogens

Question 2

How do phagocytes distinguish pathogens from non-pathogens??

Answer 2

PAMPs and DAMPs:

• pathogen associated molecular patterns: peptide sequences and carbohydrate structures that are found only on prokaryotic cells (bacteria, fungi, viruses). e.g. LPS (lipopolysaccharides) found on bacteria
• damage associated molecular patterns: human host proteins/nucleic acid only found released in infection or danger

Question 3

Pattern recognition receptors

Answer 3

Macrophages and phagocytes have PRRs: bind to PAMPs and DAMPs.
4 types of PRRs:
1) Free receptors in serum (e.g. Mannose-binding lectin)
2) Membrane bound phagocytic receptors (opsonization)
3) Membrane bound signalling receptors (fMET-LEU-PHE, toll-like receptors)
4) Cytoplasmic signalling receptors

Question 4

Membrane bound phagocytic receptors (receptors of phagocytosis)

• list examples
• explain complement receptor pathway
• explain phagocytosis

Answer 4

• mannose receptor, complement receptor, lipid receptor, scavenger receptor, Dectin-1 receptor
• Complement receptor: opsonization
• when complement is activated, bacteria is coated with C3b, which binds to a complement receptor on a macrophage/phagocyte. This binding is not enough
• C5a receptor on phagocyte (C5a is found in the serum when C5 is cleaved).
• C3b-complement receptor binding and C5a and C5a receptor binding signals to phagocyte to phagocytose the pathogen

Phagocytosis:

• bacteria engulfed into “phagosome” in macrophage
• phagosome fuses with “lysosome” that has enzymes: becomes phagolysosome, and bacteria is degraded

Question 5

Membrane bound signalling receptors

- fMET-LEU-PHE

Answer 5

• G-protein coupled receptors that can sense the presence of a pathogen
• activate intracellular signalling pathways
• fMET-LEU-PHE (fMLP) receptor
• this specific pattern of peptides (met-leu-phe) is only seen on bacteria!!!
• neutrophil: fMLP will be released from bacteria and will bind to fMLP receptor on the neutrophil; leads to activation of rac2
• rac2 –> NADPH oxidase –> generation of superoxide radicals and other ROS in a vesicle –> acidification in the vesicle –> activation of superoxide dismutase –> converts superoxide radicles into hydrogen peroxide –> kills ingested pathogen

Question 6

Membrane bound signalling receptors

- Toll-like receptors

Answer 6

• 10 TLRs in humans
• TLRs are on phagocytes, bind to pathogen ligands (cell wall components, LPS, virus nucleic acid)
• TLR signalling activates NFkB (NF kappa B) - transcription factor necessary for producing anti-inflammatory cytokines and anti-microbial peptides

Question 7

Cytoplasmic signalling receptors

Answer 7

• NOD like receptors (NLRs)
• intracellular sensors for microbial products (e.g. bacterial cell wall components)
• leads to activation of NFkB (TF for cytokines and anti-microbial peptides)
• Crohn’s disease: some individuals have a NOD-2 defect - not able to make as many antimicrobial peptides - may have a role in compromising the epithelial barrier in defences in the intestinal tract of individuals with Crohns (inflammatory bowel disease)

Question 8

QUESTION:
Pattern-recognition receptors are found on host phagocytes. What 2 types of ligands do they bind?

What transcription factor is activated through both toll-like receptors and NOD-like receptor signalling

Answer 8

1) PAMPs and DAMPs

2) NFkB