L07: Pattern Recognition Receptors

Question 1

TLR recognition

Answer 1

1. Recognise bacterial/fungal cell wall components found on cell membrane and in phagosome with pathogens
2. Recognise pathogen nuclei acids are intracellular

Question 2

Toll-like receptor structure (TLR)

Answer 2

Two important domains:

1. Leucine rich repeat (LRR) domain involved in ligand recogntiion
2. Toll/Interleukin-1 receptor (TIR) domain - cytoplasmic signalling

Question 3

TLR9

Answer 3

Recognises bacterial and viral DNA which contains unmethylated CG dinucleotides (CpG DNA). CpG DNA acts on macrophages, DCs and B cells. TLR9 induces inflammatory cytokines, promotes antigen rpesentation and induces co-stimulatory molecules on DCs. Short CpG oligonucleotides are powerful immune stimulants for clinical trial as vaccine adjuvants, treatment for infectious diseases/cancer and immunomodulators for allergy.

Question 4

Inflammasome

Answer 4

Large cytoplasmic protein complex which recruits and activates protease caspase 1. Caspase 1 cleaves pro-IL-1b and pro-IL18 into active inflammatory cytokines. Inflammasome activation also leads to inflammatory lytic cell death termed “pyroptosis”. Activation of the inflammasome is initated by:

1. Range of PAMPs/DAMPs causing oligomerisation of NLRs, particularly NLRP3
2. Cytoplasmic DNA recognition by AIM2

Question 5

AIM2 inflammasome

Answer 5

DNA in cytosol activates AIM2 inflammasome. It is a cytoplasmic DNA receptor of the macrophage which activates inflammasome to give IL-1b and cell death when DNA is introduced into the cytoplasm. Clustering of AIM2 causes recruitment of ASC. ASC clusters to initiate dimerisation of caspase 1 which then activates pathogenic destructive pathways. TLR upregulate pro-IL-1b as it is usually not abundant in macrophages.

Question 6

IL-1B/ IL-18

Answer 6

Cleaved by caspase 1 to give active forms:
IL-1B causes fever, vasodilation, hypotension, infiltration of inflammatory cells, chemokine and cytokine release, and activation of antigen presenting cells. Plays a role in inflammatory diseases and main source in macrophages, monocytes and DCs.
IL-18 promotes T cell activation

Question 7

Caspase 1

Answer 7

Inflammatory caspase. Activated by induced dimerisation and intermolecular cleavage. Protease which is activated by being recruited into the inflammasome and induced to dimerise. Contains a pro-domain region which recruits it to inflammasome

Question 8

Things that activate inflammasome

Answer 8

1. Endogenous signals - DAMPs
2. Particulate stimuli
3. Pathogen molecules - PAMPs

Question 9

Gout

Answer 9

Accumulation of monosodium urate (MSU) crystals in joints. Inflammasome activation by MSU causes IL-1B release.