Innate Immunity

where are TLRs found?

membrane or intracellular vesicles

Where are NLRs found?

cytoplasm

how does C. albicans evade neutrophils

genetic resistance to NETs, inhibit ROS production

How does S. aureus evade neutrophils

degrades DNA to prevent NETosis and converts product to deoxyadenosine - toxic to immune cells

What are the soluble mediators involved in the innate response? (Martin Luther Decided to Come down Hard on Racism)

mucins, lysozymes, defensins, cathelicidins, histatins, RegIII

mucins

may prevent microbial adherence to epithelium

How is gout treated?

NSAIDS and corticosteroids to reduce inflammation, xanthine oxidase inhibitors to reduce uric acid production

lysozyme

attacks peptidoglycan

defensins

disrupt bacterial and fungal membranes via pore formation

cathelicidins

disrupt many microbial membranes

histatins

work against pathogenic fungi

RegIII

C type lectins which target peptidoglycan

What activates complement?

mannose binding lectin (MBL), ficolin or C reactive protein (CRP). Often requires proteolysis

MBL

recognises sugars

ficolin

recognises oligosaccharides

CRP

recognises phosphorylcholine

NK cell receptor expression

exception to non clonal receptors. Express various combinations of receptors from different families so NK cells are all different

mannose receptors (C type lectin PRRs)

recognise beta-1,3-linked glucans found in fungal cell walls and internalise them for destruction

scavenger receptors

recognise anionic polymers and acetylated LDLs. Bind and internalise pathogens

scavenger receptors in atherosclerosis

make macrophages into fatty cells

How was Toll receptor discovered?

Toll deficient flies were more susceptible to infection, especially fungal infection

structure of TLRs

extracellular leucine rich repeats and intracellular sig domain Toll/IL-1R

TLR signalling cascade

MAPK upon recognising PAMPs

IL-1R signalling cascade

NFkB

intracellular TLRs

recognise parts of microbes eg DNA or RNA

what do TLR6:TLR-2 dimers form in response to

Gram +ve lipoteichoic acid

what do TLR 1:2 heterodimers form in response to?

GPI anchoring proteins or lipoproteins

MD2

accessory protein to TLR-4 which recognises LPS

What happens when MD2 recognises LPS?

• 5 of LPS’s acyl chains bind a pocket in MD2, 1 remains free

• free chain binds outer surface of another TLR-4 → homodimer

• stabilisation of dimer by LPS → signal transduction

TLR4 MyD88 dependent signalling

• adaptor TIRAP binds MyD88

• intracellular reactions occur → NFkB activation

• NF-kB → nucleus → TNFalpha, IL6 and IL1beta produced

TLR4 TRIF dependent signalling

• TRIF binds TRAM

• event cascade

• IFN-1 produced

• NFkB activated in TNF dependent manner

NOD-like receptors

• contain central nucleotide-binding oligomerisation domain

• sense bacterial invasion/cellular damage

• Activate NFkB or other pathways

CARD (caspase recruitment domains) (NLRs)

dimerise with other CARDs to induce signalling

NOD1

senses gamma-glutamyl diaminopimelic acid (iE-DAP) produced in peptidoglycan breakdown from Gram -ve and some Gram +ve

what does NOD2 recognise

muramyl dipeptide (MDP) found in most peptidoglycan

Role of pyrin domains in NLRPs

detect PAMPs and DAMPs, contributes to IBD, rheumatoid arthritis and atherosclerosis

GSDMD-N → GSDMD cleavage

mediated by caspase, causes pores in membrane (pyroptosis)

what do NLRs recognise?

• microbial ligands eg peptidoglycan and flagellin

• host ligands eg cholesterol crystals and uric acid

• environmental ligands eg asbestos

Not all NLRs act as PRRs. How else might they act?

may respond to cytokines

gout

recurrent, sudden, severe attacks of joint pain, redness and tenderness due to monosodium urate triggering the NLRP3 inflammasome

silicosis

pulmonary fibrosis after silica inhalation due to alveolar macrophages activating the NLRP3 inflammasome

CAPS

autoinflammatory disease
symptoms: fever, uticarial skin rash, arthritis and neutrophil-mediated inflammation
cause: gain of function NLRP3 mutations → IL-1beta overproduction

what is an inflammasome

protein complex which amplifies immune response and induces apoptosis

NLRP3 activation

NLRP3 monomer pyrin domains oligomerise with each other and with ASC pyrins

How does NLRP3 form an inflammasome

oligomerised ASCs recruit and activate procaspase 1 → IL1beta and IL18 activation, pyroptosis etc