ImmunologyTier 1Medical Sciences concept

Innate immunity - pattern recognition receptors and complement activation (CRP, TLRs, PAMPs)

Core concept

Innate immunity is germline-encoded, immediate and non-clonal
- PRRs recognise conserved structures that microbes cannot discard - essential for their survival, and absent from the host
- -> no memory in the classical sense (though "trained immunity" via epigenetic reprogramming of monocytes is now recognised - the basis of non-specific BCG effects)
PAMPs vs DAMPs - same receptors, different origin
- PAMPs (microbial) - LPS, lipoteichoic acid, peptidoglycan, flagellin, unmethylated CpG DNA, dsRNA, mannans, beta-glucan
- DAMPs (self or environmental) - ATP, uric acid/urate crystals, CPPD, cholesterol crystals, HMGB1, heat shock proteins, histones, mitochondrial DNA and formyl peptides; environmental asbestos, silica, alum, UV
- -> sterile inflammation in gout, atherosclerosis, trauma, ischaemia-reperfusion and burns uses exactly the same machinery as infection

Key detail

Receptor families - location tells you what they sense

Family	Location	Ligands
TLRs - surface	Plasma membrane	TLR4 - LPS (with MD-2/CD14); TLR2/1 and 2/6 - lipopeptide, peptidoglycan, zymosan; TLR5 - flagellin
TLRs - endosomal	Endosome	TLR3 - dsRNA; TLR7/8 - ssRNA; TLR9 - unmethylated CpG DNA (all nucleic acid sensors, kept inside so that self-DNA in the cytosol does not trigger them)
NLRs	Cytosol	NOD1/NOD2 - peptidoglycan fragments; NLRP3 - inflammasome
RLRs (RIG-I, MDA5)	Cytosol	Viral RNA -> type I interferon
cGAS-STING	Cytosol	Double-stranded DNA -> type I interferon
CLRs (dectin-1, mannose receptor)	Surface	Fungal beta-glucan and mannan
Scavenger receptors	Surface	Modified LDL, apoptotic cells

Signalling: most TLRs -> MyD88 -> IRAK -> NF-kB -> pro-inflammatory cytokines and costimulatory molecules
- TLR3 and TLR4 also use TRIF -> IRF3 -> type I interferon
- *This is signal 2's source: PRR engagement upregulates CD80/CD86 on the APC and licenses the adaptive response*
Soluble PRRs / opsonins
- CRP - binds phosphocholine on bacterial cell walls, damaged membranes and apoptotic cells -> activates the CLASSICAL complement pathway via C1q, without any antibody
  - Made by hepatocytes under IL-6; rises within 6-8 h, peaks at ~48 h, t1/2 ~19 h; far more dynamic than ESR
- Mannose-binding lectin and ficolins -> lectin pathway
- Surfactant proteins A and D, pentraxin-3, LPS-binding protein
Cellular arm - neutrophils, macrophages, dendritic cells, NK cells, ILCs, mast cells, gamma-delta T cells, epithelial barriers and antimicrobial peptides (defensins, cathelicidin)

Clinical relevance

Sepsis is TLR4 signalling gone wrong - LPS -> TLR4 -> massive TNF/IL-1/IL-6 -> vasodilatation, capillary leak, DIC; anti-TNF and anti-endotoxin strategies in sepsis have failed, because the response is redundant and also protective
Inherited PRR pathway defects
- IRAK-4 and MyD88 deficiency - severe pyogenic (pneumococcal, staphylococcal) infection in childhood, *with a strikingly blunted CRP and fever* - improves with age
- TLR3/UNC-93B pathway defects -> HSV encephalitis in an otherwise well child
- Anti-interferon autoantibodies and TLR7 gain-of-function -> severe COVID-19 and SLE respectively
- NOD2 variants -> Crohn's disease susceptibility; NOD2 activating mutations -> Blau syndrome
- CARD9 deficiency -> invasive candidiasis and dermatophytosis (dectin-1 pathway)
Interferonopathies (STING/SAVI, AGS, CANDLE) - constitutive cytosolic nucleic acid sensing -> JAK inhibitors are the targeted therapy
Drugs that exploit PRRs
- TLR7/8 agonist imiquimod (basal cell carcinoma, warts); TLR9 agonist CpG adjuvant in the hepatitis B vaccine (Heplisav)
- BCG in bladder cancer; alum and AS04 adjuvants; mRNA vaccine lipid nanoparticles are inherently PRR-stimulating
CRP interpretation - IL-6 blockade (tocilizumab) abolishes CRP even in overwhelming sepsis; liver failure blunts it; it is normal in many viral illnesses and in SLE flares without serositis (a raised CRP in SLE should prompt a search for infection)

Correlations

Autoinflammatory syndromes and the inflammasome
Complement activation pathways - CRP and the lectin pathway
Sepsis and septic shock
T-cell activation - signal 2 and dendritic cell licensing
Vaccine adjuvants; conjugate vs polysaccharide vaccines
Primary immunodeficiency - IRAK-4, MyD88, CARD9
Acute phase response; ESR vs CRP

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