pattern recognition receptor

**Definition:** PRRs are non-clonal, germline-encoded receptors of the innate immune system. They recognize pathogen-associated molecular patterns (PAMPs; conserved microbial motifs essential to microbe survival) and damage-associated molecular patterns (DAMPs; e.g., HMGB1, extracellular ATP, uric acid crystals, mitochondrial DNA released from injured cells). Unlike B/T-cell receptors, they do not undergo V(D)J recombination, and they respond immediately without prior exposure.

**Major PRR families (location, ligand):** - **Toll-like receptors (TLRs)** – cell surface or endosomal. - TLR2 (with TLR1 or TLR6): lipoproteins, peptidoglycan, lipoteichoic acid (Gram-positive), zymosan. - TLR3: dsRNA (endosome). - TLR4 (with MD-2 and CD14): LPS/endotoxin (Gram-negative). - TLR5: bacterial flagellin. - TLR7/8: ssRNA (endosome). - TLR9: unmethylated CpG DNA (endosome). - Signaling is via the adaptor **MyD88** (all except TLR3) → IRAK → TRAF6 → **NF-κB** → inflammatory cytokines. TLR3 and TLR4 can also signal via **TRIF** → **IRF3** → type I interferons. - **NOD-like receptors (NLRs)** – cytosolic. NOD1/NOD2 detect peptidoglycan fragments (NOD2 binds muramyl dipeptide) → NF-κB. Inflammasome-forming NLRs (e.g., NLRP3) activate caspase-1, which cleaves pro-IL-1β and pro-IL-18 into active forms. Pyroptosis is mediated by gasdermin D. - **RIG-I-like receptors (RLRs)** – cytosolic RNA helicases (RIG-I, MDA5) that detect viral RNA → MAVS (mitochondrial) → IRF3/7 → type I IFN. - **C-type lectin receptors** – e.g., Dectin-1 (β-glucan, fungi), mannose receptor (microbial mannose; promotes phagocytosis). - **cGAS–STING pathway** – cytosolic DNA sensing → type I IFN. - **Other:** scavenger receptors, complement receptors, and soluble PRRs such as mannose-binding lectin (lectin complement pathway), CRP, and LBP.

**Clinical correlations / high-yield associations:** - **Sepsis/septic shock:** LPS binds LBP/CD14/TLR4–MD-2 → massive TNF-α, IL-1, IL-6 release → fever, vasodilation, hypotension, DIC. - **MyD88 or IRAK-4 deficiency:** recurrent severe pyogenic bacterial infections (S. pneumoniae, S. aureus) in childhood with a blunted inflammatory response (low fever, low CRP). - **NOD2 mutations:** Crohn disease (loss of function; impaired defense against bacteria); Blau syndrome (gain of function). - **NLRP3 gain-of-function:** cryopyrin-associated periodic syndromes (excess IL-1; treat with anakinra, canakinumab). The NLRP3 inflammasome is also activated by monosodium urate crystals (gout) and cholesterol crystals (atherosclerosis). - **TLR3 / UNC-93B defects:** susceptibility to HSV-1 encephalitis. - **Mannose-binding lectin deficiency:** recurrent infections, especially in early childhood. - **Autoimmunity:** TLR7/9 signaling is implicated in SLE (recognition of self-nucleic acid immune complexes); TLR/IFN signature is prominent. - **Vaccine adjuvants:** work via PRRs (e.g., alum activates NLRP3; MPL is a TLR4 agonist; CpG is a TLR9 agonist in Heplisav-B).

**Functional outcomes of PRR activation:** phagocytosis, cytokine/chemokine release, type I IFN production, complement activation, upregulation of MHC II and B7 (CD80/86) co-stimulatory molecules on APCs → activation of naïve T cells (link between innate and adaptive immunity).

**Board pearl:** Remember PRR = recognizes PAMPs/DAMPs; TLR4 = LPS; TLR5 = flagellin; TLR9 = CpG DNA; TLR3/7/8 = viral RNA; NOD2 = Crohn; MyD88 = shared TLR adaptor (except TLR3).