toll-like receptor

**Definition & location:** TLRs are transmembrane PRRs expressed on macrophages, dendritic cells, neutrophils, mucosal epithelium, and some lymphocytes. Cell-surface TLRs (TLR1, 2, 4, 5, 6) detect extracellular bacterial/fungal components; endosomal TLRs (TLR3, 7, 8, 9) detect nucleic acids from viruses and bacteria.

**Key ligands (high-yield):** - TLR2 (with TLR1 or TLR6): lipoproteins, peptidoglycan, lipoteichoic acid (gram-positive bacteria), zymosan - TLR3: double-stranded RNA (viruses) - TLR4 (with MD-2 and CD14): LPS/lipid A of gram-negative bacteria; also RSV F protein - TLR5: bacterial flagellin - TLR7/8: single-stranded RNA (e.g., influenza, HIV) - TLR9: unmethylated CpG DNA motifs (bacteria, viruses)

**Signaling:** Ligand binding leads to recruitment of the adaptor protein MyD88 (used by all TLRs except TLR3; TLR4 also uses TRIF). MyD88 → IRAK → TRAF6 → activation of NF-κB and MAP kinases → transcription of pro-inflammatory cytokines (TNF-α, IL-1, IL-6, IL-12), chemokines, and adhesion molecules. TLR3, TLR4 (TRIF pathway), and TLR7/8/9 activate IRF3/IRF7 → type I interferons (IFN-α/β). TLRs also upregulate costimulatory molecules (B7/CD80/86) on APCs, bridging innate and adaptive immunity (Th1 skewing via IL-12).

**Clinical significance:** - Sepsis/septic shock: LPS binding to TLR4 (via LPS-binding protein and CD14) causes massive TNF-α, IL-1, IL-6 release → fever, vasodilation, hypotension, DIC. - MyD88 or IRAK-4 deficiency: recurrent, severe pyogenic bacterial infections (e.g., S. aureus, S. pneumoniae) in childhood, with blunted inflammatory responses (poor fever/CRP rise). - TLR3 / UNC-93B deficiency: susceptibility to HSV-1 encephalitis. - Autoimmunity: TLR7/9 recognition of self nucleic acids contributes to SLE; TLR signaling is implicated in atherosclerosis, RA, and inflammatory bowel disease. - Therapeutics: imiquimod (TLR7 agonist) for actinic keratosis, superficial basal cell carcinoma, and genital warts; CpG oligonucleotide (TLR9 agonist) is an adjuvant in the hepatitis B vaccine (Heplisav-B); monophosphoryl lipid A (TLR4 agonist) is an adjuvant in vaccines (e.g., Shingrix's AS01B, Cervarix's AS04); hydroxychloroquine partly inhibits endosomal TLR7/9 signaling. - Nomenclature: named after the Drosophila Toll protein (dorsoventral patterning and antifungal defense); Hoffmann and Beutler received the 2011 Nobel Prize for TLR discoveries.

**Related concepts to differentiate:** NOD-like receptors (NOD1/2, cytosolic; detect peptidoglycan fragments; NOD2 mutations → Crohn disease; also inflammasome formation via NLRP3), RIG-I-like receptors (cytosolic viral RNA), and C-type lectin receptors (fungal β-glucan, e.g., Dectin-1). TLRs are germline-encoded and do not undergo somatic recombination, unlike TCR/BCR.

**Board pearl:** Innate immunity = rapid, nonspecific, no memory, uses germline-encoded PRRs like TLRs. Gram-negative LPS → TLR4; gram-positive → TLR2; flagellin → TLR5; viral dsRNA → TLR3; CpG DNA → TLR9.