Makindo Medical Notes

🛡️ Toll-like Receptors (TLRs): Recognition Receptors and Triggers of Innate Immunity

The innate immune system uses pattern recognition receptors (PRRs) to detect conserved microbial signatures called pathogen-associated molecular patterns (PAMPs). These receptors provide the “early warning system” that alerts and activates downstream adaptive immunity.

🔬 Key Concepts

• TLRs are a family of PRRs found on the cell surface and within endosomal compartments.
• They are characterised by leucine-rich repeat (LRR) domains for PAMP recognition and an intracellular Toll–IL-1 receptor (TIR) domain for signalling.
• Activation of TLRs → triggers NF-κB, MAPK, and interferon-regulated pathways → cytokine release, dendritic cell maturation, and T-cell activation.
• Distribution varies: expressed on macrophages, dendritic cells, neutrophils, epithelial cells, and B cells.

🧬 Examples of PAMP Recognition

• TLR-4: Binds lipopolysaccharide (LPS) from gram-negative bacteria 🚨.
• TLR-2: Detects peptidoglycans, lipoproteins, and zymosan (fungal) – often heterodimerises with TLR-1 or TLR-6.
• TLR-3: Recognises double-stranded viral RNA (dsRNA) 🦠.
• TLR-7 & TLR-8: Detect single-stranded RNA (ssRNA) → key in antiviral immunity (influenza, SARS-CoV-2, HIV).
• TLR-9: Recognises unmethylated CpG motifs in bacterial and viral DNA 🧾.

⚔️ Functional Roles

• Bacterial defence: TLR-2 and TLR-4 drive neutrophil recruitment, cytokine storm risk in sepsis.
• Viral defence: Endosomal TLRs (3, 7, 8, 9) induce Type I interferons (IFN-α/β) for antiviral states.
• Fungal defence: TLR-2 cooperates with dectin-1 (a C-type lectin receptor) in recognising β-glucans.

🧩 Clinical Significance

• Sepsis: TLR-4 overactivation by LPS is central to septic shock physiology.
• Autoimmunity: Self-nucleic acids in immune complexes (e.g., in SLE) can activate TLR-7 and TLR-9, amplifying self-directed immunity.
• Vaccines: Some adjuvants act as TLR agonists to boost immune responses (e.g., CpG motifs for TLR-9).
• Therapeutics: TLR antagonists are being studied in conditions such as lupus, psoriasis, and inflammatory bowel disease.

💡 Exam Pearl: Think of TLRs as the “gatekeepers of immunity” — they do not recognise specific antigens like TCRs or BCRs, but rather conserved microbial “barcodes” such as LPS, dsRNA, or CpG DNA. Defects or overactivation → either immunodeficiency (rare) or exaggerated inflammation/autoimmunity.