pathogen-associated molecular pattern

**Definition:** PAMPs are conserved, essential molecular motifs found on pathogens but not on host cells, allowing the innate immune system to distinguish "non-self" without prior exposure. Because they are essential to microbial survival, they are hard to mutate away. Damage-associated molecular patterns (DAMPs; e.g., HMGB1, ATP, uric acid, heat shock proteins) are the sterile-injury counterpart and use many of the same PRRs.

**Receptors (PRRs):** Expressed on macrophages, dendritic cells, neutrophils, and epithelial cells. - **Toll-like receptors (TLRs):** - TLR2 (with TLR1 or TLR6): lipoteichoic acid, lipoproteins, peptidoglycan (Gram-positive bacteria) - TLR3: dsRNA (viral) - TLR4 (with MD-2 and CD14): LPS/endotoxin (Gram-negative bacteria) - TLR5: flagellin - TLR7/8: ssRNA (viral) - TLR9: unmethylated CpG DNA (bacterial/viral) - TLR3, 7, 8, and 9 are endosomal. The others are on the cell surface. - **NOD-like receptors (NLRs):** cytosolic. NOD1/NOD2 detect peptidoglycan fragments. NOD2 loss-of-function is associated with Crohn disease. Some NLRs form inflammasomes (NLRP3), which activate caspase-1 and produce IL-1β and IL-18. - **RIG-I-like receptors (RLRs):** cytosolic viral RNA sensors that produce type I interferons. - **C-type lectins:** e.g., dectin-1 (β-glucan, fungi) and mannose receptor (mannose on microbes). - **cGAS–STING:** cytosolic DNA sensing.

**Signaling:** Most TLRs signal through the adaptor MyD88, which activates IRAK, then TRAF6, then NF-κB. This induces TNF-α, IL-1, IL-6, IL-12, and adhesion molecules. TLR3 and TLR4 can also signal through TRIF, which activates IRF3 and produces type I interferons (IFN-α/β). MyD88 deficiency causes recurrent pyogenic bacterial infections.

**Clinical significance:** - **Septic shock:** Excessive TLR4 activation by LPS produces a "cytokine storm" (TNF-α, IL-1, IL-6). The result is vasodilation, DIC, hypotension, and fever. - **Adaptive immunity link:** PAMP recognition upregulates MHC II and B7 (CD80/86) on APCs, providing "signal 2" for T-cell activation. This is the mechanism of adjuvants (e.g., alum, MPL, CpG). - **Crohn disease:** NOD2 mutations. - **Immunodeficiency:** MyD88/IRAK-4 deficiency (pyogenic infections); TLR3 or UNC-93B defects (HSV encephalitis). - **Autoimmunity:** TLR7/9 signaling is implicated in SLE (recognition of self nucleic acids).

**Test pearls:** PAMPs are recognized by germline-encoded receptors (no somatic recombination). The response is rapid and nonspecific, and it has no memory. Match the PAMP to the receptor: LPS goes to TLR4, flagellin to TLR5, CpG to TLR9, dsRNA to TLR3, and β-glucan to dectin-1.