Pattern Recognition, Inflammasomes & Autoinflammatory Syndromes
How innate sensors sound the alarm, and what happens when it sticks
Pattern recognition: PAMPs and DAMPs
Pattern-recognition receptors (PRRs). Innate cells (macrophages, dendritic cells, neutrophils) and epithelial cells carry germline-encoded receptors that need no rearrangement and respond within minutes. They detect two kinds of alarm.
- PAMPs (pathogen-associated molecular patterns): conserved microbial molecules absent from host cells, such as LPS, flagellin, lipoteichoic acid, peptidoglycan fragments, double-stranded RNA and unmethylated CpG DNA.
- DAMPs (damage-associated molecular patterns): host molecules released by stressed or necrotic cells, such as HMGB1, extracellular ATP, uric acid crystals and extracellular DNA. DAMPs explain sterile inflammation after trauma, infarction or crystal deposition.
Toll-like receptors and their signaling
| Receptor | Location | Ligand | Typical source |
|---|---|---|---|
| TLR2 | Cell surface | Lipoteichoic acid, lipoproteins | Gram-positive bacteria, mycobacteria |
| TLR4 (+ MD-2, CD14) | Cell surface | LPS (endotoxin) | Gram-negative bacteria |
| TLR5 | Cell surface | Flagellin | Motile bacteria |
| TLR3 | Endosome | Double-stranded RNA | Viruses |
| TLR7, TLR8 | Endosome | Single-stranded RNA | RNA viruses |
| TLR9 | Endosome | Unmethylated CpG DNA | Bacteria, DNA viruses |
Adaptors. Every TLR except TLR3 signals through MyD88, which recruits IRAK-4, IRAK-1 and TRAF6 to activate NF-κB and MAP kinases. The products are TNF, IL-1, IL-6, IL-12 and chemokines: fever, the acute-phase response and neutrophil recruitment. TLR3 uses only TRIF, which activates TBK1 and IRF3 to produce type I interferon (IFN-α/β). TLR4 is unique in using both, MyD88 at the cell surface and TRIF after endocytosis. Endosomal TLR7 and TLR9 in plasmacytoid dendritic cells use MyD88 with IRF7 to make large amounts of type I interferon. The IL-1 and IL-18 receptors also signal through MyD88.
Imiquimod is a topical TLR7 agonist that boosts local interferon against genital warts, actinic keratoses and superficial basal cell carcinoma.
MyD88 and IRAK-4 deficiency. These autosomal recessive defects blunt TLR and IL-1 receptor signaling. Young children develop invasive pneumococcal, staphylococcal and Pseudomonas infections with little fever and a normal or barely raised CRP, so sepsis is easily missed. Neutrophil counts, immunoglobulins and vaccine responses are normal, which separates it from chronic granulomatous disease (NADPH oxidase), leukocyte adhesion deficiency (CD18) and X-linked agammaglobulinemia (BTK). Viral defense is largely spared because TLR3-TRIF and cytosolic sensors still work, and infections become rare after childhood as adaptive immunity matures.
Cytosolic sensors
NOD2. A cytosolic NOD-like receptor (encoded by NOD2, also called CARD15) that recognizes muramyl dipeptide from bacterial peptidoglycan and activates NF-κB. Loss-of-function variants weaken Paneth-cell antimicrobial defense and raise the risk of ileal Crohn disease; gain-of-function mutations cause Blau syndrome (granulomatous arthritis, uveitis, dermatitis).
RIG-I and MDA5. These RIG-I-like receptors detect viral RNA in the cytosol and signal through the mitochondrial adaptor MAVS to IRF3, producing type I interferon.
cGAS-STING. cGAS binds DNA that should not be in the cytosol (from viruses, bacteria or damaged nuclei and mitochondria) and synthesizes cGAMP, which activates STING, TBK1 and IRF3 to induce interferon-β. Excessive nucleic-acid sensing underlies the type I interferonopathies, such as Aicardi-Goutières syndrome.
The NLRP3 inflammasome and pyroptosis
- Signal 1: primingTLR ligands or TNF activate NF-κB, which transcribes pro-IL-1β and NLRP3
- Signal 2: activationCrystals, extracellular ATP, potassium efflux or lysosomal rupture trigger NLRP3
- AssemblyNLRP3 oligomerizes with the adaptor ASC and pro-caspase-1
- Caspase-1Cleaves pro-IL-1β and pro-IL-18 into active cytokines and cleaves gasdermin D
- PyroptosisGasdermin D N-terminal fragments form membrane pores; the cell releases IL-1β and IL-18 and bursts
Crystal triggers. Monosodium urate (gout), cholesterol crystals (atherosclerotic plaque) and inhaled silica (silicosis) are phagocytosed, damage lysosomes and activate NLRP3. The resulting IL-1β drives fever and neutrophil influx, which is why colchicine (which disrupts microtubules, blocking neutrophil migration and inflammasome assembly) and IL-1 blockade calm gout flares.
| Feature | Apoptosis | Pyroptosis |
|---|---|---|
| Key caspase | Caspase-3 (executioner) | Caspase-1 |
| Membrane | Intact; blebs and apoptotic bodies | Gasdermin D pores, lysis |
| Consequence | Silent phagocytic clearance | IL-1β, IL-18 and DAMP release; neutrophil recruitment |
Autoinflammatory syndromes
Autoinflammatory versus autoimmune. Autoinflammatory diseases arise from innate dysregulation (inflammasome, IL-1, TNF) rather than antigen-specific lymphocytes. They cause recurrent unprovoked fevers, serositis, rashes and arthritis with high CRP and serum amyloid A during attacks, but no high-titer autoantibodies or autoreactive T cells and few HLA associations. Persistently raised serum amyloid A can deposit as AA amyloid, typically presenting as nephrotic-range proteinuria with Congo red-positive deposits.
| Syndrome | Gene, inheritance | Attacks | Distinctive features | Treatment |
|---|---|---|---|---|
| Familial Mediterranean fever | MEFV (pyrin), autosomal recessive | 1–3 days | Sephardic Jewish, Armenian, Turkish, Arab ancestry; peritonitis mimicking an acute abdomen, pleuritis, arthritis, erysipelas-like leg erythema | Daily colchicine prevents attacks and AA amyloidosis |
| CAPS | NLRP3 gain of function, autosomal dominant | Cold-triggered, lasting hours to a day; near-continuous in severe forms | Urticaria-like neutrophilic rash; Muckle-Wells adds sensorineural hearing loss and amyloidosis; NOMID adds neonatal chronic meningitis | IL-1 blockade (anakinra, canakinumab) |
| TRAPS | TNFRSF1A (TNF receptor 1), autosomal dominant | Prolonged, often >1 week | Migratory myalgia with overlying erythema, periorbital edema | Corticosteroids; IL-1 blockade |
| Mevalonate kinase deficiency | MVK, autosomal recessive | 3–7 days from infancy | Triggered by vaccines; cervical nodes, abdominal pain; high IgD, urinary mevalonic acid | IL-1 blockade |
| PFAPA | Not monogenic | 3–6 days, about monthly | Onset before age 5; aphthous stomatitis, pharyngitis, cervical adenitis; well between attacks | Single dose of prednisone aborts attacks; tonsillectomy often curative |
The CAPS rash is neutrophilic, not mast-cell driven, so antihistamines and anti-IgE therapy fail while IL-1 blockers work dramatically. PFAPA is not infectious: antibiotics do nothing, growth is normal and the syndrome usually fades by adolescence.