Cascades
Pick a lesson, then walk its steps. Each step opens the mechanism, what fails if that component is absent, and the clinical read-out.
Immunology Academy · foundation track
One navigable beginner path through existing Mechanism lessons. Teaching simplifications are labelled; claim-level Gate C coverage is separate and may still be sparse. Progress is stored in this browser only — we do not claim course completion, certification, or Gate C evidence coverage.
Track status: navigable · Local quiz checks 0/6 · Lessons opened 0/3
- 1. not opened yetInnate sensing (TLR4 → NF-κB)
Trace LPS recognition to NF-κB-driven inflammatory transcription.
- 2. not opened yetCytokine networks (IL-6 chain)
Explain classical vs trans IL-6 signalling at a teaching level.
- 3. not opened yetInflammation effector (NLRP3 → IL-1β)
State the two-signal requirement for IL-1β release.
Innate sensing (TLR4 → NF-κB)
Lesson content is curated teaching material. Relationship-level approved cites on linked edges are independent of Academy progress.
Objectives
- Trace LPS recognition to NF-κB-driven inflammatory transcription.
- Distinguish MyD88 vs TRIF branches as a teaching scaffold.
- Name one clinical timing lesson from failed TLR4 blockade in sepsis.
Teaching simplifications
- Cascades are linearised; real cells run parallel and feedback pathways.
- LPS→TLR4 is the archetype, not every innate sensor.
Graph concepts
Check understanding
Local practice only — not a credential, not SME sign-off, not evidence approval.
Which adaptor initiates the early Myddosome after TLR4 ligation at the plasma membrane?
Which outputs are driven quickly by NF-κB after TLR4 signalling?
Innate sensing: TLR4 → NF-κB
A macrophage meets LPS. Which receptors detect it, and how does a gene get switched on within 30 minutes?
Perturbation experiments
Break one component and follow the consequence chain to the clinical read-out.
Target: IRAK4
- TLR4 and IL-1R still bind ligand
- Myddosome cannot form
- No NF-κB activation through MyD88
- Little TNF/IL-6 → little fever and CRP
- Neutrophil recruitment is delayed
- Invasive pyogenic bacterial infection with deceptively mild inflammation
Clinical read-out. IRAK4/MyD88 deficiency: prophylactic antibiotics and vaccination; risk falls after adolescence.
Target: TLR4 antagonist
- TLR4 sensing occurs within minutes of bacteraemia
- Patients present hours later
- TNF, IL-1 and DAMPs (HMGB1) now sustain inflammation independently
- Blocking the trigger no longer removes the cascade
- Later phases may be immunosuppressive, not hyperinflammatory
Clinical read-out. Timing, not mechanism, explains many failed sepsis trials (eritoran, anti-TNF).
Target: Glucocorticoid receptor
- Steroid binds cytosolic GR → nuclear translocation
- GR tethers to p65 and AP-1 (transrepression)
- GR induces IκBα, GILZ, MKP-1 and annexin A1
- TNF, IL-1, IL-6 and chemokine transcription falls
- Broad suppression, benefit in hyperinflammation, harm when pathogen clearance is still needed
Clinical read-out. RECOVERY: dexamethasone reduced mortality in patients needing oxygen, but not (possibly harmful) in those without hypoxia.