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Layer 03 · Mechanism · Module A

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.

16LESSONS
12STEPS IN THIS CASCADE
3PERTURBATION EXPERIMENTS

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. 1. not opened yetInnate sensing (TLR4 → NF-κB)

    Trace LPS recognition to NF-κB-driven inflammatory transcription.

  2. 2. not opened yetCytokine networks (IL-6 chain)

    Explain classical vs trans IL-6 signalling at a teaching level.

  3. 3. not opened yetInflammation effector (NLRP3 → IL-1β)

    State the two-signal requirement for IL-1β release.

This lesson is outside the foundation track. Open Innate sensing (TLR4 → NF-κB) to continue the Academy path.

TCR signalling: antigen recognition to gene transcription

How does a T cell convert antigen recognition into activation?

CD4+ T Helper CellCD8+ Cytotoxic T CellRegulatory T Cell (Treg)Dendritic Cell
TCRCD3T-cell receptor signallingCD28Co-stimulation (signal 2)Calcineurin inhibitorAbatacept

Perturbation experiments

Break one component and follow the consequence chain to the clinical read-out.

Target: ZAP-70 (step 5)

  1. CD3 ITAMs may still be phosphorylated by Lck
  2. But ZAP-70 cannot bind, no kinase to phosphorylate LAT/SLP-76
  3. The signalosome cannot form
  4. PLCγ1 is not activated, no IP3 or DAG production
  5. All three transcription factor branches fail: NFAT, NF-κB, and AP-1
  6. No IL-2 transcription, no proliferation, no effector differentiation
  7. T-cell activation and development are defective

Clinical read-out. Clinical link: ZAP-70 deficiency causes SCID (T−B+NK+ with absent CD8+ T cells). In CLL, ZAP-70 expression indicates unmutated IGHV and worse prognosis.

Target: Co-stimulation (CD28 vs CTLA-4)

  1. CTLA-4 is upregulated after T-cell activation and competes with CD28 for CD80/CD86
  2. CTLA-4 has higher affinity, wins the competition
  3. CD28 co-stimulation is reduced or abolished
  4. PI3K-AKT-mTOR signalling is diminished
  5. T-cell activation threshold rises
  6. Without sufficient co-stimulation, T cells may enter anergy
  7. Net effect: immune response is dampened, tolerance is promoted

Clinical read-out. Abatacept (CTLA-4-Ig) mimics CTLA-4 → immunosuppression in RA. Ipilimumab (anti-CTLA-4) releases the brake → melanoma immunotherapy.

Target: NF-κB (step 8b)

  1. NF-κB stays in the nucleus instead of cycling back
  2. Anti-apoptotic genes (Bcl-xL, Bcl-2, c-FLIP) are continuously expressed
  3. Survival signals maintain T cells beyond their normal lifespan
  4. Inflammatory cytokines (IL-6, TNF, IL-1β) are persistently produced
  5. The normal contraction phase (apoptosis of effector cells) fails
  6. Chronic inflammation develops, tissue damage accumulates
  7. Lymphoproliferation may progress to lymphoma in some contexts

Clinical read-out. Chronic NF-κB drives RA, IBD, lymphoma. CBM mutations found in lymphomas. Anti-NF-κB: corticosteroids, JAK inhibitors, bortezomib.