ID: h-eda0cdbe
Hypothesis
ITGAX/CD11c Targeting to Eliminate Pro-inflammatory DAM in ALS
NOT RECOMMENDED.
EvidencePending (0%)📖 0 cit🗣 1 debates✓ 4 support✗ 4 oppose
✓ All Quality Gates Passed
🧪 Overview
NOT RECOMMENDED. Cell-type selectivity problem: CD11c is the canonical dendritic cell marker. Border-associated macrophages, meningeal DCs, and perivascular APCs all express CD11c. An ADC targeting CD11c would deplete these populations, impairing CNS immune surveillance. Mechanistic contradiction: PMID:30948433 shows TDP-43 drives CD11c+ expansion via TREM2, but TREM2 is hypothesized as protective—eliminating TREM2-activated cells is paradoxical. CD11c+ microglia in EAE show reparative signatures and may be required for remyelination.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["ITGAX CD11c<br/>Dendritic Cell Integrin Alpha Chain"]
B["CD18 Beta-2 Integrin Dimer<br/>Immune Cell Adhesion"]
C["ICAM-1 and ICAM-2 Binding<br/>Leukocyte Transmigration"]
D["Microglial Activation<br/>Pro-inflammatory Phenotype"]
E["Phagocytic Activity<br/>Debris and Aggregate Clearance"]
F["Adaptive Immune Cross-talk<br/>T-cell and B-cell Recruitment"]
G["ITGAX Blockade<br/>CD11c siRNA or Small Molecule"]
A --> B
B --> C
C --> D
D --> E
D --> F
G -.->|"inhibits"| D
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style D fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#1b5e20,stroke:#81c784,color:#81c784⚖️ Evidence
⚖️ Evidence Matrix4 supports4 contradicts
Supports
CD11c+ microglia show dual DAM-inflammation signature distinct from CD11c- population
Supports
TDP-43 pathology drives CD11c+ microglial expansion via TREM2-dependent mechanism
Contradicts
CD11c is the canonical dendritic cell marker; ADC would deplete meningeal/perivascular DCs
Contradicts
CD11c+ microglia in EAE show reparative signatures required for remyelination
Contradicts
If TDP-43 drives CD11c+ via TREM2, and TREM2 is protective, eliminating TREM2-activated cells is paradoxical
Contradicts
No CD11c ADC exists for neurodegeneration; cell-type selectivity unproven
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — ITGAX
No curated PDB or AlphaFold mapping for ITGAX yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for ITGAX/CD11c Targeting from GTEx v10.
💉 Clinical Trials
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for ITGAX.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
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🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF an anti-CD11c antibody-drug conjugate is administered to SOD1-G93A ALS mice to deplete CD11c+ cells, THEN CNS immune surveillance will be compromised, evidenced by a ≥50% reduction in perivascular | Significant depletion of border-associated macrophages and perivascular APCs (≥50% reduction by flow cytometry), accompanied by impaired viral clearance from CN | — no observation — | pending | 0.35 |
| IF CD11c+ microglia are depleted via anti-CD11c ADC in TDP-43 Q331K knock-in mice modeling ALS-associated proteinopathy, THEN disease progression will accelerate by ≥30% and remyelination capacity wil | Accelerated motor decline (rotarod latency reduced by ≥30% versus baseline), decreased survival (median reduced by ≥3 weeks), reduced CD11c+/TREM2+ microglia fr | — no observation — | pending | 0.28 |
🔮 Falsifiable Predictions (2)
pendingconf 35%
IF an anti-CD11c antibody-drug conjugate is administered to SOD1-G93A ALS mice to deplete CD11c+ cells, THEN CNS immune surveillance will be compromised, evidenced by a ≥50% reduction in perivascular macrophage numbers and ≥2-fold increase in CNS viral load after intracerebral challenge with HSV-1 w
Predicted outcome: Significant depletion of border-associated macrophages and perivascular APCs (≥50% reduction by flow cytometry), accompanied by impaired viral clearan
Falsification: Perivascular macrophage populations remain within 20% of vehicle-treated controls, and viral clearance kinetics are unchanged—indicating CD11c ADC does not impair CNS immune surveillance, contradictin
pendingconf 28%
IF CD11c+ microglia are depleted via anti-CD11c ADC in TDP-43 Q331K knock-in mice modeling ALS-associated proteinopathy, THEN disease progression will accelerate by ≥30% and remyelination capacity will decline by ≥40% compared to ADC-treated WT controls within 12 weeks, because CD11c+ cells driven b
Predicted outcome: Accelerated motor decline (rotarod latency reduced by ≥30% versus baseline), decreased survival (median reduced by ≥3 weeks), reduced CD11c+/TREM2+ mi
Falsification: Motor function and survival remain unchanged or improve in CD11c ADC-treated TDP-43 Q331K mice compared to vehicle, and remyelination markers show no reduction—indicating CD11c+ cells are not protecti
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting
0 contradicting
0 neutral
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