Fibromyalgia: H1 × H2 unified mechanism

Chain · evidence weight per link · disruption points — anchored on Sanchez/Goebel/Dong 2025 (bioRxiv preprint)

established emerging inferred bridging intervention break-point Hover any node for a preview · Click for full definition + paper links (Esc or backdrop to close)
H1 × H2 unified mechanism — vertical flow read top to bottom · arrow style encodes evidence tier · ① – ⑥ are intervention break-points Gut dysbiosis microbial SCFA / BA shifts trigger Viral / HERV SARS-CoV-2 · EBV · HERV-W trigger Stress / trauma HPA-axis activation trigger 1 Bile acid elevation Jakobsson 2026 — 24 BAs ↔ anti-SGC IgG emerging B-cell / plasma cell activation · Talwar 2025 (LC) emerging 2 FM-IgG (circulating pathogenic IgG) Goebel 2021 passive transfer · Krock 2023 titer ↔ severity Seefried 2025 — 37% of FM positive · Hanani 2026 multi-ganglia emerging ★ FM-IgG → MRGPRX2 — Sanchez 2025 Mrgprb2 KO or MC ablation each abolish IgG-pain phenotype 3 4 Substance P (CSF↑ in FM) established biomarker MC-SP loop via MRGPRX2 / NK1R established · Aitella 26 5 HαT (TPSAB1↑) — amplifier ↑MC count · ↑MRGPRX2 Lyons 19 · Simeone 26 inferred · ~5% pop MAST CELL + MRGPRX2 ★ H1 × H2 convergence node Multiple ligands converge on one receptor: FM-IgG · Substance P · HαT amplification ★ click for the full story 6 MC mediators released IL-6 · histamine · tryptase · TNF-α · chymase established Estrogen ↑ at gfWAT (lipedema) bridging · Amato 26 Satellite glia + sensory neuron sensitization multi-ganglia: DRG · trigeminal · nodose · sympathetic (Hanani 26) central sensitization machinery: NMDA-LTP · glial cytokines emerging (multi-ganglia) + established (CS machinery) Widespread pain core FM phenotype established Multimodal hypersensitivity pressure · temp · light · sound · odor established Long-COVID extension — Mignolet 2026 (Acta Neuropathologica) LC-IgG passive transfer → DRG → sensory pain (no cognitive transfer) structurally mirrors Goebel paradigm in PASC — predicts MRGPRX2 mechanism extends to post-COVID FM (Q78) bridging · cross-condition Six intervention break-points — click any numbered red circle above ① FMT/colesevelam · ② daratumumab · ③ FcRn block / plasmapheresis+IVIG · ④ ★ barzolvolimab (MRGPRX2) · ⑤ aprepitant (NK1R) · ⑥ cromolyn ★ ④ is the new intervention class unlocked by Sanchez 2025 — Phase 2/3 chronic urticaria, no IND barrier for FM repurposing
Reads top to bottom. Substance P (established CSF biomarker) and HαT (heritable amplifier) feed the MAST CELL + MRGPRX2 convergence from the sides; estrogen-at-gfWAT (bridging, lipedema mechanism) feeds from below-left. The MAST CELL node is the H1 × H2 convergence — Sanchez/Goebel/Dong 2025 shows Mrgprb2 KO OR MC ablation each independently abolish the IgG-induced pain phenotype.