Fibromyalgia: H5b — immune-barrier-calcium intersection chain (candidate)

Sibling to H5 · ORAI1+STIM1+MYO9B+OCLN+TJP1+CTLA4 · docks directly into CA-I1 intersection of the calcium-dysregulation hypothesis · genetic-substrate amplifier of the H1×H2 mechanism

established emerging inferred bridging intervention break-point Hover any node for a preview · Click for full definition + paper links (Esc or backdrop to close)
H5b immune-barrier-calcium intersection — vertical flow three-domain intersection · docks into CA-I1 · amplifies H1×H2 at the calcium-handling substrate Level 1 — Genetic substrate (three-domain intersection) IMMUNE IMMUNE + CALCIUM (★ H5b signature) BARRIER CTLA4 T-cell coinhibitory checkpoint tolerance failure bridging · abatacept shared with H5 ★ ORAI1 CRAC channel pore · SOCE in T cells + MC ★ STIM1 ER calcium sensor · ORAI1 gating partner MYO9B (Rho-GAP) OCLN (occludin) TJP1 (ZO-1 scaffold) 1 Level 2 — Trigger intersection (shared with H1) Gut dysbiosis · Viral infection · Stress / trauma · (gluten exposure in HLA-DQ2/DQ8 carriers — H5 framing overlap) Level 3 — Process layers (where the genetics get expressed) T-cell hyperactivation ← ORAI1/STIM1 SOCE → NFAT ← CTLA4 tolerance failure → autoreactive B-cell help bridging ★ MC hyperresponsiveness ← ORAI1/STIM1 SOCE in MC ★ CA-I1 intersection → magnified MRGPRX2 response bridging · CA-I1 anchor Barrier failure ← MYO9B + OCLN + TJP1 three TJ molecular layers → antigen / PAMP translocation bridging 2 3 4 Level 4 — Downstream effectors (H5b merges into H1×H2) Plasma cell expansion → FM-IgG production IL-21-driven · Talwar 2025 framework emerging (H1 node) Bile acid translocation (Jakobsson 2026) 24 BAs ↔ anti-SGC IgG · barrier-amplified emerging (H1 node) Level 5 — H1×H2 convergence (★ amplified at CA-I1) FM-IgG (Goebel 2021 · Seefried 2025 · Sanchez 2025 · Hanani 2026) emerging · H5b predicts genetic-amplifier enrichment in this subset 5 ★ CA-I1 intersection: MC × STIM1/Orai1 SOCE downstream of MRGPRX2 / NK1R / ER-IP3R H5b prediction: ORAI1/STIM1 risk-allele carriers show magnified SOCE per unit FM-IgG → magnified MC degranulation ★ click for the CA-I1 mechanism + click ⑥ for CRAC blocker arm established mechanism · FM-direct evidence is the H5b gate 6 MC mediators released (amplified per H5b genotype) IL-6 · histamine · tryptase · TNF-α · chymase Satellite glia + sensory neuron sensitization multi-ganglia: DRG · trigeminal · nodose · sympathetic (Hanani 2026) emerging (existing H1 node) Widespread pain core FM phenotype established Multimodal hypersensitivity pressure · temp · light · sound · odor established B-Gen-3 + B-Gen-4 — H5b cross-chain integration B-Gen-3: H5b module ↔ CA-I1 intersection — docks 6-gene signature into existing calcium hypothesis at the MC × SOCE intersection. B-Gen-4: H5b T-cell SOCE arm ↔ H1 autoantibody pathway — ORAI1/STIM1 also amplify autoreactive T-cell NFAT → B-cell help → FM-IgG. bridging · sibling to H5 (option-b 2026-05-24) · H5b-direction-pending alongside H5 ★ The discriminating H5b cure-path test CRAC channel inhibitor (CM4620 / Auxora) vs MRGPRX2 antagonist (barzolvolimab) — head-to-head in H5b-stratified FM patients. CRAC blockade acts at calcium-handling layer regardless of receptor input; MRGPRX2 antagonism blocks one specific receptor. If CRAC outperforms MRGPRX2 antagonism in H5b carriers, H5b is a real distinct subset. If equivalent, H5b is stratification not new biology. Six intervention break-points — click any numbered red circle above ① ORAI1/STIM1 genotyping + functional SOCE · ② ★ CRAC channel inhibitor (Auxora) · ③ larazotide acetate ④ abatacept (CTLA-4-Ig) · ⑤ cromolyn (MC stabilization) · ⑥ MRGPRX2 antagonist (head-to-head with ②)
Reads top to bottom. H5b is the sibling chain candidate to H5 (option-b decision 2026-05-24). The six-gene module is a genuine three-domain intersection: ORAI1+STIM1 (immune AND calcium via SOCE) + MYO9B+OCLN+TJP1 (three molecular layers of the tight junction) + CTLA4 (T-cell tolerance). H5b does not propose a new chain — it proposes a genetic-substrate-amplified version of the existing H1×H2 mechanism at the CA-I1 calcium intersection. The discriminating cure-path test is head-to-head CRAC channel inhibitor (CM4620/Auxora — Calcimedica Phase 2/3 pancreatitis program) vs MRGPRX2 antagonist (barzolvolimab) in H5b-stratified FM-IgG-positive patients. Full framework: H5b chain document.