Fibromyalgia: H5 — autoimmune-genetic-risk chain (candidate)

Celiac + T1DM autoimmune-genetic signature → upstream substrate for the FM-IgG-positive H1 subset · new bridging-tier chain proposed 2026-05-24

established emerging inferred bridging intervention break-point Hover any node for a preview · Click for full definition + paper links (Esc or backdrop to close)
H5 autoimmune-genetic-risk chain — vertical flow read top to bottom · subset hypothesis (anti-SGC-IgG-positive ~37%) · merges into H1 at the FM-IgG node Level 1 — Genetic risk substrate (heritable, present from birth) HLA-DQ2 / DQ8 MHC class II haplotypes presents gluten peptides bridging · ~$50/sample test CTLA4 T-cell coinhibitory checkpoint tolerance failure → autoreactivity bridging · abatacept-druggable PTPN22 (R620W) TCR/BCR signaling threshold autoreactive lymphocyte escape bridging · stratifier only IL2 / IL21 (4q27) Treg maintenance + Tfh cytokine germinal-center hyperactivity bridging · low-dose IL-2 IL2RA (CD25) high-affinity IL-2 receptor Treg dysfunction (MS-shared) bridging TNF (promoter) cytokine arm shared with RA anti-TNF biologics FDA-approved established (ontology) MYO9B Rho-GAP, barrier integrity celiac susceptibility bridging CLDN2 (claudin-2) tight-junction protein larazotide-druggable bridging TGM2 (tissue tTG) celiac autoantigen anti-tTG IgA = ~$50 test bridging 1 Level 2 — Trigger intersection (environmental hit on genetic background) Gluten exposure HLA-DQ2/DQ8 carriers trigger (H5-specific) Gut dysbiosis microbial SCFA / BA shifts trigger (shared w/ H1) Viral infection EBV · SARS-CoV-2 · HERV trigger (shared) Stress / trauma HPA-axis activation trigger (shared) 2 Level 3 — Process layers (where genetics get expressed) Barrier failure ← MYO9B + CLDN2 variants → bacterial / BA translocation bridging (H5 substrate) Tolerance failure ← HLA-DQ2/DQ8 + CTLA4 + PTPN22 → autoreactive lymphocyte escape bridging Treg incompetence ← IL2RA + CTLA4 + IL2/IL21 → unrestrained Tfh / B-cell help bridging 3 4 5 Level 4 — Downstream effectors (H5 merges into H1) Bile acid translocation Jakobsson 2026 — 24 BAs ↔ anti-SGC IgG emerging (H1 anchor — H5 supplies genetic upstream) Germinal-center hyperactivity IL-21-driven · Talwar 2025 LC framework emerging B-cell / plasma-cell activation → FM-IgG production (anti-SGC IgG, Sanchez 2025 substrate) emerging (existing H1 node) Level 5 — Convergence with H1 (Sanchez 2025 mechanism) FM-IgG (circulating pathogenic IgG) Goebel 2021 · Krock 2023 · Seefried 2025 · Sanchez 2025 · Hanani 2026 emerging · H5 hypothesizes genetic-risk-stratified enrichment 6 MAST CELL + MRGPRX2 ★ Sanchez 2025 — Mrgprb2 KO + MC ablation each abolish IgG-pain FM-IgG · substance P · HαT amplification — all converge here ★ click to see the unified H1×H2 mechanism page Satellite glia + sensory neuron sensitization multi-ganglia activation (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-1 + B-Gen-2 — cross-chain integration B-Gen-1: H5 module is the genetic-substrate-stratified upstream of the H1 chain (subset of the ~37% FM-IgG+ patients). B-Gen-2: Celiac-spectrum disease shares HLA-DQ2/DQ8 + MYO9B + CLDN2 + TGM2 with H5 — mechanistically-justified cross-condition anchor. bridging · H5 direction-pending · Kerrebijn 2025 GWAS-null at population level interpretable as subset-mechanism dilution Six intervention break-points — click any numbered red circle above ① stratification screen (HLA + anti-tTG) · ② gluten-free trial · ③ larazotide acetate · ④ ★ abatacept · ⑤ low-dose IL-2 · ⑥ anti-TNF biologics
Reads top to bottom. H5 is a SUBSET hypothesis targeting the ~37% anti-SGC-IgG-positive FM patients (Seefried 2025). Levels 1–4 are H5-specific (genetic substrate → trigger intersection → process layers → downstream effectors); Levels 5–6 are shared with the existing H1 chain (FM-IgG → MRGPRX2 → MC → SGC → symptoms). Kerrebijn 2025 GWAS at population level shows no immune-tissue heritability enrichment — sharpening result, not refutation: the right test instrument is case-only PRS within FM-IgG-positive cohorts, not biobank-scale GWAS. Two cheapest immediate tests: HLA-DQ2/DQ8 typing (~$50–100/sample) and anti-tTG IgA seroscreen (~$50–100/sample). See the H5 chain document for the full framework.