Fibromyalgia is not a single disease but a final common pathway that several distinct upstream mechanisms can feed into. This page maps the six chain candidates the project currently tracks. Each chain has an interactive mechanism map (linked from each card), a confidence tier (emerging or bridging), and a set of intervention break-points where the chain can be interrupted clinically.
H1 × H2 is the project's most-developed mechanism, anchored on the Sanchez/Goebel/Dong 2025 MRGPRX2 receptor finding that collapses two previously-separate hypotheses into one chain. H3 describes the systems-level phenotype all chains converge on. H4, H5, and H5b are 2026 candidate chains — bridging-tier, awaiting FM-direct closure evidence — that propose distinct genetic-substrate or peripheral-metabolic upstreams feeding the same effector mechanism.
The project's most-developed chain. Sanchez 2025 MRGPRX2 anchor.
Gut dysbiosis → bile-acid translocation → B-cell activation → FM-IgG production → MRGPRX2 binding on mast cells → degranulation → satellite glia + sensory neuron sensitization → widespread pain.
H3 emergingSystems-level phenotype all chains converge on.
Interoceptive-inference failure (Herman 2026 emBODY task, Strube 2026 framework) + thalamocortical decoupling (Hou 2026 rs-fMRI) + flare dynamics. Population-genetics anchor: Kerrebijn 2025 FM GWAS shows FM heritability is exclusively brain-tissue-enriched.
H4 bridgingAdipose tissue → leptin → microglial activation. Candidate 2026-05.
Adipose tissue dysfunction → leptin elevation → BBB transit → LepRb engagement on microglia → JAK2/STAT3 + MAPK/ERK + PI3K/Akt signaling → M1 microglia → IL-1β + IL-6 + TNF-α → central sensitization + sickness-behavior loop.
H5 bridgingCeliac + T1DM autoimmune-genetic signature. Candidate 2026-05.
Within the anti-SGC-IgG-positive 37% FM subset, a genetically-defined subgroup carries the celiac+T1DM autoimmune-genetic risk module: HLA-DQ2/DQ8 + CTLA4 + PTPN22 (tolerance triad) + IL2/IL21 + IL2RA (Treg regulation) + TNF + MYO9B + CLDN2 + TGM2 (gut-barrier + celiac-autoantigen axis). Merges with H1 at the FM-IgG production node.
H5b bridgingSOCE-amplifier signature docking into CA-I1. Sibling to H5. Candidate 2026-05.
Six-gene module straddling three project domains: ORAI1 + STIM1 (immune AND calcium via SOCE — docks directly into CA-I1 intersection) + MYO9B + OCLN + TJP1 (three molecular layers of the tight junction) + CTLA4 (T-cell tolerance). Predicts ORAI1/STIM1 risk-allele carriers within FM-IgG-positive patients have *amplified* MC degranulation per unit FM-IgG via the calcium-handling substrate.
The most defensible synthesis claim, given current evidence: H1, H2, H4, H5, and H5b are alternative or co-occurring upstream biological mechanisms; H3 is the systems-level phenomenon they all produce. Some FM patients are dominantly H1 (anti-SGC IgG positive, no MC involvement); some are dominantly H2 (MC-active, IgG-negative); some are both (the H1×H2 unified-mechanism core); H4 enriches in metabolic-syndrome-comorbid patients; H5/H5b stratify the H1-positive subset by genetic substrate. All five biological chains produce the same H3 systems-level dysregulation (predictive-coding deficit, network FC abnormalities, flare dynamics) — but via different upstream routes and therefore responsive to different interventions.
The project's current narrowing trajectory, as of May 2026, points to H1×H2 as the leading single-chain candidate for the largest FM-IgG-positive subset — with H4, H5, and H5b serving as further patient stratifiers (sub-selection within H1-positive) rather than as competing chains. Recursive narrowing over the next 6–12 months of ingestion will refine this hypothesis hierarchy further.