Simeone 2026 — HαT/TPSAB1 extends to mucosal MC physiology via MRGPRX2 amplification

One-paragraph summary

This review extends the Lyons 2019 anchor on hereditary α-tryptasemia (HαT) — the autosomal-dominant TPSAB1 copy-number variation affecting 4-6% of European-ancestry individuals — into its gastrointestinal physiology consequences. HαT increases duodenal mast cell count and is associated with increased mucosal expression of MRGPRX2 (the non-IgE MC-activating receptor that Sanchez 2025 identifies as the effector receptor for FM-IgG-induced sensitization). In coexisting celiac disease, HαT predicts persistent GI symptoms despite gluten-free diet. In inflammatory bowel disease, HαT acts as a disease modifier with elevated mucosal MC activation. The headline relevance to the FM project: HαT supplies a heritable genetic substrate that pre-loads patients for the H1×H2 unified mechanism described by Sanchez 2025 — more MCs, more MRGPRX2, therefore more FM-IgG-mediated sensitization per unit antibody. HαT-positive FM patients should be a clean clinical subgroup with predictable mechanism.

Claims as triples

• TPSAB1_duplication — causes → elevated_baseline_tryptase [established prior; reinforced here; confidence: established]
• TPSAB1_duplication — causes → increased_mucosal_MC_count [evidence: duodenal biopsy literature; confidence: emerging]
• TPSAB1_duplication — modulates → MRGPRX2_expression [evidence: review-tier from primary studies; confidence: emerging — KEY LINK]
• TPSAB1_duplication — predicts → persistent_celiac_GI_symptoms [evidence: clinical cohort data; confidence: emerging]
• TPSAB1_duplication — modulates → inflammatory_bowel_disease_phenotype [evidence: emerging cohort data; confidence: emerging]
• MRGPRX2 — present_in → intestinal_mucosa_MC [evidence: review-tier; confidence: emerging — NEW ENTITY/LOCATION]
• HαT — bridges → intestinal_permeability [via MC mediator release at mucosa; confidence: bridging]

Methods note

Narrative review synthesizing evidence from primary studies of HαT in GI conditions (celiac disease, IBD), with mechanistic emphasis on MC density and receptor expression. No new primary data. Authors include Glover SC (UF), Konnikova L (Yale), Therrien A (Mass General Brigham) — established mast-cell-disease clinical investigators.

Limitations

• Review-tier evidence; no new patient cohort. MRGPRX2-expression-in-HαT claim depends on the primary studies it cites; these should be located and verified before tier promotion.
• HαT effects in non-GI tissues (skin, CNS) less developed in this review; the FM-relevant claim that HαT patients have systemically elevated MRGPRX2 is partially inferential.
• Cohort sizes in cited primary studies are small to moderate; HαT genetics are not yet population-routine, so most studies are tertiary referral cases with selection bias toward symptomatic HαT.

Open questions raised

• Q-NEW (Q80): What fraction of FM patients are HαT-positive? Project's existing Lyons 2019 anchor establishes ~5% population frequency; FM-specific genotyping has not been done. If HαT-positive fraction in FM is >5%, HαT enrichment in FM is suggestive of mechanism contribution. Q44 (TPSAB1 ddPCR in FM cohort) is the design.
• Q-NEW (Q81): Do HαT-positive FM patients show enhanced response to MRGPRX2 antagonists vs HαT-negative FM patients in stratified trial design? Direct test of the heritable-amplifier hypothesis.
• Does HαT-positive FM correlate with anti-SGC IgG titer (Krock 2023 / Seefried 2025 quartile)? If HαT amplifies the IgG-MRGPRX2-MC mechanism, HαT-positive patients should show stronger correlation between titer and severity.
• Is the mucosal MC + intestinal-permeability axis the entry point that connects B2 (microbiome → FM) to the H2 (MC) chain? HαT may be the heritable substrate that makes microbiome-driven antigen translocation more pathogenic.

Triangulation notes

• Direct mechanistic complement to Sanchez 2025 (same batch ingestion). Where Sanchez 2025 shows FM-IgG → MRGPRX2 → MC activation as the operative mechanism, Simeone 2026 shows that HαT genetically elevates the MRGPRX2-expressing MC pool. Together they predict HαT-positive FM patients should have a stronger Sanchez-mechanism phenotype.
• Extends Lyons 2019 anchor with mucosal-physiology mechanism. Lyons 2019 was already in the project as the heritable substrate for the H2-MC subtype; Simeone 2026 supplies the molecular pathway (MRGPRX2 elevation) connecting Lyons to Sanchez.
• Bridges H2 (MC) to B2 (microbiome → FM): HαT-elevated mucosal MC activation provides the physiology by which intestinal barrier compromise (Dorta-Aguilar 2023, Kishore 2026 anchors) → antigen translocation → MC activation → systemic effect could operate as a self-amplifying loop.
• Aligns with Christoforou 2026 cromolyn pilot mechanism: the high-dose cromolyn protocol in ME/CFS+MCAS patients may be working specifically on the mucosal-MC pool that HαT enlarges.

Bridges

• B2 (Microbiome ↔ FM via SCFA / bile acids → satellite glia → autoantibody production) — strengthened. HαT supplies a heritable amplifier of intestinal MC activation, which can be triggered by microbiome-derived ligands (LPS, MRGPRX2 has known bacterial-product ligands).
• B-NEW: HαT genetic substrate ↔ H1×H2 unified mechanism: proposes that ~5% of population (HαT-positive) are genetically pre-loaded for the Sanchez-mechanism. If HαT enrichment in FM is found to be 2-3× population baseline (i.e., 10-15% of FM is HαT-positive), this becomes a heritable risk factor for FM specifically.