Work

The Origins of Allergy: An Outside‐In, Bioenergetic Hypothesis

Year: 2026

Type: review

Abstract: Allergic disease has risen too rapidly for inherited susceptibility to explain it, and the risk variants so far reported lie in the epithelial barrier and in type-2 immunity. We propose a five-layer model in which epithelial barrier and bioenergetic dysfunction may precede and promote type-2 immune deviation rather than arise solely as its consequence, progressing from (1) barrier and bioenergetic dysfunction, with mitochondrial DNA escaping into the cytosol, through (2) danger sensing and (3) epithelial-immune communication, to (4) type-2 immune amplification and (5) a systemic layer of circulating IgE, neurogenic amplification and the atopic march, with reciprocal inflammatory feedback. Layer 1 is also the least measured: standard immune panels carry almost none of these genes, and no genome-wide association study has implicated the mitochondrial genome or its nuclear regulators. From 1856 catalogued transcriptomic series, 985 of them expression series, we drew 116 case-control cohorts from 110 series, 3776 patients and 2164 controls, with Layer 1 prespecified as 350 genes across 19 domains. Of 212 module estimates nine survived false-discovery correction: two type-2 positive controls, two cytosolic sensing and inflammasome modules, raised in oesophageal tissue (Hedges' g +1.70) and atopic skin (+1.27), and five bioenergetic modules in oesophageal tissue. In eosinophilic oesophagitis the mitochondrial clearance limb was reduced in every one of thirteen cohorts (HIF1A -1.94, BNIP3-1.98). STING1 increased in all thirteen skin cohorts that measured it while MAVS fell in ten of thirteen oesophageal cohorts, and a STING1 minus MAVS contrast separated the allergic epithelia from psoriasis, chronic obstructive pulmonary disease and asthma without exception (exact p 0.029). In one series of clinically uninvolved atopic skin KEAP1 increased while NFE2L2, claudin-1 and filaggrin decreased (p < 0.001), in tissue that is not inflamed; pooled across nine series the directions largely hold without reaching significance. Broad suppression of mitochondrial programmes across allergic tissues was not supported: the phenotype is tissue-dependent, present in eosinophilic oesophagitis and atopic dermatitis, absent in nasal polyposis and established asthma and conditional in allergic rhinitis. Prospective and experimental studies must establish temporal and causal relationships.

Source: Allergy

DOI: 10.1111/all.70532