该研究通过代谢组学分析揭示了花生过敏及由此引发的过敏性休克中代谢途径的改变，尤其是尿酸水平的升高。研究人员发现，尿酸在过敏反应中起着关键作用，其缺失可以防止过敏和过敏性休克的发生。此外，代谢分析还显示了花生过敏患者在口服挑战后的独特代谢特征。这些发现为花生过敏的新型生物标记物和潜在治疗策略提供了线索。
Abstract:
BACKGROUND: The ontogeny of peanut allergy (PA) is poorly understood, and the treatment of its most severe manifestation, peanut-induced anaphylaxis (PIA), remains limited to rescue epinephrine. We argued that an untargeted metabolomic analysis would be a useful hypothesis-generating tool to identify novel biomarkers, mediators and possibly therapeutic targets in PA and PIA.
METHODS: Models of PA and PIA used in this thesis involved either the oral administration of peanut along with cholera toxin or the topical application of peanut on tape-stripped skin. Liquid-chromatography mass-spectrometry (LC-MS) was performed to identify chemical changes in the serum of mice undergoing sensitization and anaphylaxis. Flow cytometry as well as in vivo gain-of-function and loss-of-function immunological studies were used to determine the biological significance of particular molecules in sensitization.
RESULTS: LC-MS followed by multivariant analysis showed that the purine metabolism pathway was altered with elevated levels of uric acid (UA) in sensitized mice. UA depletion using allopurinol and uricase fully prevented the development of the allergic and anaphylactic phenotype. Conversely, administration of UA crystals, instead of cholera toxin or tape stripping along with peanut induced a typical allergic and anaphylactic phenotype. The effects of UA and UA crystals are likely a consequence of effects on the activation of resident dendritic cells. Post-challenge metabolic analysis also revealed a distinct metabolic signature in sensitized mice, highlighted by an increase in several metabolites such as histamine. Likewise, peanut allergic patients display a distinct metabolic profile after oral peanut challenge.
CONCLUSION: We identified UA, released after damage to the mucosa and/or skin, as a critical alarmin that facilitates the development of Th2 immunity, specifically PA and PIA. Metabolomics analyses of either mice undergoing anaphylaxis or peanut allergic children subjected to a peanut oral challenge provided an extensive overview of metabolomic changes underlying these conditions. Further studies may lead to the identification of novel biomarkers and mediators.
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