# Shedding Light on FIRE Syndrome: An Overview of a Novel Condition in Eosinophilic Esophagitis
## 6 Proposed Pathogenic Mechanisms
This phenomenon, which has been thought to be restricted to lymphoid organs, has been described in other mucosal sites such as the gastrointestinal, nasal, or bronchial mucosa [44; 45; 46]. In their study, [PERSON] et al. demonstrated the presence of germline transcripts (GLIs), AID, and IgE heavy chain (C\(\epsilon\)) mRNA in the esophageal mucosa of EoE patients, which are essential for CSR [39]. The authors state that a limitation of this study would be that biopsies were taken with a substantial delay after allergen exposure, so the presence of circular transcripts or switch circles, which is needed to confirm the ongoing process of CSR, could not be determined. Consequently, the possibility that CSR occurred in another location and primed B cells migrated to the esophagus cannot be excluded [39]. On that basis, together with significantly upregulated IL-4 and IL-13 expression in EoE patients and the presence of IgE-bound mast cells, these findings suggest the local esophageal priming for IgE synthesis and a potential local IgE-mediated response in EoE that could consequently explain FIRE syndrome manifestations [39]. A hypothesis concerning the pathophysiology of this syndrome suggests the involvement of a local, immediate hypersensitivity reaction. While skin pick tests (SFTs) are used to identify IgE-mediated sensitization to foods, their utility in EoE and particularly in FIRE syndrome is limited [9; 17]. In fact, SPTs with suspected foods may be negative, likely due to the esophagus being the primary site of the sensitization [9; 17]. A study by [PERSON] et al. introduced the use of esophageal prick testing (EPT) involving direct injection of suspected allergens into the esophageal mucosa [47]. They demonstrated that 63% of known trigger foods elicited a positive result in EPT, characterized by erythema, edema, and muscle contraction with esophageal obstruction. These responses were absent in healthy controls, supporting the idea of a localized IgE-mediatedmechanism in a subset of EoE patients [47]. In contrast, only 18% of suspected triggers were identified through SPTs [47]. Furthermore, transcriptomic analysis of the esophageal mucosa following EPT exposure revealed an upregulation of genes associated with acute allergic inflammation, such as _TNFF18_ (_GITRL_) [48]. This gene is also known to play a role in other atopic diseases, such as asthma and atopic dermatitis, but its role in the early phase of the food-induced immune response is still to be determined [48; 49; 50]  
Although these findings support the presence of an immediate, localized esophageal immune response, their clinical application in FIRE syndrome remains limited. It is still unclear whether positive EPT or SPTs results in EoE patients correlate directly with FIRE syndrome symptoms. No studies have yet evaluated the diagnostic accuracy of EPT or SPT in relation to this syndrome. While EPT may prove useful in identifying esophageal-specific sensitization and distinguishing immune-mediated reactions from mucosal irritation, its sensitivity, specificity, and diagnostic value in FIRE syndrome remain to be formally established though prospective studies [19]. Moreover, EPT is invasive, not yet standardized, and may not fully replicate natural exposure during eating [47; 48]. Nevertheless, the epithelial barrier defect due to the inflamed esophageal mucosa may compensate for this shortcoming. Dysfunction of the epithelial barrier has been described in EoE [46; 51]. It is characterized by a decreased mRNA expression of key epithelial barrier proteins such as filaggrin, involucrin, desmoglein-1, and the antiprotease encoded by the _SPINK7_ gene [52]. Decreased esophageal impedance further indicates an epithelial barrier impairment in EoE [53]. The decreased epithelial barrier function involves dilated intercellular spaces and likely facilitates allergen penetration in the esophageal mucosa [54].