# Shedding Light on FIRE Syndrome: An Overview of a Novel Condition in Eosinophilic Esophagitis
## 6 Proposed Pathogenic Mechanisms
This results in increased ATP release, leading to an amplified response in sensory neurons, potentially contributing to esophageal pain signaling [71, 72]. The activation of these channels further adds to esophageal enhanced pain perception through the release of neuropeptides, including substance P and calcitonin gene-related peptide (CGRP) [73]. Data show that a prolonged increase in esophageal C-fiber excitability with intensified vagal nocicport stimulation is correlated with local mast cell activation [70]. Interestingly, TRPV1 has been found to be upregulated in active EoE and inactive EoE with associated persistent pain [67]. [PERSON] et al. showed that esophageal hypersensitivity could also be attributed to other ion channels like ASIC1 and ASIC3, which are upregulated in patients with reflux esophagitis and in rodent models of esophagatitis [74, 75]. Taken together, these data underscore the importance of the connection between esophageal mast cell infiltration and pain perception in patients with EoE. The contribution of chemical irritation in the pathogenesis of FIRE syndrome could account for the immediate onset and high intensity of pain. However, this hypothesis remains theoretical in nature and further research is needed to confirm it. To summarize, the pathophysiological mechanisms underlying FIRE syndrome have not been investigated to date. However, several hypotheses could be formulated based on the key pathways implicated in EoE etiology. The increase in esophageal B cell population accompanied by evidence suggesting a potential local CSR mechanism and an elevated IgE-bearing cell number within the esophageal mucosa supports the idea that an IgE-mediated mechanism could be involved in the generation of the localized immediate hypersensitivity reaction observed in FIRE syndrome [39, 41]. This immediate response has been demonstrated before in EoE patients, where esophageal prick tests with suspected triggers evoked signs suggestive of immediate reactivity [47]. Furthermore, the mucosal barrier dysfunction known to occur in EoE may create a favorable environment for allergen penetration, thereby promoting their interaction with the immune cells [46, 51, 52, 53, 54, 55, 56]. The resulting immediate response appears to lead to mast cell degranulation with the release of important proinflammatory mediators such as prostaglandandins, leukotrienes, and thromboxes. Given the increased presence of mastocytes in the muscular layers of the esophagus, mast cell degranulation could potentially explain the motility dysfunction and pain seen in FIRE syndrome [37, 66]. Additionally, the stimulation of acid-sensing ion channels such as TRPV1 and ASICs further promotes pain generation, suggesting a potential role of the neuroimmune interaction in the pathology [69; 70; 71; 72; 73; 74; 75]. These hypotheses about the mechanisms will necessitate further investigations and thoroughly conducted studies to elucidate their implication in patient management. The key postulated ideas are depicted in Figure 3.  
Given the novelty of FIRE syndrome, most of the proposed mechanisms discussed in this section are extrapolated from EoE, or other related allergic disorders and should be considered exploratory. While some pathways are supported by experimental or histologic findings in EoE, others remain theoretical. Table 3 outlines the key proposed mechanisms, their biological basis, and the types of evidence available. \begin{table}
\begin{tabular}{c c c} \hline \hline
**Proposed FIRE** & **Basis/Supporting Data** & **Evidence Type** \\ \hline Epithelial barrier & Loss of tight junction proteins; allergen penetration with local antigen deposition & Histologic and transcriptomic data from EoE \\ \hline Local IgE-mediated & Increased B cells and CSR & Clinical and molecular \\ response in the esophagus & gene expression; IgE + cells & studies in EoE \\ \hline \hline \end{tabular}
\end{table} 
Table 3: Proposed pathophysiological mechanisms in FIRE syndrome.