# Shedding Light on FIRE Syndrome: An Overview of a Novel Condition in Eosinophilic Esophagitis
## 6 Proposed Pathogenic Mechanisms  
The pathophysiological mechanisms underlying FIRE syndrome are still unknown and remain largely speculative due to limited available data. The immediate onset of symptoms, their reproducibility upon trigger exposure, and the common association with other allergic diseases point to the involvement of a rapid immune-mediated response [17]. Furthermore, the confinement of symptoms to the esophagus strongly suggests the association of localized immunological mechanisms [16]. The esophagus is not merely a passive conduit for food but also serves as an immunologically active organ [33]. In a healthy esophagus, immune cells are present across all tissue layers and contribute to both tissue homeostasis and defense mechanisms. T lymphocytes make up the most abundant immune cell population [34]. CD8+ cytotoxic T cells are scattered throughout the epithelium and muscularis layers, whereas CD4+ helper T cells are primarily situated in the lamina propria [34]. Unlike T lymphocytes, the B lymphocytes are found in a small number in the esophageal mucosa, mainly situated in the vascular papillae and lamina propria, and are absent in the muscularis mucosae and muscularis externa [34]. Mastocytes, with a previously underestimated presence in the esophageal mucosa, have been shown to comprise the most abundant immune cell population in the muscular layers, suggesting a potential role in motility regulation and sensory perception [34;35]. Alongside  
Figure 2: Proposed diagnostic algorithm for FIRE syndrome. We summarized the main clinical features of FIRE syndrome from the available literature and formulated a potential diagnostic algorithm [16; 17; 18; 19]. mast cells, macrophages represent another prevalent immune cell type within the muscle layers of the esophagus, but their exact function is still unclear. Their presence suggests a potential role in the regulation of esophageal motility, similar to their function in other intestinal segments [34; 36]. These findings highlight the esophageal role in initiating and modulating immune responses, with significant implications for both physiological and pathological processes [37]. The pathophysiology of EoE involves epithelial barrier defects with dysregulated epithelial-immune cell interaction and Th2-driven eosinophil mucosal infiltration [37]. These complex mechanisms lead to chronic, progressive inflammation and tissue remodeling with fibrosis, leading to esophageal dysfunction [37]. Unlike chronic Th2-driven inflammation, which dictates EoE pathophysiology, immediate immune responses may be involved in FIRE syndrome, with some potential key pathways including IgE-mediated hypersensitivity response, mast cell activation response, or neuroimmune interactions [16; 17; 18; 19]. Although B lymphocytes are not abundant in healthy esophageal tissue, EoE patients exhibit a significantly higher number of B cells, particularly localized in the vascular papillae and peripapillary region, compared with healthy controls [38; 39]. In murine models of EoE induced by intranasal exposure to Aspergillus fumigatus, the esophageal B lymphocyte population exhibited an approximate twofold increase [40]. B cells have been shown to be actively recruited in the esophageal mucosa of EoE patients independently of patients' atopic status [39]. Their implication in FIRE syndrome may depend on local IgE class switching occurring in response to local allergen exposure. Upon activation, B lymphocytes (CD20+) undergo class switch recombination (CSR), expressing other antibody isotopes such as IgG, IgA, and IgE [41]. The process involves the recombination of heavy chain gene segments and the generation of circular transcripts, leading to the synthesis of mature IgE mRNA and protein expression [41]. The CSR to IgE, a key player in atopic diseases, is driven by IL-4 and IL-13 signaling, in conjunction with CD40-CD40L interactions and the upregulation of activation-induced cytidine deaminase (AID) [39; 42; 43].