# Shedding Light on FIRE Syndrome: An Overview of a Novel Condition in Eosinophilic Esophagitis
## 6 Proposed Pathogenic Mechanisms
Esophageal intramucosal antigen deposition has been demonstrated in a study conducted by [PERSON] et al., showing detectable intraepithelial gluten deposition in active EoE patients [55]. Furthermore, the presence of aeroallergens such as _Dermatophagoides farinae_ has been described at the epithelial level in adults with EoE [56]. Their inherent proteolytic quality may further contribute to esophageal epithelial dysfunction, as demonstrated in other allergic conditions such as asthma [57]. Additionally, the altered microbiome seen in EoE patients could contribute to epithelial barrier dysfunction by decreasing beneficial metabolite synthesis (e.g., short-chain fatty acids) and increasing the production of lipopolysaccharidesaccharides and pathogen-associated molecular patterns (PAMPs), which can damage the epithelium and increase its permeability [58; 59]. Subsequent to the impairment of the esophageal epithelial barrier, an increased number of type 2 innate lymphoid cells (ILC2s) is observed. The activation of these cells, mediated by thymic stromal-derived lymphopoetin (TSLP) and IL-33, triggers an early inflammatory response [60; 61]. Combined with local antigen presence, these findings create a favorable environment for a local immediate hypersensitivity response to food allergens in FIRE syndrome. Expanding upon Th2-mediated inflammation, sustained Th2 immune response to allergens involves an increase in proinflammatory cytokines such as IL-4, IL-13, and IL-5, with a subsequent increase in eosinophil count [37]. Eosinophil-derived IL-9 has been shown to display an increased expression in active EoE, stimulating esophageal mast cell accumulation and contributing to an altered epithelial barrier [62]. Notably, the number of mast cells significantly increases during active EoE compared to healthy individuals [39; 63]. Furthermore, the percentage of IgE-positive cells is increased in atopic compared to non-atopic EoE patients [63]. The infiltrated mast cells may be activated through various pathways and degranulate, releasing a variety of proinflammatory mediators [37; 64]. Importantly, mast cells are the main immune cell population in the musculars externa and therefore can affect esophageal motility upon activation, potentially leading to a transient esophageal motor dysfunction [34; 65]. This effect is partially due to their capacity to release a diverse range of mediators upon activation, including prostaglandandins, leukotrienes, and thromboxanes, that contribute to increased vascular permeability and smooth muscle contraction [37, 66]. This mechanism may be particularly relevant in FIRE syndrome, where symptoms such as pain, tightening, or pressure-like sensations occur immediately after food exposure, consistent with mast-cell-driven hypersensitivity and smooth muscle contraction. Given the high intensity and rapid onset of FIRE symptoms, it is plausible that local mast cell degranulation could contribute to this phenomenon, either by mediator release or neuroimmune interactions amplifying sensory hypersensitivity. [PERSON] et al. 's study demonstrated that increased esophageal mast cell density was strongly correlated with pain perception, whereas no significant association was observed between mast cell number and dysphagia [67]. The pain perception is linked to high mast cell numbers but not to eosinophil count. This was further supported by the findings of a clinical trial where anti-IL-5 therapy reduced eosinophilic infiltration in EoE but had no effect on esophageal pain, suggesting mast cells rather than eosinophils are the main drivers of pain perception and symptom severity [68]. While mast cell activation involvement in FIRE is a plausible contributor, it remains speculative and is not yet confirmed by dedicated studies. Local mast cell degranulation, followed by tryptase release, can increase the sensitivity of ion channels found on esophageal nociceptive C-fibers, such as transient receptor potential vanilloid 1 (TRPV1) and acid-sensing ion channels (ASICs) [69, 70].