# Pollen-Food Allergy Syndrome: Allergens, Clinical Insights, Diagnostic and Therapeutic Challenges
## 4 PFAS Pathogenesis  
Briefly, the pathogenesis of PFAS, like that of other IgE-mediated allergic reactions, involves a complex interplay of immune mechanisms. It begins with sensitization, where allergen exposure, typically through inhalation or ingestion, leads antigen-presenting cells, such as dendritic cells, to process the allergen and present it to naive T-helper (Th) cells [65]. In allergic individuals, these Th cells differentiate into Th2 cells, which release cytokines like IL-4, IL-5, and IL-13. These cytokines promote the production of allergen-specific IgE antibodies by B cells. The IgE antibodies bind to receptors on mast cells and basophils, priming them for subsequent exposures. Upon re-exposure to the allergen, cross-linking of IgE on the surface of these cells triggers their degranulation, releasing histamine and other inflammatory mediators (Figure 1) [66]. Th2 cytokines might further amplify the allergic cascade by recruiting eosinophils, which exacerbate tissue inflammation and sustain hypersensitivity reactions [67]. This cascade of immune events demonstrates the centrality of Th2-driven responses in PFAS. However, the interaction between other immune cells and pathways adds further complexity. For example, basophils and mast cells play complementary roles, with basophils serving as a primary source of IL-4 during the sensitization phase [68]. Additionally, eosinophils, recruited through chemotactic signals such as eotaxin, release cytotoxic granules that damage epithelial barriers and exacerbate inflammation [67]. The chronic involvement of these cells may lead to tissue remodeling, potentially compounding the allergic response over time [69]. In the case of PFAS, this mechanism occurs in individuals previously sensitized to pollen who subsequently consume raw plant-based foods containing allergens that cross-react with the sensitizing pollen allergens [31]. For cross-reactivity to occur, a significant degree of similarity--typically more than 70%--is required between the primary protein sequences of the pollen allergens and those in the triggering food [70]. This degree of molecular homology is critical because IgE antibodies, which were initially generated in response to the pollen allergen, recognize and bind to similar epitopes on food proteins. These epitopes trigger the immune response, resulting in the characteristic symptoms of PFAS, which may range from mild oral itching to severe systemic reactions like anaphylaxis [44]. In addition to protein sequence similarity, the three-dimensional conformation of these proteins plays a pivotal role in cross-reactivity. Proteins with conserved structural motifs that resemble those of pollen allergens are more likely to bind IgE and activate immune cells. Advances in molecular modeling have revealed that even minor variations in protein folding or side-chain orientation can influence allergenicity, underscoring the complexity of immune recognition in PFAS [71]. Moreover, the stability of the allergenic proteins influences whether the cross-reactive epitopes remain intact during food processing or digestion, directly impacting the severity and type of allergic reaction [72]. Proteins that resist degradation by digestive enzymessuch as trypsin and pepsin are more likely to remain intact during gastrointestinal transit. These stable proteins can retain their allergenic potential, increasing the likelihood of interaction with immune cells in the gut-associated lymphoid tissue (GALT). For example, LTPs, known for their robust stability, are frequently implicated in severe PFAS cases [73]. Environmental factors and food processing methods can further modulate the allergenicity of these proteins. Heat treatment, for instance, can denature some proteins, reducing their allergenic potential, while others, like profilins, are highly heat-labile and lose their IgE-binding capacity when cooked [74].