Sensitization to a food allergen through the unified airway
The first or new sensitization to food allergens may happen if they come by inhalation promoting food allergies, asthma, allergic rhinitis, atopic dermatitis, and systemic anaphylaxis development. Food allergic reactions by inhalation often occur in individuals already sensitized to the food, generally by ingestion. The recurrence, however, can appear due to de novo sensitization through inhalation. The dual-allergen exposure hypothesis postulates that early oral exposure to food allergens induces tolerance, whereas exposure at non-gastrointestinal sites, such as the skin or respiratory tract, results in food sensitization and allergy development [20; 21; 22]. The gut has a potent tolerogenic network, which consist of pro-tolerogenic cells and molecules due to the specific autonomous enteric nevrous system and mucosal immune system [23; 24]. The gut is a zone of allergen tolerance. On the whole, food allergy is often a series of allergic episodes, does not look like a typical atopic disease, and represents a known exception to the rule conceived by evolution.
More commonly reported inhaled food allergens are wheat flour, seafood (preferentially, crustaceans), soy, peanut, hen’s egg, and milk [25]. The exposure to food allergens may proceed at home, in schools, restaurants, grocery stores, commercial flights, and occupational environments. Inhalation of food allergen depends on its airborne presence. Food processing, such as boiling, steaming, or frying, can release significant quantities of food allergens and promote the inhalation route of sensitization [25]. However, the respiratory route appears not to be isolated and is combined with gastrointestinal and transcutaneous sensitization to food allergens, though the airway route in food allergies is still underestimated.
On the one hand, many food allergens are found in household dust [26; 27], and many food allergens causing occupational allergies act as primary sensitizers through inhalation, with no evidence of cross‐reactivity to other common inhalant allergen sources [14]. On the other hand, food sources contain food products (cereals, plants/vegetables/fruits/spices, seeds, herbal teas, mushrooms, seafood, and farm products), additives (colorants, thickening agents, sulfites, and enzymes), and food contaminants (mites, insects, fungi, and parasites) [28; 29]. These agents commonly represent proteins (>10 kDa) derived from food sources, which may operate as respiratory sensitizers through the unified airway [14].
Food allergens penetrate the body via the unified airway route, get into the nasal and lung submucosae, where the immune system responds to these allergens. Researchers demonstrated the peanut allergens triggered IL-33 and thymic stromal lymphopoietin (TSLP) synthesis in primary human nasal or bronchial epitheliocytes and stimulated maturation and migration of peanut-specific nasal/lung mDC-1 cells to draining lymph nodes. In addition, inhalational exposure to peanut and indoor dust induced peanut-specific Th2 cell differentiation and accumulation of Tfh cells in draining lymph nodes, which were associated with increased B cells numbers and peanut-specific IgE and IgG1 production [20].
In response to a food allergen (see Fig. 1), epitheliocytes produce alarmins (danger signal), IL-25, IL-33, and TSLP, which upregulate group 2 innate lymphoid (ILC2) cells, dendritic (DCs) cells, and type 2 helper T (Th2) cells. Pro-immunogenic neuropeptide neuromedin U promotes ILC2 cells [30; 31; 32]. Conversely, endogenous neuropeptide calcitonin-gene-related peptide (CGRP) is a critical negative regulator of ILC2 responses in vivo [33; 34]. The alarmins are essential stimulators of type 2 immunity, as they lead to the production of IL-5, IL-9, and IL-13, but they can participate in the IgE-independent pathway of allergic inflammation [32; 35]. Toll-like receptors (TLRs) related to pattern recognition receptors (PRRs) bind to pathogen-associated molecular (PAMP) patterns or damage-associated molecular (DAMP) patterns, and after signaling, promote the release of alarmins, synthesis of cytokines, and development of pyroptosis, creating the link between adaptive and innate immunity.