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.