The oral mucosa or mucosal lining consists of primarily non-keratinized stratified squamous epithelia and a highly vascularized connective tissue called the lamina propria, which underlies the epithelia [1]. The oral mucosa is an immunocompetent site, whose function is primarily tolerogenic [1,2,3]. It lines the inside of the mouth and therefore acts as a physical barrier; nevertheless, it also contains immune cells that help maintain mucosal homeostasis [1]. Therefore, an intact and fully functional oral mucosa is crucial to prevent immune reactions to innocuous environmental antigens [4].

In several allergic and autoimmune diseases, the oral mucosa has been proven to undergo a remodeling process. This remodeling is characterized by a leaky epithelial barrier, a fibrotic lamina propria, the release of inflammatory mediators, and the recruitment of immune infiltrate [5,6,7].

The interaction between epithelial and immune cells at the mucosal linings has been proven to be critical in the onset and maintenance of allergic inflammation [5]. Therefore, an intact and fully functional mucosal barrier is considered crucial in the maintenance of mucosal homeostasis, as it protects the host immune system from the exposure to allergenic molecules and noxious environmental triggers [21]. The oral mucosa is the first immune tissue that encounters allergens upon ingestion of food. Oral exposure to allergens is complex in terms of immunological effects. In the relatively short time that food proteins are in the mouth, they should be bio-accessible. Therefore, the bio-accessibility of allergens at this stage may be a determinant for sensitization [45]. The continuous exposure of the oral mucosa to environmental triggers (antigens, allergens, or contaminants) induces a remodeling process in the oral epithelial barrier. This remodeling is maintained over time. An impaired oral mucosal barrier can therefore facilitate allergen access. Additionally, the damaged epithelium secretes the alarmins IL-25, IL-33, and TSLP. This triggers a local inflammatory immune response characterized by increased expression of pro-inflammatory cytokines and higher numbers of immune cells being recruited to the oral mucosa [5]. The chronic exposure to the allergen and its access to the mucosa-associated immune system together with the sustained local inflammation is reflected systemically, e.g., by increased IL-33 plasma levels [5,46]. This results in a positive feedback loop promoting further remodeling and inflammatory events in an otherwise pro-tolerogenic environment.

Food allergy is defined as “an adverse health effect resulting from a specific immune response that occurs reproducibly on exposure to a particular food” [47] that is causing a growing clinical problem. IgE-mediated reactions usually occur within two hours (they can even occur after few minutes) of ingestion of food and affect the skin, gastrointestinal tract, respiratory tract, and, less frequently, the cardiovascular system. In the most severe cases of anaphylaxis, multiple organ systems are involved and may include cardiovascular collapse.

It is currently not understood why some people develop allergic sensitization to foods while most people are immunologically tolerant, but the evidence suggests that environmental factors are important. The increased exposure to biological and chemical air pollutants such as protease enzymes, tobacco, or particulate matter (the so called exposome) has been proven responsible for disrupting the integrity of the epithelial barrier by degrading the intercellular junctions and triggering epithelial alarmin release [48]. The epithelial disruption leads to Th2 immune responses responsible for allergy development [49,50,51]. The “barrier regulation” hypothesis [52] postulates that allergic sensitization begins with the damage of the epithelial barrier [48,53]. Individuals with food allergies have their barrier permeability increased [54,55,56]. Thus, barrier impairment may itself lead to a predisposition toward atopy [57].

Moreover, the route of exposure is another crucial factor in food allergy. Food allergens brought in contact by non-oral routes contribute to allergic sensitization. In fact, epidemiological studies in humans indicate that non-oral contact with food allergens is correlated with the risk of a child developing food allergy [58,59,60]. In addition, symptomatic food allergy is often observed when a child eats the allergenic food for the first time, which is consistent with a previous sensitization phenomenon by non-oral routes [31]. Although there is growing evidence to support a disrupted and inflamed skin barrier as being responsible for the development of food sensitization [61], results from a large randomized controlled trial for the prevention of food allergy were negative [62]. The BEEP (Barrier Enhancement for Eczema Prevention) evaluated whether applying petrolatum-based oils or moisturizers from the first few weeks of life could prevent atopic dermatitis and food allergy and, on the contrary, found an increased rate of infections and a trend toward increased food allergy in the intervention group [62,63], in accordance with the PreventADALL trial on atopic dermatitis [63]. The role of epicutaneous sensitization in the development of food allergy has been extensively reviewed recently [57]. Regarding molecular mechanisms, allergic sensitization is thought to require the activity of T cells that express Th2 cytokines, such as IL-4 and IL-13. However, the exact nature of the T cell support required for the allergen-specific B cells to turn into the IgE-producing plasma cells in humans has not been described yet. Similarly, it is not clear to what extent the change to IgE class occurs in various tissues of the body. In addition, other cell types, such as tissue-resident mast cells, secrete IL-4, IL-13, and other cytokines that can influence the differentiation of B cells [64]. High titers of allergen specific IgE antibodies of high affinity are often detected in patients with symptomatic allergy. These antibodies bind to FcεRI in tissue-resident mast cells and circulating basophils, where they are involved in early or immediate hypersensitivity responses when interacting with allergens. It has also been reported that allergen-specific IgE may contribute to the pathogenesis of allergies by facilitating antigen presentation and epitope spread by means of the uptake of antigen–IgE complexes by the low-affinity IgE receptor, CD23, present on DCs, B lymphocytes, and other APCs [65,66,67,68]. IgE can also help transport the antigen from the lumen via CD23 receptors on the surface of epithelial cells, as it has been shown in the human gut, in cultures of human respiratory epithelial cells [69], and in a mouse model of allergy [70].

In the case of profilin sensitization, the oral mucosa has been proven to be altered and is associated with disease progression [71,72,73,74,75,76]. Profilin is a pollen aeroallergen that normally plays a limited role as a food allergen because it is easily degraded by proteases and acidic conditions. However, it can sensitize some pollen allergic individuals in areas of high allergen exposure. In the study by Rosace et al. [5], grass pollen allergic patients from overexposed areas in Spain were subjected to an oral challenge with profilin. The observed reactions ranged from local reactions such as oral allergy syndrome (OAS), angioedema, and oral pruritus, to severe systemic reactions such as urticaria and asthma. The patients that were allergic to profilin presented a progressive oral mucosal remodeling, characterized by decreased expression of TJ (claudin-1 and occluding) and AJ (E-cadherin) proteins, which led to a leaky epithelial barrier, increased angiogenesis and acanthosis, and augmented collagen deposition in the lamina propria. These processes have been previously associated with mucosal remodeling [77,78,79] and are comparable with those described from patients with other inflammatory pathologies [80,81]. In addition, an increased IL-33 expression was also observed in the severe allergic patients, i.e., those orally sensitized to profilin with a clinical history of severe allergic reactions. The epithelial damage might be associated with the IL-33–dependent ILC2 population located in the mucosal epithelium [82,83,84]. As profilin is present in all vegetables, it would contribute to sustaining the inflammatory allergic response, thereby causing allergic reactions to food [85]. This suggests that oral epithelial remodeling could be a key process for the acquisition of a severe allergic phenotype in patients with profilin-mediated food allergy.

In addition, the bio-accessibility of allergens at the oral cavity may be key to induce oral remodeling and allergic reactions. Allergen bio-accessibility may be modulated by the composition, volume, and pH of saliva [45]. Koppelman et al. [45] investigated the release of peanut allergens from lightly roasted peanut flour in the saliva in different conditions. The allergens Ara h2 and Ara h6, which are the most potent peanut allergens [86,87,88], were rapidly released from the food matrix, while Ara h1 and Ara h3 were poorly released. Therefore, Ara h2 and Ara h6 may be the first peanut allergens that individuals are exposed to upon ingesting lightly roasted peanut flour and may trigger immune responses in the oral mucosa. It remains to be determined whether this is also the case for other peanut-containing foods. Their early release provides them with the unique opportunity to interact with the oral mucosal immune system, which, in the case of accidental ingestion of hidden peanut allergens, can provoke life-threatening anaphylactic reactions in peanut-allergic patients [89,90,91].