Epicutaneous sensitization in the development of food allergy: What is the evidence and how can this be prevented?

Abstract

There is increasing evidence regarding the importance of allergic sensitization through the skin. In this review, we provide an overview of the atopic march and immune mechanism underlying the sensitization and effector phase of food allergy. We present experimental models and human data that support the concept of epicutaneous sensitization and how this forms one half of the dual-allergen exposure hypothesis. We discuss specific important elements in the skin (FLG and other skin barrier gene mutations, Langerhans cells, type 2 innate lymphoid cells, IL-33, TSLP) that have important roles in the development of allergic responses as well as the body of evidence on environmental allergen exposure and how this can sensitize an individual. Given the link between skin barrier impairment, atopic dermatitis, food allergy, allergic asthma, and allergic rhinitis, it is logical that restoring the skin barrier and prevention or treating atopic dermatitis would have beneficial effects on prevention of related allergic diseases, particularly food allergy. We present the experimental and human studies that have evaluated this approach and discuss various factors which may influence the success of these approaches, such as the type of emollient chosen for the intervention, the role of managing skin inflammation, and differences between primary and secondary prevention of atopic dermatitis to achieve the desired outcome.

Keywords: atopic dermatitis; cutaneous sensitization; emollient; filaggrin gene; food allergy.

Figure 1:

Factors leading to skin barrier dysfunction: The skin is constantly exposed to environmental factors, both natural (eg, bacteria, viruses, fungi, food and aero allergens) and man-made (e.g., detergents, high pH creams and lotions). In those genetically predisposed to allergic disease (e.g., filaggrin, SPINK5, and loricrin mutations), these factors lead to skin barrier dysfunction, epicutaneous damage, and allergic sensitization.

Figure 2:

Pathways for skin barrier dysfunction and eczema leading to food allergy: Food allergy is manifested through the skin (1) the initial step towards food allergy is skin barrier impairment caused by environmental pollutants, detergents, infections, and genetics. (2) Skin barrier impairment leads to skin inflammation and clinical atopic dermatitis. (3) Exposure of allergens through skin that has an impaired barrier (dry) or has clinical atopic dermatitis leads to sensitization and food allergy.

Figure 3:

Dual-allergen Exposure: Increasing evidence suggests that early life allergen exposure through the skin causes T cell deviation towards a Th2 allergenic type and subsequent food allergy whereas early oral exposure causes T cell deviation towards tolerogenic Th1 and Treg subtypes (dual allergen exposure hypothesis).

Figure 4:

Mechanism of sensitization phase in allergic disease. During the allergic sensitization phase, in the setting of an impaired barrier, specific resident dendritic cell (DC) subsets capture allergens in the skin and transport the allergens to draining lymph nodes where they are processed and presented to naïve CD4+ T cells. Within the lymph nodes, the presence of IL-4 and IL-13 favors B cell isotype switching to specific IgE cells that differentiate into plasma cells and produce large amounts of allergen-specific IgE antibodies (sIgE). The sIgE bind to high-affinity FcεRI receptors on the surface of mast cells and basophils. During the sensitization phase, a memory pool of allergen-specific B cells and allergen-specific CD4 positive T helper 2 cells are generated.

Figure 5:

Mechanism of effector phase in allergic disease. During the effector, which follows the sensitization phase, subsequent encounters with a previously sensitized allergen leads to IgE-cross linking and activation of basophils and mast cells. Degranulation of mast cells and basophils leads to the release of preformed and de novo mediators which cause the symptoms of the immediate phase reaction as well as the subsequent late-phase reaction by activating memory allergen-specific Th2 cells.

Figure 6:

Effect of twice-daily EpiCeram® vs standard skin care for the first 6 months on skin prick test reactivity to food allergens at 12 months. Results were limited to intervention participants who were treated at least 5 times per week on average. Per protocol analyses revealed a significant reduction in food sensitization at 12 months in the treatment group (0%, 0 of 21) compared to the control group (19%, 7 of 36). Reproduced with permission from Lowe AJ, Leung DYM, Tang MLK, Su JC, Allen KJ. Ann Allergy Asthma Immunol. 2018 Feb;120(2):145–151.