Allergic sensitization can be induced via multiple physiologic routes in an adjuvant-dependent manner

Abstract

Background Oral exposure to food allergens may be limited in infancy and the initial site of antigen exposure likely plays an important role in food allergy induction. Objective To examine the impact of different routes of exposure using milk allergens, with and without adjuvant, on sensitization. Methods C3H/HeJ mice were repeatedly exposed to the milk allergen α-lactalbumin (ALA), with or without cholera toxin (CT). Sensitization routes used were intragastric, cutaneous, intranasal, and sublingual. Anaphylaxis severity was assessed by symptoms and body temperature in response to oral or systemic challenge. Antigen-specific serum antibodies were measured by ELISA. The mechanism of adjuvant activity of cutaneous CT was also determined. Results Sensitization to ALA as measured by allergen-specific IgE occurred by all routes of sensitization, and was maximal in response to cutaneous exposure. Sensitization was dependent on CT and did not occur to antigen alone by any route. Mucosal, but not cutaneous exposure, resulted in a robust allergen-specific IgA response. Anaphylaxis occurred in all sensitized groups when orally challenged with ALA. Topical CT induced migration of langerinneg dermal DCs to the lymph node, resulting in enhanced proliferation and Th2 cytokine production from responder T cells. Conclusions Sensitization can occur via all physiologic routes when adjuvant is present. The skin is a potent and likely important physiologic route of sensitization whereby adjuvant induces an efflux of antigen-bearing dermal DCs to the lymph node that generate a pro-allergic Th2 response.

Skin exposure promotes a Th2-dependent sensitization to peanut allergens

“…We demonstrated previously that mice can be sensitized to cow's milk allergens through the epicutaneous route, but only in the presence of exogenous adjuvant (19). To determine whether this adjuvant dependence also applies to the potent food allergen peanut, we exposed mice to crude protein extracts from peanut.…”

“…Sensitization to antigens after epicutaneous exposure has been shown previously to be dependent on additional factors, including skin damage (17), presence of inflammation (22), or use of exogenous adjuvants such as SEB (23) or cholera toxin (19). We hypothesized that peanut could be inducing "adjuvant-free" sensitization by providing inherent adjuvant activity.…”

“…Using purified Ara h 1 and Ara h 2, we examined the contribution of these allergens in mice sensitized to CPE. Mice exposed to peanut developed detectable IgE antibodies against both Ara h 1 and Ara h 2 (Supplemental Figure 4C), and basophil activation tests performed with whole blood from peanut-sensitized mice showed a similar threshold of reactivity to the 2 dompresence of adjuvant, which was needed to drive dermal DCs to the draining lymph node (19). Our previous studies indicate that skin exposure is not inherently sensitizing and that some form of adjuvant activity is needed to drive sensitization through the skin.…”

Emerging therapies for food allergy

“…Allergen-specific, Th2-deviated CD4 + T cells predominantly produce cytokines, such as IL-4, IL-5, IL-9, and IL-13, which promote IgE production, eosinophil proliferation, and trafficking of inflammatory cells to tissues. The predominant mechanism by which food allergy develops remains controversial, with some studies suggesting that primary sensitization through skin contact may be even more important than exposure via the gut (9). Active gastrointestinal tolerogenic mechanisms appear to be important in preventing food allergy in general, as children with genetic defects in generating regulatory T cells frequently have severe allergic disease (10,11).…”

Allergic reactions compared between BN and Wistar rats after oral exposure to ovalbumin

“…Still, it must be acknowledged that the natural route of feeding during the sensitization period was not taken into account (Dearman and Kimber, 2001). Clearly, food allergens can induce anaphylaxis via intra-gastric, sublingual, nasal, or cutaneous routes; nevertheless, oral exposure to food allergens occurs quite often, starting at the earliest stages of a life (Dunkin et al, 2011). Therefore, in the present study, we investigated the extent of allergic reactions compared between BN and Wistar rats following oral exposure to ovalbumin.…”