The Initiation of Th2 Immunity Towards Food Allergens

Abstract

In contrast with Th1 immune responses against pathogenic viruses and bacteria, the incipient events that generate Th2 responses remain less understood. One difficulty in the identification of universal operating principles stems from the diversity of entities against which cellular and molecular Th2 responses are produced. Such responses are launched against harmful macroscopic parasites and noxious substances, such as venoms, but also against largely innocuous allergens. This suggests that the established understanding about sense and recognition applied to Th1 responses may not be translatable to Th2 responses. This review will discuss processes and signals known to occur in Th2 responses, particularly in the context of food allergy. We propose that perturbations of homeostasis at barrier sites induced by external or internal subverters, which can activate or lower the threshold activation of the immune system, are the major requirement for allergic sensitization. Innate signals produced in the tissue under these conditions equip dendritic cells with a program that forms an adaptive Th2 response.

Keywords: IgE; Th2 immunity; alarmins; allergens; allergic disease; allergic sensitization; food allergy; initiation of allergy.

Figure 1

Converging pathways leading to Th2 sensitization. (A) Several triggers (external; e.g., CT, SEB, TS, or internal; e.g., skin barrier dysfunction) share the ability to subvert the microenvironment and produce an alarmin signature which converges on IL-12 inhibition on DCs and upregulation of Th2 polarizing co-stimulatory molecules. These activated DCs sample bystander allergens and migrate to secondary lymphoid tissue. (B) Activated DCs present allergen to cognate naïve CD4 T cells and provide co-stimulation resulting in Th2 differentiation. (C) Th2 cells activate allergen-specific B cells, leading to IgE class switching, plasma cell differentiation, and production of allergen-specific IgE.

Figure 2

External and internal subversion of the steady state can lead to food allergic sensitization. (A) Allergen exposure alone results in damage that is ‘not likely’ sufficient to cause food allergy. (B) Exposure to allergen in combination with a Th2-inducing external subverter results in damage that is ‘most likely’ sufficient to cause allergy. (C,D) Exposure to allergen in combination with an internal subverter that either 1 (increases basal level of damage) or 2 (decreases the threshold of Th2 activation) is ‘somewhat likely’ sufficient to cause allergy.