Role of cellular immunity in cow's milk allergy: pathogenesis, tolerance induction, and beyond

Abstract

Food allergy is an aberrant immune-mediated reaction against harmless food substances, such as cow's milk proteins. Due to its very early introduction, cow's milk allergy is one of the earliest and most common food allergies. For this reason cow's milk allergy can be recognized as one of the first indications of an aberrant inflammatory response in early life. Classically, cow's milk allergy, as is true for most other allergies as well, is primarily associated with abnormal humoral immune responses, that is, elevation of specific immunoglobulin E levels. There is growing evidence indicating that cellular components of both innate and adaptive immunity play significant roles during the pathogenesis of cow's milk allergy. This is true for the initiation of the allergic phenotype (stimulation and skewing towards sensitization), development and outgrowth of the allergic disease. This review discusses findings pertaining to roles of cellular immunity in allergic inflammation, and tolerance induction against cow's milk proteins. In addition, a possible interaction between immune mechanisms underlying cow's milk allergy and other types of inflammation (infections and noncommunicable diseases) is discussed.

Figure 1

The cascade of allergic inflammation. Allergen's exposure to inflammatory DCs allows these cells to process and to present allergen-derived peptides to naïve CD4⁺ T cells. In the presence of IL-4 (from an unknown source), naïve CD4⁺ T cells differentiate into proallergic T_H2 cells. Concurrently, it appears that there is an impairment of T_Reg-cell frequency and/or activity; hence, no suppression is exerted on T_H2-cell activity. Subsequently, T_H2 cells will drive B cells, via cell contact as well as IL-4 and IL-13, to undergo immunoglobulin class-switch recombination, in which they eventually produce IgE. Along with the antibody production, B cells also secrete significant amount of κ and λ Ig-free light chains (Ig-fLCs). IgE and Ig-fLCs will then bind to mast cells and basophils, causing sensitization (not shown). Following subsequent exposure to allergen, cross-linking of surface-bound antibodies occurs (not shown), causing mast cells and basophils to degranulate and release their biologically active substances, including histamine, IL-4, and IL-5. Released IL-4 amplifies the differentiation of T_H2 and IgE-producing B cells, while released IL-5, also secreted by T_H2 cells, causes accumulation and activation of eosinophils in the affected tissues. Similarly, histamine activates epithelial or endothelial cells to release eotaxin that also attracts eosinophils into the tissues. Activated eosinophils release active substances, including major basic and eosinophilic cationic proteins that are toxic to the surrounding cells, contributing to further inflammation.