Factors Influencing the Allergenicity and Adjuvanticity of Allergens

Stephan Deifl; Barbara Bohle


Immunotherapy. 2011;3(7):881-893. 

In This Article

Type I Allergy

During the past decades, allergic diseases have tremendously increased and today, IgE-mediated hypersensitivity reactions of the immune system affect more than 25% of the population in industrialized countries. Atopy-prone individuals develop IgE antibodies specific for allergens. These soluble allergen-specific IgE antibodies bind to the high-affinity Fc-ε receptor (FcεRI) expressed on the surface of effector cells, such as basophils and mast cells. Upon repeated allergen encounter, surface-bound IgE antibodies on sensitized effector cells are cross-linked, resulting in activation and immediate mediator release. Among several inflammatory mediators, histamine is the main cause of the early clinical symptoms characteristic for IgE-mediated allergic manifestations (e.g., rhinitis, conjunctivitis or airway obstruction).

The development of IgE-mediated responses to allergens requires a series of molecular and cellular interactions that involve both the innate and the adaptive immune system (Figure 1). Allergens have to pass through the epithelial barriers in the respiratory and gastrointestinal tract or through the skin. They may also pass the conjunctival epithelium, as recently demonstrated by light and electron microscopy.[1] Then, allergens are internalized and processed by antigen-presenting cells (APCs). Currently, dendritic cells (DC) are considered to be the most potent APCs that act as a linker of innate and adaptive immune responses. Immature DC efficiently take up and process antigens. They also express a variety of pattern-recognition receptors (PRRs) on their surface that recognize conserved pathogen-associated molecular patterns, which in turn serve as danger signals for the immune system. Upon activation via PRRs, DCs produce cytokines and upregulate the surface expression of MHC class I and II molecules and costimulatory molecules such as CD40, CD80 and CD86. Activated DCs migrate to lymph nodes where they present epitopes contained in peptides bound to MHC class II molecules to naive CD4+ T lymphocytes. Selected T helper cells with the T-cell receptor specific for the presented peptides (signal 1) are activated. Signal 2 is provided by costimulatory molecules on the surface of DC and necessary for full T-cell activation leading to proliferation (i.e., clonal expansion) and cytokine production. Certain cytokines (signal 3) present in the microenvironment during T-cell priming determine the differentiation of naive T cells into different effector cell subsets. Th2 cells represent one subset of allergen-specific CD4+ T cells that synthesize high amounts of the cytokines IL-4, IL-13 and IL-5, but little or no IFN-γ. Other subsets of CD4+ T cells are Th1 cells that produce high levels of the signature cytokine IFN-γ, a potent antagonist of IL-4; and CD4+ Treg cells. The latter actively suppress effector T cells either by cell–cell contact or by the immunosuppressive cytokines IL-10 and TGF-β.[2,3]

Figure 1.

Development of IgE-mediated responses to allergens.
B: B cell; Ba: Basophil; DC: Dendritic cell; T: CD4+ T cell.

In atopic individuals, the inadequate balance between allergen-specific Th2 cells by Th1 and Treg cells promotes an aberrant Th2-dominated response to allergens. Allergen-specific Th2 cells have been identified in the peripheral blood and nasal mucosa of patients suffering from allergic rhinitis, as well as in the bronchial alveolar lavage fluid of allergic individuals with asthma and in skin lesions of allergic patients with atopic dermatitis.[4–7] The differentiation of Th2 cells is driven by the presence of IL-4 during their priming.[8] IL-4 is also an important growth factor for Th2 cells. Both IL-4 and IL-13 are important switch factors for B cells to produce IgE antibodies. Upon interaction with allergen-specific Th2 cells, B lymphocytes with corresponding allergen-specific B-cell receptors develop into plasma cells and produce allergen-specific IgE antibodies. As B cells express the low-affinity receptor for IgE (FcεRII, CD23) on their surface, they can act as APCs that effectively internalize allergen–IgE complexes by receptor-mediated uptake.[9] The interaction between B and T lymphocytes again promotes the induction of Th2 responses.[10,11] In addition to their pivotal role for IgE production that mediates the early inflammatory response in allergy, allergen-specific Th2 cells are also involved in late-phase responses.[12,13] Late-phase reactions are characterized by recruitment, activation and tissue infiltration of T lymphocytes, eosinophils, basophils and neutrophils. The important role of allergen-specific Th2 cells in late-phase responses was demonstrated by the observation that intradermal administration of short, non-IgE-binding T-cell-activating peptides derived from the major cat allergen Fel d 1 elicited late asthmatic responses in cat-allergic patients.[14] Thereby, it was also demonstrated that T-cell-dependent late-phase reactions may even occur in the absence of an early IgE/mast cell-dependent response.[15] In summary, allergen-specific Th2 cells play a fundamental role in the induction and maintenance of IgE-mediated allergy. Recently, new subsets of Th cells, such as Th17 and Th9 cells, have been reported to influence airway hypersensitivity reactions and asthma in humans.[16,17] These subsets may play a role in the chronic phase of allergic inflammation and tissue remodelling.