Allergens

Allergens are almost always proteins, but not all proteins are allergens. For a protein antigen to display allergenic activity, it must induce IgE production, which must lead to a type 1 hypersensitivity response upon subsequent exposure to the same protein. Biochemical properties of the allergen, stimulating factors of the innate immune response around the allergen substances at the time of exposure, stability of the allergen in the tissues, digestive system, skin, or mucosa, and the dose and time of stay in lymphatic organs during the interaction with the immune system are all factors hat may cause an antigen to become an allergen. This is distinguished from general antigen responses, which induce a state of immune responsiveness without associated IgE production.

Most allergens are usually proteins of 10-70 kd molecular weight; molecules < 10 kd do not bridge adjacent IgE antibody molecules on the surfaces of mast cells or basophils; most molecules > 70 kd do not pass through mucosal surfaces, a feature needed to reach antigen-presenting cells (APCs) for stimulation of the immune system. Allergens frequently contain proteases, which promote barrier dysfunction and increase allergen penetration into host tissues. Low molecular weight moieties such as drugs can become allergens by reacting with serum proteins or cell membrane proteins to be recognized by the immune system. Carbohydrate structures have also been identified as allergens. This finding is most relevant with the increasing use of biologics in clinical practice; patients with cetuximab-induced anaphylaxis have IgE antibodies in specific for galactose-α-l,3-galactose (Chapter 146).

T Cells

Everyone is exposed to potential allergens. Atopic individuals respond to allergen exposure with rapid expansion of T helper type 2 (Th2) cells that secrete cytokines, such as interleukins IL-4, IL-5, and IL-13, favoring IgE synthesis and eosinophilia. Allergen-specific IgE antibodies associated with atopic response are detectable by serum testing or positive immediate reactions to allergen extracts on prick skin testing (Chapter 135). The Th2 cytokines IL-4 and IL-13 play a key role in immunoglobulin isotype switching to IgE (Fig. 134-1). IL-5 and IL-9 are important in differentiation and development of eosinophils. The combination of IL-3, IL-4, and IL-9 contributes to mast cell activation. Th2 cytokines are important effector molecules in the pathogenesis of asthma and allergic diseases; acute allergic reactions are characterized by infiltration of Th2 cells into affected tissues. In addition, IL-25 and IL-33 contribute to Th2 response and eosinophilia.

Figure 134-1 Role of Th2 cytokines in allergic cascade. DC, dendritic cell; EOS, eosinophil; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; Th2, T helper type 2 cell.

A fraction of the immune response to allergen results in proliferation of T helper type 1 (Th1) cells. Th1 cells are typically involved in the eradication of intracellular organisms, such as mycobacteria, because of the ability of Th1 cytokines to activate phagocytes and promote the production of opsonizing and complement-fixing antibodies. The Th1 component of allergen-specific immune response contributes to chronicity and the effector phase in allergic disease. Activation and apoptosis of epithelial cells induced by Th1 cell–secreted interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and Fas-ligand constitute an essential pathogenetic event for the formation of eczematous lesions in atopic dermatitis and bronchial epithelial cell shedding in asthma.

Chronic allergic reactions are characterized by infiltration of Th1 and Th17 cells. This is important because Th1 cytokines such as IFN-γ can potentiate the function of allergic inflammatory effector cells such as eosinophils and thereby contribute to disease severity. Cytokines in the IL-17 family act on multiple cell types, including epithelial cells and APCs, to cause the release of chemokines, antimicrobial peptides, and pro-inflammatory cytokines to enhance inflammation and antimicrobial responses. In addition, recently identified Th9 cells produce IL-9 but not other typical Th1, Th2 and Th17 cytokines and constitute a distinct population of effector T cells that promotes tissue inflammation. Figure 134-2 depicts the complex cytokine cascades involving Th1, Th2, Th9, and Th17 cells.

Figure 134-2 Effector T-cell subsets. Following antigen presentation by dendritic cells (DCs), naïve T cells differentiate into Th1, Th2, Th9, and Th17 effector subsets. Their differentiation requires cytokines and other cofactors that are released from dendritic cells and also expressed in the micromilieu. T-cell activation in the presence of interleukin-4 (IL-4) enhances differentiation and clonal expansion of Th2 cells, perpetuating the allergic response. IFN-γ, interferon-gamma; TGF-β, transforming growth factor-beta.

(From Akdis CA, Adkis M: Mechanisms and treatment of allergic disease in the big picture of regulatory T cells, J Allergy Clin Immunol 123:735–746, 2009.)

T regulatory (Treg) cells are a subset of T cells thought to play a critical role in expression of allergic and autoimmune diseases. These cells have the ability to suppress effector T cells of either the Th1 or Th2 phenotypes (Fig. 134-3). Treg cells express CD4⁺CD25⁺ surface molecules and immunosuppressive cytokines such as IL-10 and transforming growth factor-β (TGF-β1). The forkhead box/winged-helix transcription factor gene FOXP3 is expressed specifically by CD4⁺CD25⁺ Treg cells and programs their development and function. Adoptive transfer of Treg cells inhibits the development of airway eosinophilia and protects against airway hyperreactivity in animal models of asthma. T cell response to allergens in healthy individuals shows a wide range, from no detectable response to involvement of active peripheral tolerance mechanisms mediated by different subsets of Treg cells. Individuals who are not allergic even though they are exposed to high doses of allergens, such as beekeepers and cat owners, show a detectable allergen-specific IgG4 response accompanied by IL-10–producing Treg cells. It is thought that CD4⁺CD25⁺ Treg cells play an important role in mitigating the allergic immune response and that the lack of such cells may predispose to the development of allergic diseases. Patients with mutations in the human FOXP3 gene lack CD4⁺CD25⁺ Treg cells and develop severe immune dysregulation, with polyendocrinopathy, food allergy, and high serum IgE levels (XLAAD/IPEX disease) (Chapter 120).

Figure 134-3 FoxP3⁺ CD4⁺CD25⁺ and Tr1 cells contribute to the control of allergen-specific immune responses in several major ways: Suppression of dendritic cells that support the generation of effector T-cells; suppression of Th1, Th2, and Th17 cells; suppression of allergen-specific immunoglobulin (Ig) E, and induction of IgG4 and/or IgA; suppression of mast cells, basophils, and eosinophils; interaction with resident tissue cells and remodeling, and suppression of effector T-cell migration to tissues. IL-10, interleukin 10.

(From Akdis CA, Adkis M: Mechanisms and treatment of allergic disease in the big picture of regulatory T cells, J Allergy Clin Immunol 123:735–746, 2009.)

Antigen-Presenting Cells

Dendritic cells, Langerhans cells, monocytes, and macrophages have the ability to present allergens to T cells and thereby modulate allergic inflammation by controlling the type of T-cell development. Antigen-presenting cells are a heterogeneous group of cells that share the property of antigen presentation in the context of the major histocompatibility complex (MHC) and are found primarily in lymphoid organs and the skin. Dendritic cells (DCs) and Langerhans cells are unique in their ability to prime naïve T cells and are responsible for the primary immune response, or the sensitization phase of allergy. Monocytes and macrophages are thought to contribute to activating memory T-cell responses upon re-exposure to allergen, which characterizes the elicitation phase of allergy.