Allergy and the Immunologic Basis of Atopic Disease

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 on 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 factors that 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 proteins with molecular weight of 10-70 kDa. Molecules <10 kDa do not bridge adjacent IgE antibody molecules on the surfaces of mast cells or basophils. Most molecules >70 kDa 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 skin and mucosal epithelial 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 can also be allergens and are most relevant with the increasing use of biologics in clinical practice; patients with cetuximab-induced anaphylaxis have IgE antibodies specific for galactose-α-1,3-galactose.

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 interleukin (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 skin-prick testing. The Th2 cytokines IL-4 and IL-13 play a key role in immunoglobulin isotype switching to IgE ( Fig. 166.1 ). 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. IL-9 is responsible for mucus production. 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, IL-33, and thymic stromal lymphopoietin (TSLP) secreted from epithelial cells on exposure to allergens and respiratory viruses contribute to Th2 response and eosinophilia.

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 (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 lesions of 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. Th17 and Th22 cells link the immune response to tissue inflammation; IL-17A and IL-17F and IL-22 are their respective prototype cytokines. Although both T-helper cell subsets play roles in immune defense to extracellular bacteria, IL-17 augments inflammation, whereas IL-22 plays a tissue-protective role. 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 proinflammatory cytokines to enhance inflammation and antimicrobial responses. In addition, 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. Fig. 166.2 depicts the complex cytokine cascades involving Th1, Th2, Th9, Th17, and Th22 cells.

T-regulatory (or regulatory T) cells (Tregs) 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 Th1, Th2, Th9, Th17, and Th22 phenotypes ( Fig. 166.3 ). Tregs express CD4 ⁺ CD25 ⁺ surface molecules and immunosuppressive cytokines such as IL-10 and transforming growth factor-β (TGF-β ₁ ). The forkhead box/winged-helix transcription factor gene FOXP3 is expressed specifically by CD4 ⁺ CD25 ⁺ Tregs and programs their development and function. Adoptive transfer of Tregs 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 Tregs. 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 Tregs. It is thought that CD4 ⁺ CD25 ⁺ Tregs 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 ⁺ Tregs and develop severe immune dysregulation, with polyendocrinopathy, food allergy, and high serum IgE levels (XLAAD/IPEX disease) (see Chapter 152 ). In addition to Treg cells, IL-10–secreting and allergen-specific Breg cells increase during allergen-specific immunotherapy and may play a role in allergen tolerance.