**1. Allergic mechanism**

An allergen is defined as a normally harmless substance, found in the environment or food, which can produce asthma, fever, eczema, or gastrointestinal discomfort upon contact with

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

a previously sensitized person. An allergy is commonly defined as an immediate or type I hypersensitivity reaction where symptoms appear rapidly and are caused by exposure to exogenous macromolecules known as antigens or allergens. The hypersensitivity reaction has two phases: sensitization, when the subject is first exposed to the antigen, and the subsequent reaction, when the subject is again exposed to the antigen [1]. **The first sensitization** of a body begins with the first contact with an antigen, which induces an allergy. The allergen pene‐ trates the airways of the body or other tissues and is found by antigen‐presenting cells (APCs) such as macrophages and/or dendritic cells, which encyst and proteolytically cleave the for‐ eign substance. The peptide fragments generated, known as T cell epitopes, are directed to the outer membrane of the APC by the major histocompatibility class II (MHC II) complex in the form of a complex peptide‐MHC class II [2]. The T‐helper lymphocytes (Th1 and/or Th2) recognize these exposed epitopes and together with B cells initiate the immune response. The activation clones specific for the antigen, Th2 cells, are essential for the development of atopic diseases, because these cells activated by contact with APCs produce cytokines and interleukins 4 (IL‐4) and 5 (IL‐5). These interleukins act as signals, among other functions, for the biosynthesis of immunoglobulin E (IgE) by B lymphocytes. An immunoglobulin, IgE, binds to the surface of mast cells and basophils by FcЄRI receptors. A subsequent exposure to the same antigen, **the second sensitization**, leads to a substantial allergic response. The antigen‐specific segments (IgE epitopes) are cross‐linked to the IgE bound to the mast and/or basophil cells after interaction with the allergen, activating intracellular messengers, and the subsequent release of cellular mediators such as histamine and prostaglandins, which in turn induce physiological and anatomical changes that trigger the allergic symptoms of immedi‐ ate hypersensitivity [3, 4].

IgE antibodies generated in response to a specific allergen interact with this allergen and trigger a series of intracellular reactions leading to the release of histamine and other inflam‐ matory mediators. Histamine plays a key role in the allergic response. The release of hista‐ mine causes the smooth muscles of the gastrointestinal and respiratory tracts to contract, stimulates nerves, and dilates blood vessels [5, 6]. These effects of histamine include, among other clinical manifestations, erythema, flushing, nasal congestion, pruritus, headache, hypo‐ tension, tachycardia, and bronchoconstriction [5]. There are four main subtypes of histamine receptors: H1, H2, H3, and H4. These receptors are G‐protein‐coupled receptors that transfer extracellular signals via G proteins, acting as intermediates between cell‐surface receptors and second intracellular messengers [6, 7]. The H1 receptor is the main mediator subtype of the allergic response causing allergic symptoms. In addition to its role in the immediate aller‐ gic response, histamine contributes to the late allergic response by stimulating the production of cell‐adhesion molecules, class II antigens, and cytokines [6].

#### **2. Tolerance induction**

Immune tolerance can develop against any substance, and multiple mechanisms are involved. The lack of response of immune tolerance can lead to the development of various diseases such as:

• allergies

a previously sensitized person. An allergy is commonly defined as an immediate or type I hypersensitivity reaction where symptoms appear rapidly and are caused by exposure to exogenous macromolecules known as antigens or allergens. The hypersensitivity reaction has two phases: sensitization, when the subject is first exposed to the antigen, and the subsequent reaction, when the subject is again exposed to the antigen [1]. **The first sensitization** of a body begins with the first contact with an antigen, which induces an allergy. The allergen pene‐ trates the airways of the body or other tissues and is found by antigen‐presenting cells (APCs) such as macrophages and/or dendritic cells, which encyst and proteolytically cleave the for‐ eign substance. The peptide fragments generated, known as T cell epitopes, are directed to the outer membrane of the APC by the major histocompatibility class II (MHC II) complex in the form of a complex peptide‐MHC class II [2]. The T‐helper lymphocytes (Th1 and/or Th2) recognize these exposed epitopes and together with B cells initiate the immune response. The activation clones specific for the antigen, Th2 cells, are essential for the development of atopic diseases, because these cells activated by contact with APCs produce cytokines and interleukins 4 (IL‐4) and 5 (IL‐5). These interleukins act as signals, among other functions, for the biosynthesis of immunoglobulin E (IgE) by B lymphocytes. An immunoglobulin, IgE, binds to the surface of mast cells and basophils by FcЄRI receptors. A subsequent exposure to the same antigen, **the second sensitization**, leads to a substantial allergic response. The antigen‐specific segments (IgE epitopes) are cross‐linked to the IgE bound to the mast and/or basophil cells after interaction with the allergen, activating intracellular messengers, and the subsequent release of cellular mediators such as histamine and prostaglandins, which in turn induce physiological and anatomical changes that trigger the allergic symptoms of immedi‐

IgE antibodies generated in response to a specific allergen interact with this allergen and trigger a series of intracellular reactions leading to the release of histamine and other inflam‐ matory mediators. Histamine plays a key role in the allergic response. The release of hista‐ mine causes the smooth muscles of the gastrointestinal and respiratory tracts to contract, stimulates nerves, and dilates blood vessels [5, 6]. These effects of histamine include, among other clinical manifestations, erythema, flushing, nasal congestion, pruritus, headache, hypo‐ tension, tachycardia, and bronchoconstriction [5]. There are four main subtypes of histamine receptors: H1, H2, H3, and H4. These receptors are G‐protein‐coupled receptors that transfer extracellular signals via G proteins, acting as intermediates between cell‐surface receptors and second intracellular messengers [6, 7]. The H1 receptor is the main mediator subtype of the allergic response causing allergic symptoms. In addition to its role in the immediate aller‐ gic response, histamine contributes to the late allergic response by stimulating the production

Immune tolerance can develop against any substance, and multiple mechanisms are involved. The lack of response of immune tolerance can lead to the development of various diseases

of cell‐adhesion molecules, class II antigens, and cytokines [6].

ate hypersensitivity [3, 4].

68 Allergen

**2. Tolerance induction**

such as:


The generation of regulatory T (Treg) cells initiates tolerance. Peripheral tolerance is initi‐ ated by the secretion of IL‐10 and TGF‐β by allergen‐specific Treg cells during continu‐ ous exposure. The induction of allergen‐specific tolerance is associated with an increase in FOXP3+CD25+CD3+ cells in the nasal mucosa [9]. Atopic individuals have a reduced capacity to proliferate CD25+ and CD4 Treg cells, which indicates the mechanisms of failure of toler‐ ance allergens. A clonal shift occurs during tolerance fromTh1, Th2 to Th1 (**Table 1**). B cells are stimulated by the action of IL‐10 to produce IgG (particularly IgG4) and to suppress IgE production, which prevents the development of allergic symptoms in the tolerogenic indi‐ vidual [9–11] (**Table 2**).

If an allergy is not properly diagnosed and treated, it tends to progress to a severe and chronic debilitating disease.

Many treatments have been developed to circumvent the symptoms of allergic diseases, most of which use histamine inhibitors that mask the symptoms of the allergy. Allergen‐specific immunotherapy (ASIT), however, is the only long‐term preventive and long‐term treatment for allergic diseases. ASIT involves the administration of a specific allergen, so it induces a specific immunological tolerance to the allergen. ASIT has been used for more than 100 years, but the mechanism of action has only recently been resolved [12].


**Table 1.** Molecules with effector functions in allergen tolerance.


**Table 2.** Roles of cells in allergen tolerance.

In this chapter, we will describe the most common allergy treatments using antihistamines and emphasize the new methodologies of allergen‐specific immunotherapy (ASIT) as a pro‐ phylactic treatment and IgE blockade as a therapeutic treatment.
