Types of allergy
According to WAO-EAACI consensus [5, 6], “hypersensitivity” dominates in the definition of allergy: allergy is a hypersensitivity reaction initiated by immunological mechanisms. EAACI also gives the following definition [5]: hypersensitivity causes objectively reproducible symptoms or signs that develop after exposure to a specific stimulus in doses to which normal subjects are tolerant. In these definitions, allergy is nominated as hypersensitivity, which is inaccurate because hypersensitivity is the first stage of an allergic reaction that ends with the release of mediators from the cells. They can be detected not only in vitro after incubation of sensitized basophils with allergen, but also in vivo even without allergy clinic signs [7, 8, 9]. Released mediators nonspecifically involve other leukocytes, which is usually called the “late phase” of the reaction. However, this is the initial stage of hyperreactivity, i.e. the second stage of allergy, in which all local cells and tissues are involved, which ultimately causes clinical symptoms (Fig. 2). We can assume that allergy is an increased response of a genetically predisposed organism to low doses of allergens (immune) or any pathogens – substances and physical factors (nonspecific) that do not cause such a reaction in the vast majority (≈85% or more) of healthy people.
Therefore, allergy includes two types of reactions that develop in succession in two stages – hypersensitivity , which is realized at the cellular-molecular level, ending with the release of mediators, and hyperreactivity , leading to the development of a local (hyperemia, edema, etc.) and general reaction involving various cells and tissue structures (Fig. 2).
Specific immune allergy develops as a result of an adaptive immune response with the formation of IgE, non-IgE antibodies and immune T and B lymphocytes (Fig. 3). EAACI divides IgE-dependent reactions into atopic and non-atopic. Atopy , as defined by EAACI [6], is a personal or familial tendency to produce IgE antibodies in response to low doses of allergens, usually proteins, and to develop typical symptoms such as asthma, rhinoconjunctivitis or eczema/dermatitis. However, there are other mechanisms of atopy: inducing effects of physical exercise in some patients, detection of nonspecific bronchial hyperreactivity in patients with allergic asthma, impaired skin barrier function in atopic patients, genetically determined dysfunction of the autonomic regulation of body systems – increased cholinergic reactivity and α-adrenergic reactivity and decreased β-adrenoreactivity. Therefore, in atopy, along with IgE antibodies, there is nonspecific hypersensitivity and hyperreactivity.
In addition, granulocytes (neutrophils, etc.) and even platelets can participate in IgE-mediated reactions. Atopic neutrophils have FcεRI [10], FcεRII (CD23), and galectin-3 receptors [11]. They are also present on all leukocytes and platelets that bind IgE and can interact with allergens (Fig. 3).
Other types of non-IgE allergy and, accordingly, immune hypersensitivity are carried out by IgG, possibly IgM and IgA antibodies with the participation of granulocytes, as well as immune T and B lymphocytes (see Fig. 3). Based on these types of hypersensitivity and subsequent hyperreactivity, immediate allergic reactions arise (cytotoxic, immunocomplex reactions), as well as delayed type allergy mediated by immune T cells, which includes 4 subtypes of hypersensitivity [4]. However, each of these subtypes of allergy is accompanied by hyperreactivity with clinical signs. At the same time, hypersensitivity, i.e. sensitization of cells, determined in vitro , is not called allergy, and in vivo with low doses of allergens it can occur without clinical manifestations [8, 9].
Nonspecific immune allergy (Fig. 2) is realized after nonspecific activation by pathogens of humoral factors and cells of innate and adaptive immunity. Often it is dose-dependent and is observed only at high doses of pathogen. Its example is non-immune complement activation via the alternative or lectin pathway with the release of anaphylatoxins and clinical presentation of anaphylaxis (shock). It can occur after intravenous administration of more than 50-100 ml of solutions of drugs or blood substitutes. Activation of lymphocytes by mitogens and superantigens, degranulation of basophils, eosinophils and neutrophils under the influence of nonspecific agents and physical factors (cold, heat, vibration, sunlight, physical activity) can induce nonspecific hypersensitivity, leading to hyperreactivity and the development of allergic diseases.
Nonspecific non-immune allergy (Fig. 3) is an increased reaction of non-immune cells to the action of a pathogen to which there is hypersensitivity, which causes the release of mediators and cytokines from them. They engage other cells in response and induce hyperreactivity, which leads to clinical symptoms of allergy.
Hypersensitivity is an increased reaction of cells or humoral systems of a predisposed organism to an allergen or nonspecific pathogen that act on cell receptors or key molecules and cause the release of intracellular products – cytokines, mediators, enzymes, or induce cascade activation of humoral systems (for example, complement). The resulting hypersensitivity products activate other cells and tissues, involving them in the reaction, which leads to the development of hyperreactivity reaction of tissues, mucous membranes, smooth muscles, nervous and endocrine systems.
Both immune and non-immune hypersensitivity depend on the number and affinity of cell receptors interacting with a particular pathogen, and the activity of structures that receive signals of this interaction and lead to the release of mediators, cytokines, enzymes from cells, or to cascade activation of humoral factors of the immune and neuroendocrine systems.
Hyperreactivity is an increased response of various cells, systems and organs of the body to mediators and cytokines released during the hypersensitivity reaction and causing clinical symptoms or signs to low or high doses of the pathogen that do not cause such a reaction in most people. It is always nonspecific but can differ in induced clinical syndromes when it develops after a specific immune or non-immune hypersensitivity due to differences in the spectrum of mediators. Hyperreactivity as body’s aggregate response to a hypersensitivity reaction depends on different systems, cells, humoral factors, which are nonspecifically involved in a pathologically increased response accompanied by damage to cells, tissues and organs.
Using skin tests with an allergen, it is possible to determine the minimum dose of an allergen that causes allergic skin reaction, which includes both hypersensitivity of basophils and hyperreactivity of cells and structures of skin (blood vessels, epithelium, etc.) to mediators released by them. However, the assessment of skin tests for an allergen is carried out according to the degree of hyperreactivity (edema, hyperemia).
Bronchial hyperreactivity can be inhibited using β2receptor agonists or glucocorticosteroids. However, their hypersensitivity persists, which is detected after the abolition of these drugs.
Nonspecific hyperreactivity after nonspecific hypersensitivity, as well as after specific allergen-specific hypersensitivity, leads to the induction of clinical symptoms from the skin (hyperemia, edema, etc.), nasal mucous membranes, bronchi, intestines, etc. (hypersecretion, edema, smooth muscle contraction) by nonspecific stimuli: smoke, cold air and various irritants. For example, in nasal nonspecific hyperreactivity various symptoms are induced: rhinorrhea, edema, obstruction of the nasal passages with external stimuli – cigarette smoke, cold and other irritants. However, they cause similar types of hyperreactivity and clinics in allergic and non-allergic rhinitis [11].