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].