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\begin{document}

\title{Allergy -- hypersensitivity with hyperreactivity}



\author[1]{Dmitry Novikov}%
\affil[1]{Vitebsk State Order of Peoples’ Friendship Medical University}%


\vspace{-1em}



  
  \date{May 08, 2024}


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\selectlanguage{english}
\begin{abstract}
A definition of allergy is proposed, including its two stages: 1)
hypersensitivity (without clinical manifestations) and 2)
hyperreactivity with clinical signs. A specific immunologically mediated
allergy depends on the presence of antibodies of different isotypes and
immune T and B lymphocytes against an allergen. Nonspecific allergy is
hypersensitivity and hyperreactivity of the immune system and any cells,
as well as humoral systems, to the pathogen. Anergy is the second type
of pathologically altered reduced reactivity that can be of
allergen-specific (immune) and non-immune types.%
\end{abstract}%



\sloppy


\textbf{Allergy -- pathologically altered body reactivity}

The term ``allergy'' proposed by C. Pirquet in 1906 denoted
the\emph{acquired change} in the specific reaction of the body to
infectious antigens in tuberculosis and syphilis {[}1{]}.

The classic nomenclature of 4 types of hypersensitivity was proposed by
P.G. Gell and R.R. Coombs {[}2{]}. However, the term
''hypersensitivity'' began to replace ''allergy''. Therefore, the
proposal of Ring J. et al. {[}3{]}, Jutel M., Ring J. {[}4{]} to revise
the nomenclature for allergy is very timely.

We propose for discussion the definitions of allergy, hypersensitivity
and hyperreactivity that differ from the generally accepted ones.

\textbf{The reactivity of an organism} is a genetically determined
aggregate local and/or general variant of response of its systems --
immune, nervous, endocrine, integumentary tissues (skin, mucous
membranes) and organs to a pathogen-irritant.

The problem of changing of reactivity to external stimuli has been of
interest in medicine for many centuries. \emph{The norm of reactivity}is
the midline that distinguishes a diseased person from a healthy one.
Changes in reactivity can be \emph{physiological} and\emph{pathological}
(Fig. 1). Body reactions to any pathogens can be\emph{normergic} ,
\emph{hyperergic} , \emph{hypoergic} and\emph{anergic} . Their
appearance depends on the genetic predisposition and pathogens. Allergy
is usually associated only with increased reactivity. However, there is
a decrease in reactivity: \emph{hypoergic}and \emph{anergic} response,
which is often observed with immunodeficiencies, but also occurs in
allergy. Immunodeficiencies are accompanied by genetically reduced
reactivity and, apparently, should be a type of anergy.

Therefore, two main types of pathological reactivity should be
distinguished: allergy with \emph{increased} reactivity and anergy
with\emph{reduced} reactivity. C. Pirquet {[}1{]} considered allergy as
an ``altered'' reaction of an organism, i.e. increased and reduced.
However, allergists are not ready for such understanding of allergy,
even if it is generally correct.

\textbf{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 \emph{in vitro} after incubation of sensitized
basophils with allergen, but also \emph{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 \emph{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 -- \emph{hypersensitivity} , which is realized
at the cellular-molecular level, ending with the release of mediators,
and \emph{hyperreactivity} , leading to the development of a local
(hyperemia, edema, etc.) and general reaction involving various cells
and tissue structures (Fig. 2).

\emph{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. \emph{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 \selectlanguage{greek}α-\selectlanguage{english}adrenergic reactivity and decreased \selectlanguage{greek}β-\selectlanguage{english}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 Fc\selectlanguage{greek}ε\selectlanguage{english}RI
{[}10{]}, Fc\selectlanguage{greek}ε\selectlanguage{english}RII (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 (\emph{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 \emph{in vitro} , is not called
allergy, and \emph{in vivo} with low doses of allergens it can occur
without clinical manifestations {[}8, 9{]}.

\emph{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.

\emph{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.

\textbf{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.

\textbf{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
\selectlanguage{greek}β\selectlanguage{english}\textsubscript{2}receptor agonists or glucocorticosteroids. However,
their hypersensitivity persists, which is detected after the abolition
of these drugs.

\emph{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{]}.

\textbf{Dose-dependence of hypersensitivity and hyperreactivity}

These two stages of allergy are related by the dose-dependent effect of
allergens and non-specific inducers. However, hyperreactivity is
completely dependent on the degree, intensity of hypersensitivity,
therefore, the dose of an allergen or inducer determines only the degree
of specific or nonspecific hypersensitivity. The need for high doses of
inducers for nonspecific types of allergy is due to the relatively low
concentration, expression of cell receptors or activating molecules of
humoral factors that respond to them (for example, complement).

Hypersensitivity of cells is easily detected \emph{in vitro} by their
release of mediators, cytokines and enzymes. All leukocytes, if they are
sensitized actively (lymphocytes) or passively (with antibodies --
granulocytes, platelets) respond to the allergen by the release of these
substances and degranulation to low doses of allergens, as well as by
change in phenotype, expression of receptors and CD antigens. In some
patients, nonspecific inducers, for example drugs with nonspecific
hypersensitivity to them, also provoke such a response {[}12, 13{]}.

The \emph{in vivo} response to allergens and nonspecific inducers is
assessed by the level of hyperreactivity: by the degree of skin reaction
(hyperemia, edema, etc.), or reaction of bronchi (bronchospasm), as well
as by the clinical symptoms of allergy that it causes (urticaria,
rhinorrhea, etc.) It was possible to evaluate hypersensitivity \emph{in
vivo} without hyperreactivity and clinical symptoms after developing in
our clinic {[}7, 8, 9{]} low-dose allergen-specific nasal and
oral-pharyngeal tests that do not cause clinical symptoms, but are
recorded by an increase in the level of allergy biomarkers in nasal
secretions and oral fluid. Doses of allergens in these tests were
reduced by 20-200 times compared with those used in conventional
provocative tests, which induce clinical symptoms.

\textbf{Allergy is a specific immune and nonspecific non-immune reaction
of \emph{hypersensitivity} of cells and humoral systems of a
genophenotypically predisposed organism to allergens, as well as to
various pathogens, that cause the release of mediators that induce
increased nonspecific reactions of other cells and systems, which leads
to the development of \emph{hyperreactivity}, damaging tissue.}

\textbf{Role of other systems and cells in allergy}

Nonspecific allergy (nonspecific hypersensitivity and hyperreactivity)
may occur due to the initial genetically and/or phenotypically altered
reaction of various cells and humoral systems.

In allergic reactions, \emph{leukotrienes} are involved. Under the
influence of various pathogens on leukocytes, phospholipase A is
activated, which involves in the metabolism arachidonic acid from
phospholipids of cell membranes. The products of its metabolism --
eicosanoids -- are involved in the formation of \emph{leukotrienes}
and\emph{prostaglandins} , inflammatory mediators that cause the
development of hyperreactivity. LT-B4 is a strong chemoattractant for
neutrophils and eosinophils, it stimulates inflammation, LT-C4 enhances
edema and histamine release, prostaglandin PGD2 causes smooth muscle
contraction.

Immunoneuroendocrine interactions determine overall body homeostasis and
its reactivity. The cytokines of the immune system affect the functions
of neurons, synapses, cells of the endocrine system. On the other hand,
neurotransmitters and hormones alter the responses of the immune system.

\emph{Dysmetabolic} -- a dysregulatory nonspecific variant of allergy is
characterized by the fact that with genetically determined metabolic
abnormalities, pathogens and provoking factors induce the release of
mediators and cytokines. The receptor-mediator imbalance in the
regulation of the cumulative effects of the immune, nervous and
endocrine systems on various impacts usually determines the development
of nonspecific allergy.

\emph{An imbalance in the regulation of the nervous system} can cause
the occurrence of nonspecific allergy. The sympathetic nervous system
through \selectlanguage{greek}β-\selectlanguage{english}adrenergic receptors (\selectlanguage{greek}β\selectlanguage{english}\textsubscript{1} -- constriction,
\selectlanguage{greek}β\selectlanguage{english}\textsubscript{2} -- dilatation), and the parasympathetic through
M-cholinergic receptors (constriction) regulate smooth muscle tone and
the release of mediators from cells. The predominance of the activity of
the parasympathetic nervous system over the sympathetic, decrease in the
activity and number of \selectlanguage{greek}β\selectlanguage{english}\textsubscript{2} receptors on the cells during
stimulation by nonspecific agents leads to the predominance of
M-cholinergic receptors and inflammatory mediators. The increased
activity of non-cholinergic excitatory nerves causes the release of
neuropeptides: vasoactive intestinal peptide (VIP) -- substance P,
neurokinin A, calcitonin gene-related peptide (CGRP), inducing edema,
hypersecretion, bronchospasm, skin reactions.

Dysfunctions of the endocrine system (thyroid hormones, cortisol,
estrogens, etc.) lead to a change in reactivity. Often there
are\emph{dishormonal} allergy variants caused by impairments in the
relationship of the hypothalamus-pituitary-adrenal cortex, which leads
to primary or secondary adrenal insufficiency and steroid dependence in
the treatment of pathology, for example, bronchial asthma, chronic
urticaria. In cases of impaired ovarian function and menstrual cycle,
menopause, an imbalance of estrogen and progesterone develops, which is
the cause of urticaria and asthma.

Any cells can participate in the development of allergy (Fig.
3).\emph{Nonspecific} allergic reactions, apparently, can be triggered
and carried out by those cells that have receptors that bind the
pathogen, or signal structures that respond to the physical factor
(light, cold). However, their response should be increased. Epithelial
and endothelial cells, fibroblasts and other cells are capable of
secreting cytokines, enzymes and other molecules under the influence of
pathogens and, if their response is abnormal, increased, this can lead
to the development of allergy (Fig. 2).

Epithelium stimulated by pathogens secretes IL-25, IL-33 and thymic
stromal lymphopoietin (TSLP). These cytokines mobilize the migration of
dendritic cells to the lymph nodes, where they activate na\selectlanguage{ngerman}ïve T
lymphocytes in Th2, which are involved in allergy.

Smooth muscle cells have receptors for mediators and cytokines of
allergic reaction and their contraction is an important sign of allergic
diseases (asthma, rhinitis, intestinal allergy).

Vascular endothelium responds to hypersensitivity mediators with an
increase in permeability, which leads to edema, skin hyperemia,
subendothelial leukocyte infiltration. Endothelial cells secrete a
number of cytokines.

Fibroblasts, when activated by neurotransmitters and cytokines, secrete
the precursors of collagen and elastin proteins, as well as
mucopolysaccharides, and cytokines.

Therefore, allergy as pathologically altered reactivity may include
immune and non-immune mechanisms.

\textbf{Anergy}

Anergy is a hyporeactive type of reactivity usually observed to
infectious antigens. It can be specific (immune) and nonspecific --
non-immune. With it, there is no hyperreactivity, but there is tolerance
to an allergen or immunosuppression after the use of immunosuppressants.

\emph{Allergen-specific immuno-mediated anergy} is due to hypo- or
areactivity to allergens in a patient with allergy and can be
immunosuppressive or immunoregulatory. After successful
allergen-specific immunotherapy (ASIT), patients remain allergic, but
they develop anergy to the allergen. Such anergy differs from
pathological anergy, in which there is no response to stimulation with
an antigen (infectious or non-infectious) due to a genetically
determined lack of response or due to immunosuppression.

\emph{Pathological anergy} can cause immunodeficiency diseases and
infections.

On the other hand, ``immunity'' which is unsusceptibility to infection,
can be also essentially considered anergy. Additional data on the
commonality and differences of these concepts is needed.

\emph{The anergy of non-immune cells} , especially epithelial cells
releasing defensins and antibacterial peptides, often leads to immune
deficiency and the development of infections.

\textbf{Conclusion}

Thus, our proposals for nomenclature and classification of allergy
include the following points:

1. Pathologically altered body reactivity can be of two types:
increased, hyperreactive -- allergy, and reduced -- anergy.

2. Allergy includes two reaction stages: 1) hypersensitivity (without
clinical manifestations) and 2) hyperreactivity with clinical symptoms.

3. A specific immunologically mediated allergy depends on the presence
of antibodies of different isotypes and immune T and B lymphocytes to
the allergen.

4. Nonspecific allergy is hypersensitivity and hyperreactivity of the
immune system and any cells, as well as humoral systems, to the
pathogen.

5. Anergy is the second type of pathologically altered reduced
reactivity, and it can be allergen-specific (immune) and non-immune. A
kind of antigen-specific anergy to an infection agent may be immunity
itself, although at first glance it seems absurd. But normergia is a
normal immune response to infection, while hyperergic reponse is a
disease.

\textbf{References}

\begin{enumerate}
\tightlist
\item
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\item
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\item
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\end{enumerate}

\par\null

Figure 1. Types of body reactivity

Figure 2. Type I (immediate) allergy

ECFs -- eosinophil chemotactic factors, PAF -- platelet-activating
factor, NCFs -- neutrophil chemotactic factors, PDGF -- platelet-derived
growth factor

Figure 3. Types of allergy and structures realizing it\selectlanguage{english}
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