Advances of modern natural science. Allergens that induce the development of humoral allergic reactions

An allergic reaction is a change in the ability of the human body to respond to environmental influences upon repeated exposure to it. A similar reaction develops as a response to the influence of substances of a protein nature. Most often they enter the body through the skin, blood or respiratory organs.

Such substances are foreign proteins, microorganisms and their metabolic products. Since they are able to influence changes in the body's sensitivity, they are called allergens. If substances that cause a reaction are formed in the body when tissue is damaged, they are called autoallergens or endoallergens.

External substances that enter the body are called exoallergens. The reaction manifests itself to one or more allergens. If the latter occurs, it is a polyvalent allergic reaction.

Mechanism of action causing substances is as follows: upon initial exposure to allergens, the body produces antibodies, or antibodies, - protein substances that resist a specific allergen (for example, pollen). That is, the body develops a protective reaction.

Repeated exposure to the same allergen entails a change in the response, which is expressed either by the acquisition of immunity ( decreased sensitivity to a specific substance), or an increase in susceptibility to its action, up to hypersensitivity.

An allergic reaction in adults and children is a sign of development allergic diseases(bronchial asthma, serum sickness, urticaria, etc.). Genetic factors play a role in the development of allergies, which is responsible for 50% of cases of reactions, as well as the environment (for example, air pollution), allergens transmitted through food and air.

Harmful agents are eliminated from the body by antibodies produced by the immune system. They bind, neutralize and remove viruses, allergens, microbes, harmful substances that enter the body from the air or with food, cancer cells, dead after injuries and tissue burns.

Each specific agent is resisted by a specific antibody, for example, the influenza virus is eliminated by anti-influenza antibodies, etc. Thanks to the well-established functioning of the immune system, they are eliminated from the body harmful substances: It is protected from genetically foreign components.

Lymphoid organs and cells take part in the removal of foreign substances:

• spleen;
• thymus;
• The lymph nodes;
• peripheral blood lymphocytes;
• lymphocytes bone marrow.

They all form a single organ of the immune system. Its active groups are B- and T-lymphocytes, a system of macrophages, thanks to the action of which various immunological reactions are ensured. The task of macrophages is to neutralize part of the allergen and absorb microorganisms; T- and B-lymphocytes completely eliminate the antigen.

Classification

In medicine, allergic reactions are distinguished depending on the time of their occurrence, the characteristics of the mechanisms of the immune system, etc. The most used classification is according to which allergic reactions are divided into delayed or immediate types. Its basis is the time of allergy occurrence after contact with the pathogen.

According to the classification, the reaction:

1. immediate type- appears within 15–20 minutes;
2. slow type- develops within a day or two after exposure to the allergen. The disadvantage of this division is the inability to cover the diverse manifestations of the disease. There are cases when the reaction occurs 6 or 18 hours after contact. Based on this classification, it is difficult to attribute similar phenomena to a certain type.

A widespread classification is based on the principle of pathogenesis, that is, the peculiarities of the mechanisms of damage to cells of the immune system.

There are 4 types of allergic reactions:

1. anaphylactic;
2. cytotoxic;
3. Arthus;
4. delayed hypersensitivity.

Allergic reaction type I also called atopic, immediate type reaction, anaphylactic or reaginic. It occurs within 15–20 minutes. after interaction of reagin antibodies with allergens. As a result, mediators (biologically active substances) are released into the body, from which the clinical picture of a type 1 reaction can be seen. These substances include serotonin, heparin, prostaglandin, histamine, leukotrienes, etc.

Second type more often associated with the occurrence of drug allergies, which develop due to hypersensitivity to medications. The result of an allergic reaction is the combination of antibodies with modified cells, which leads to the destruction and removal of the latter.

Type 3 hypersensitivity(precitipin, or immunocomplex) develops as a result of the combination of immunoglobulin and antigen, which together leads to tissue damage and inflammation. The cause of the reaction is soluble proteins that re-enter the body in large quantities. Such cases include vaccinations, transfusions of blood plasma or serum, infection with blood plasma fungi or microbes. The development of the reaction is facilitated by the formation of proteins in the body during tumors, helminthiases, infections and other pathological processes.

The occurrence of type 3 reactions may indicate the development of arthritis, serum sickness, visculitis, alveolitis, Arthus phenomenon, nodular periarteritis and etc.

Allergic reactions Type IV, or infectious-allergic, cell-mediated, tuberculin, delayed, arise due to the interaction of T-lymphocytes and macrophages with carriers of a foreign antigen. These reactions make themselves felt during contact dermatitis of an allergic nature, rheumatoid arthritis, salmonellosis, leprosy, tuberculosis and other pathologies.

Allergies are provoked by microorganisms that cause brucellosis, tuberculosis, leprosy, salmonellosis, streptococci, pneumococci, fungi, viruses, helminths, tumor cells, altered body proteins (amyloids and collagens), haptens, etc. Clinical manifestations of reactions are different, but most often infectious-allergic, in the form of conjunctivitis or dermatitis.

Types of allergens

There is no single classification of substances that lead to allergies yet. They are mainly classified according to the route of penetration into the human body and their occurrence:

• industrial: chemicals (dyes, oils, resins, tannins);
• household (dust, mites);
• animal origin (secrets: saliva, urine, gland secretions; hair and dander, mainly from domestic animals);
• pollen (pollen from grasses and trees);
• (insect poisons);
• fungal (fungal microorganisms that enter with food or by air);
• (complete or haptens, that is, released as a result of the metabolism of drugs in the body);
• food: haptens, glycoproteins and polypeptides contained in seafood, cow's milk and other products.

Stages of development of an allergic reaction

There are 3 stages:

1. immunological: its duration begins from the moment the allergen enters and ends with the combination of antibodies with the allergen that has re-emerged in the body or persists;
2. pathochemical: it implies the formation in the body of mediators - biologically active substances resulting from the combination of antibodies with allergens or sensitized lymphocytes;
3. pathophysiological: differs in that the resulting mediators manifest themselves by providing pathogenic effect on the human body as a whole, especially on cells and organs.

Classification according to ICD 10

The database of the international classification of diseases, which includes allergic reactions, is a system created by doctors for ease of use and storage of data on various diseases.

Alphanumeric code is a transformation of the verbal formulation of the diagnosis. In the ICD, an allergic reaction is listed as number 10. The code consists of letter designation in Latin and three numbers, which makes it possible to encode 100 categories in each group.

Classified under number 10 in the code the following pathologies depending on the symptoms of the disease:

1. rhinitis (J30);
2. contact dermatitis(L23);
3. urticaria (L50);
4. unspecified allergy (T78).

Rhinitis, which is of an allergic nature, is divided into several subtypes:

1. vasomotor (J30.2), resulting from autonomic neurosis;
2. seasonal (J30.2), caused by pollen allergy;
3. hay fever (J30.2), which appears during flowering of plants;
4. (J30.3), which is the result of the action chemical compounds or insect bites;
5. unspecified nature (J30.4), diagnosed in the absence of a definitive response to tests.

The ICD 10 classification contains group T78, which contains pathologies that occur during the action of certain allergens.

These include diseases that are manifested by allergic reactions:

• anaphylactic shock;
• other painful manifestations;
• unspecified anaphylactic shock, when it is impossible to determine which allergen caused the immune system reaction;
• angioedema (Quincke's edema);
• unspecified allergy, the cause of which - the allergen - remains unknown after testing;
• conditions accompanied by allergic reactions with an unspecified cause;
• other unspecified allergic pathologies.

Kinds

To allergic reactions fast type accompanied by severe course, belongs to anaphylactic shock. Its symptoms:

1. decreased blood pressure;
2. low body temperature;
3. convulsions;
4. respiratory rhythm disturbance;
5. heart disorder;
6. loss of consciousness.

Anaphylactic shock is observed with secondary exposure to an allergen, especially with the introduction of drugs or their external use: antibiotics, sulfonamides, analgin, novocaine, aspirin, iodine, butadiene, amidopyrine, etc. acute reaction is life-threatening and therefore requires emergency medical care. Before this, the patient needs to ensure an influx fresh air, horizontal position and heat.

To prevent anaphylactic shock, you should not self-medicate, since uncontrolled medication use provokes more severe allergic reactions. The patient should make a list of drugs and products that cause reactions and report them to the doctor at the doctor’s appointment.

Bronchial asthma

The most common type of allergy is bronchial asthma. It affects people living in a certain area: with high humidity or industrial pollution. Typical sign pathologies - attacks of suffocation, accompanied by soreness and scratching in the throat, coughing, sneezing and difficulty breathing.

Asthma is caused by allergens that spread in the air: from and to industrial substances; food allergens that cause diarrhea, colic, and abdominal pain.

The cause of the disease is also sensitivity to fungi, microbes or viruses. Its onset is signaled by a cold, which gradually develops into bronchitis, which, in turn, causes difficulty breathing. The cause of the pathology is also infectious foci: caries, sinusitis, otitis media.

The process of forming an allergic reaction is complex: microorganisms that act on a person for a long time clearly do not worsen health, but quietly form an allergic disease, including a pre-asthmatic condition.

Prevention of pathology includes taking not only individual measures, but also public ones. The first is hardening, carried out systematically, quitting smoking, playing sports, regular home hygiene (ventilation, wet cleaning, etc.). Public measures include increasing the number of green spaces, including park areas, and separating industrial and residential urban areas.

If a pre-asthmatic condition makes itself known, it is necessary to begin treatment immediately and in no case self-medicate.

After bronchial asthma, the most common is urticaria - a rash on any part of the body, reminiscent of the consequences of contact with nettles in the form of itchy small blisters. Such manifestations are accompanied by an increase in temperature to 39 degrees and general malaise.

The duration of the disease ranges from several hours to several days. An allergic reaction damages blood vessels, increases capillary permeability, resulting in blisters due to swelling.

The burning and itching is so severe that patients can scratch the skin until it bleeds, causing infection. The formation of blisters is caused by exposure to heat and cold on the body (heat and cold urticaria are distinguished accordingly), physical objects (clothing, etc., which cause physical urticaria), as well as dysfunction gastrointestinal tract(enzymopathic urticaria).

In combination with urticaria, angioedema or Quincke's edema occurs - a rapid-type allergic reaction, which is characterized by localization in the head and neck area, in particular on the face, sudden appearance and rapid development.

Edema is a thickening of the skin; its sizes vary from a pea to an apple; there is no itching. The illness lasts from 1 hour to several days. It may reappear in the same place.

Quincke's edema also occurs in the stomach, esophagus, pancreas or liver, accompanied by discharge and pain in the spoon area. The most dangerous places for angioedema to occur are the brain, larynx, and root of the tongue. The patient has difficulty breathing, and the skin becomes bluish. A gradual increase in symptoms is possible.

Dermatitis

One type of allergic reaction is dermatitis - a pathology that is similar to eczema and occurs when the skin comes into contact with substances that provoke a delayed-type allergy.

Strong allergens are:

• dinitrochlorobenzene;
• synthetic polymers;
• formaldehyde resins;
• turpentine;
• polyvinyl chloride and epoxy resins;
• ursols;
• chromium;
• formalin;
• nickel.

All these substances are common both in production and in everyday life. More often they cause allergic reactions in representatives of professions that involve contact with chemicals. Prevention includes organizing cleanliness and order in production, the use of advanced technologies that minimize the harm of chemicals upon contact with humans, hygiene, etc.

Allergic reactions in children

In children, allergic reactions occur for the same reasons and with the same characteristic features, as in adults. From an early age, symptoms of food allergies are detected - they arise from the first months of life.

Hypersensitivity observed to products of animal origin(, crustaceans), plant origin(nuts of all types, wheat, peanuts, soybeans, citrus fruits, strawberries, strawberries), as well as honey, chocolate, cocoa, caviar, cereals, etc.

IN early age influences the formation of more severe reactions in older age. Since food proteins are potential allergens, foods containing them are most likely to cause a reaction, especially cow's milk.

Allergic reactions in children caused by food, are diverse, since different organs and systems can be involved in the pathological process. The clinical manifestation that occurs most often is atopic dermatitis - a skin rash on the cheeks, accompanied by severe itching. Symptoms appear within 2–3 months. The rash spreads to the torso, elbows and knees.

It is also characteristic acute urticaria- itchy blisters of various shapes and sizes. Along with it, angioedema appears, localized on the lips, eyelids and ears. There are also defeats digestive organs accompanied by diarrhea, nausea, vomiting, and abdominal pain. Respiratory system in a child it is not affected in isolation, but in combination with pathology of the gastrointestinal tract and is less common in the form of allergic rhinitis and bronchial asthma. The cause of the reaction is increased sensitivity to egg or fish allergens.

Thus, allergic reactions in adults and children are varied. Based on this, doctors offer many classifications, which are based on the time of the reaction, the principle of pathogenesis, etc. The most common diseases of an allergic nature are anaphylactic shock, urticaria, dermatitis or bronchial asthma.

Introduction

In recent decades, there has been a sharp increase in the incidence of allergy diseases throughout the world. What is this connected with? First of all, with the deteriorating environmental situation. The so-called antigens that provoke an allergic reaction can enter the body with food, inhaled air, or through contact with mucous membranes or skin. Contact with pets, various chemicals, pollen or dust results in unpleasant symptoms for many. To cope with allergies you need qualified assistance allergist. It is he who will prescribe an examination, identify the true cause of the allergy and prescribe adequate treatment. Self-medication in case of allergies will not only not help, but can also cause irreparable harm. Medicine has described cases of fatal allergic reactions to the most seemingly ordinary foods or after contact with animals. About what happens in the body after an antigen enters, how to prevent the development of allergies, what are the urgent measures If an allergic reaction occurs, you will find out by reading this book.

This reference book describes in detail modern methods of diagnosing allergic diseases, traditional and non-traditional methods and principles of their treatment, provides characteristics of drugs used for allergies, and also provides nutritional features for patients with allergies and physical therapy exercises. A separate chapter is devoted to the prevention of allergic diseases.

Chapter 1
Allergic reactions – hypersensitivity reactions

The immune response is a series of molecular and cellular reactions that occur in the body after exposure to an antigen, resulting in the formation of humoral or cellular immunity. The development of one or another type of immunity is determined by the properties of the antigen, the genetic and physiological capabilities of the body. During this period, the body’s ability to quickly respond to this is formed by neutralizing and removing microorganisms and substances that have invaded the body and change the properties of the antigen. In some cases, with excessively strong and prolonged exposure to an antigen, the immune reaction becomes damaging to the body. This reaction is called a hypersensitivity reaction, or allergic reaction.

Depending on the rate of development, an immediate-type hypersensitivity reaction and a delayed-type reaction are distinguished.

Features of humoral immunity

Three types of cells take part in humoral immunity:

– macrophages;

– T-lymphocytes;

– B-lymphocytes.

Macrophages phagocytose the antigen and, after intracellular proteolysis, present its peptide fragments on their cell membrane to T helper cells. T-helpers cause activation of B-lymphocytes, which begin to profile, transform into blast cells, and then, through a series of successive mitoses, into plasma cells that synthesize antibodies specific to a given antigen. Immune-competent cells produce regulatory substances, cytokines.

To activate T-helper cells, the effect of interleukin 1, secreted by a macrophage upon contact with an antigen, is necessary, interleukin 2, and for the activation of B-lymphocytes - lymphokines produced by T-helper cells - interleukins 4, 5, 6.

Plasma cells synthesize antibodies in the form of immunoglobulin molecules. There are 5 classes of immunoglobulins - A, M, G, D and E.

JgA (immunoglobulins A) make up 15% of the total number of immunoglobulins, they are contained in secretions and provide protection against toxins and pathogenic substances.

JgM (immunoglobulin M) is a high molecular weight immunoglobulin found in blood serum. It makes up 10% of the total number of immunoglobulins. These are the first antibodies that are produced after infection and immunization, but more often by antibodies to immunoglobulin G.

JgG (immunoglobulin G) makes up 75% of serum immunoglobulins. They can be found in the intercellular fluid and are capable of fixing complement. These immunoglobulins effectively appotylite particles, neutralize particles, bacteria.

JgD (immunoglobulin D) is found in traces and, together with JgM, can bind antigens.

JgE (immunoglobulin E) is found in very small quantities. When antigens bind mast cells are a trigger for the release of histamine, a slow-reacting substance of anaphylaxis, eosinophil chemotaxis factor and other mediators responsible for immediate hypersensitivity reactions. When antibodies combine with an antigen, they form immune complexes.

Elimination of the allergen occurs due to activation of the complement system, leading to the destruction of bacterial or other foreign cells.

The complement system is a group of plasma proteins, the activation of which leads to the release of histamine from mast cells and platelets, an increase in vascular permeability, and a reduction in smooth muscle, neutralization of certain substances, cell lysis.

Features of cellular immunity

T lymphocytes take part in cellular immunity, which manifests itself in delayed-type hypersensitivity. These cells recognize antigen bound to the cell membrane. In the presence of antigens, T cells turn into T-blast forms of cells, then transform into T-effectors, which secrete biologically active substances - lymphokines (or mediators of delayed-type hypersensitivity). Under their influence, these cells accumulate in places of antigenic irritation. Due to this, macrophages, neutrophils, basophils, and eosinophils are attracted to the site of antigenic irritation. Target cells can be lysed due to the synthesis of lymphotoxin.

Another group of T-killer cells is represented by lymphocytes that are cytotoxic to cells infected with viruses, tumor cells, and allografts.

In another mechanism of cytotoxicity, antibodies recognize target cells and effector cells respond to these antigens.

Zero cells, monocytes, and lymphocytes have this ability.

Allergens

As a result of the interaction of the body's immunocompetent system with the allergen, specific sensitization develops, which is accompanied by clinical manifestations that are considered an allergic disease.

Allergens are all substances that carry genetically foreign information and, when they enter the body, cause specific immune reactions. They can be substances of organic or inorganic nature (antigenic or non-antigenic, simple substances - iodine, chromium, platinum) or complex protein or protein-polysaccharide and protein-lipid complexes (serum, tissue, bacterial, fungal), as well as false compounds of non-protein nature , such as house dust allergens.

Allergens can be medicines, dyes and detergents, various synthetic polymers, cosmetics and perfumes.

Simple low-molecular-weight products can acquire allergenic properties in the body after binding to serum and tissue proteins. Exoallergens are numerous substances that enter the body from the outside.

Exoallergens include allergens of non-infectious origin:

1) household (house dust, library dust, daphnia);

2) medicinal (antibiotics, etc.);

3) epidermal (human epidermis, animal epidermis, bird feathers, wool, hair, fur);

4) pollen (flowers of cultivated plants, flowers of wild plants, meadow grasses, weeds, trees, shrubs, agricultural crops);

5) chemicals (gasoline, benzene, etc.);

6) food allergens (livestock meat, poultry meat and eggs, fish products, plant products, and dairy products);

7) insects (stinging, blood-sucking, arachnids).

TO infectious allergens relate:

1) bacterial – various types of pathogenic and non-pathogenic bacteria, their metabolic products;

2) fungal allergens (pathogenic and non-pathogenic fungi), pathogens of fungal diseases, mold; 3) various types of viruses; 4) various types of protozoa; 5) saprophytes and opportunistic organisms.

Molds cause allergies in 30% of cases, nutritional supplements– 21%, house dust mites – 20%, plant pollen – 16%, food – 14%, medications– 12%, pets – 8%.

The most common food allergens (listed in order of frequency of reaction):

- cow's milk;

– chicken eggs;

– vegetables (celery, tomatoes);

– grains;

– spices;

- yeast.

One patient may be allergic to several pathogens.

Main allergens and factors causing exogenous allergic diseases

Types of allergic reactions

The main cause of allergic reactions is congenital or acquired failure of the function of regulatory suppressor cells.

Genetic predisposition in patients is associated with inherited characteristics of the body. If allergies are registered in both parents, then their children inherit atopy in 50%. If only one parent had an allergy, the risk of getting sick is 30%. The effect of environmental products does not need explanation, but allergy mediators play an important role, including histamine, which is an endogenous toxin and is eliminated through the liver. If the liver is overloaded and the body cannot remove histamine, allergic symptoms occur.

The variety of allergic reactions has led to the creation of a large number of classifications of allergic reactions.

Ado A.D. (1978) divides all true allergic reactions into 2 large groups:

1) immediate type reactions (or reactions with circulating antibodies);

2) slow reactions (or cell type).

In the pathogenesis of immediate-type allergic reactions, 3 stages are distinguished: immunological, pathochemical and pathophysiological.

The immunological reaction is an allergen-antibody reaction; it determines the development of the entire complex of processes and its specificity. The pathochemical stage develops as a result of antigen-antibody, when a number of biologically active substances are released from the tissues. The third stage is a consequence of the second stage and is a complex of disorders that characterize the clinical picture of allergic reactions.

The allergic response consists of 3 phases: sensitization, immediate allergic reaction and delayed allergic reaction.

The sensitization process can take up to 4 years until mast cells begin to stimulate an allergic response to a specific allergen.

In case of cross-allergy, an allergic response can occur without prior sensitization (for example, to penicillin drugs). Previous sensitization may be caused by an environmental allergen. Therefore, the first contact can provoke a severe allergic reaction.

Cross-allergy is typical for food allergens: grass pollen can cause cross-reactions to tomatoes and cereals, natural latex can cause cross-reactions to bananas and avocados.

An immediate allergic reaction develops after preliminary exposure of the allergen to mast cells with the formation of JgE.

Mediators, such as histamine, increase vascular permeability and fluid flow. Leukotrienes and prostaglandins cause inflammation. Basophils and other immunocompetent cells are involved in the process. Clinical manifestations of this reaction are itching and sneezing.

The delayed-type reaction is due to the action of cytokines that are produced by mast cells and T-2 lymphocytes 4–10 hours after repeated exposure. The main cells associated with a delayed allergic reaction.

Depending on the type of tissue damage, there are 4 types of allergic reactions.

Type I – anaphylactic reaction. This is an immediate hypersensitivity reaction with anaphylaxis and reagin reaction. At the first contact with the antigen, predisposed individuals produce antibodies - reagins, JgE, they are fixed on the membrane of mast cells, basophils, and smooth muscle cells. Upon repeated contact with the antigen, immune complexes are formed. This stimulates mast cell degranulation and the release of biologically active substances such as histamine, slow-reacting substance of anaphylaxis, eosinophil chemotactic factor.

Clinical type I reaction is detected when:

– anaphylactic shock;

– urticaria;

– angioedema;

– vasomotor rhinitis;

– bronchial asthma.

Type II – cytotoxic reaction. In this type of reaction, antibodies such as immunoglobulin JgG and JgM circulate freely in the blood, while endogenous or exogenous antigens are attached to the cell membrane.

The complement system is involved in antibodies (JgM).

With the participation of complement, the metic or inflammatory activity of the cell is manifested. The antibodies produced are specific to the popular membrane and wall of the lungs blood vessels. These antigen-antibody reactions lead to glomerulonephritis and pulmonary vasculitis. This is manifested by hemoptysis. In addition, a type II reaction can cause the formation of cytotoxic antibodies against any tissue.

A cytotoxic reaction occurs during immunohemolysis due to drug allergies and post-transfusion complications.

Type III is an immune complex reaction, which can be characterized by an Arthus phenomenon-type reaction (or an immune complex reaction). This reaction of the humoral type occurs 2–6 hours after antigenic stimulation, during which precipitating antibodies combine with the antigen. This is accompanied by the formation of microprecipitates inside and around small vessels, leading to thrombosis and destruction of the vessels. The higher the level of antibodies, the greater the intensity and duration of the reactions in which neutrophils are destroyed with the release of lysosomal enzymes. Allergic reactions of this type include systemic lupus erythematosus, characterized by the deposition immune complexes in various areas, as well as the glomerulonephric membrane, pleura, pericardium, synovial membranes, vessels, complexes.

In addition, an example of an allergic reaction of this type can be systemic serum sickness and local reaction, which develops in the case of antigen injection, eye damage in the form of marginal keratitis and some other damage to the organs of vision.

Among the diseases of the “complexes” are exogenous allergic alveolitis, post-streptococcal glomerulonephritis, ulcers small intestine at typhoid fever, rheumatoid arthritis, etc.

Type IV allergic reaction is a delayed-type hypersensitivity reaction. It is cellular. Humoral antibodies and the complement system do not take part in it. Sensitized T lymphocytes, activated by antigens, turn into cytotoxic cells capable of killing bacteria on other target cells. Effector T lymphocytes, using hypersensitivity mediators, stimulate other lymphocytes, neutrophils and macrophages.

The latter also cause damage. These reactions of cellular immunity occur during tuberculosis and fungal diseases, in addition, they cause the development of goiter and contact dermatitis. This type of reaction is observed in transplants and also in bone marrow transplants.

IN clinical settings In the pathogenesis of many allergic diseases, it is difficult to differentiate the types of reactions, since there is often a combination of these reactions. In each specific case, it is important to correctly identify the predominance of one or another type of allergic reaction.

Characteristics of immediate and delayed types of hypersensitivity (according to V.V. Medunitsin)

Chapter 2
Diagnosis of allergic diseases

To make a diagnosis allergic disease It is necessary to conduct a thorough general clinical examination, as well as additional research methods to identify specific allergens. To identify allergies in a patient, you need:

– taking anamnesis;

– physical examination;

– immunological study.

Specific diagnosis of allergic diseases includes, in addition to collecting anamnesis, allergological, immunological and instrumental research methods.

Anamnesis

Taking an anamnesis is the most universal method for diagnosing allergies; it is necessary for the correct selection of further examination, exclusion of non-allergic diseases, and prescribing adequate effective treatment. The main factors in the study of allergy history: 9 causes and time of appearance of the first symptoms of the disease;

– general well-being, characteristics of the patient’s main complaints by organs and systems;

– the dynamics of the occurrence of symptoms depending on the season, by day, month, year, season, in different places;

– hereditary predisposition;

– factors influencing the course of pregnancy (factors of intrauterine sensitization, excess carbohydrates in the pregnant woman’s diet, taking medications, blood group incompatibility, smoking, various diseases and etc.);

– study of the food regime, diet features, food diary, reaction to various food products;

– if possible, identifying causes that may predispose to allergies (for example, diseases of the digestive system, taking antibiotics, preventive vaccinations, perinatal lesions central nervous system, contact with animals, insect bites, changes in residence, season of the year, weather conditions, etc.);

– previous antiallergic treatment, its effectiveness;

– results of previously conducted examinations, their results;

– living conditions of the patient;

– the patient’s profession and occupational hazards.

A correctly collected anamnesis allows the allergist to suspect an allergen or group of allergens for specific diagnosis.

Skin tests

The method is based on the determination of antibodies not only in the shock organ, but also on the skin (reagins).

The following skin tests are distinguished:

– drip;

– application;

– scarification;

– scarification and application;

– intradermal.

In allergy diagnostics, skin tests, as they are more accessible, are used quite often. When the corresponding allergen is applied to the skin, a specific antigen-antibody reaction is provoked, accompanied by the release of biologically active substances (histamine, etc.), which after 15–20 minutes cause the formation of a blister surrounded by a zone of hyperemia (immediate reaction, blistering), which occurs after 15–20 minutes. In delayed-type reactions, lymphoid cells are of primary importance with the formation of an infiltrate after 24–48 hours. The history and clinical picture of the disease indicate which allergens need to be tested with skin.

To avoid local and general complications skin tests are performed no earlier than 7–10 days after the acute allergic reaction subsides. Antihistamines and corticosteroids are discontinued 1–2 days before the study. With general hormone therapy, which suppresses general and local allergic reactions, skin tests are performed only 2 months after discontinuation of corticosteroids.

Indications for skin tests are medical history, indications of the role of a particular allergen or group of allergens in the history.

Currently, many both infectious and non-infectious allergens are known. Infectious allergens include:

– microbial;

– mold allergens;

– helminth allergens.

Non-infectious allergens include:

– pollen;

– household;

– epidermal;

– food;

– insect allergens.

Contraindications for skin testing are:

– exacerbation of the underlying disease;

– exacerbation concomitant diseases;

– decompensated diseases internal organs;

– spicy infectious diseases;

– pregnancy, lactation, the first 2 days of the menstrual cycle.

A drop and skin test with rubbing of the allergen into intact skin is carried out if there is a suspicion of very high sensitivity. The test technique involves applying a drop of allergen to the skin of the forearm treated with 70% alcohol and after 15–20 minutes measuring the size of the papule and hyperemia.

Sometimes a drop of the food allergen is rubbed into intact skin with a stick. If there are no changes on the skin after 15–20 minutes, the tests are considered negative.

Usually, to control these tests, a drop of an isotonic solution is placed in parallel at a distance of 4–5 cm from the first sample. The test is usually performed with only one allergen.

The patch test is used more often for drug allergies. A drop of the medicinal substance is applied to the skin of the forearm, which is fixed with a piece of sterile gauze, and on top - with compress paper and a patch. But it is more convenient to perform tests using ready-made testoplast (a tape made of indifferent material, divided into squares, in the center of which a circle of 1 layer of filtered paper is fixed). An allergen or control solution is placed into the hole in the tape. Testoplast is removed after 24 hours. If skin itching the bandage is removed earlier.

The test is recorded 30 minutes after removal of the testoplast, 48 hours or more (up to 7 days) from the moment the sample is taken. A negative reaction is a skin reaction similar to the reaction with saline.

With a positive delayed-type reaction, inflammatory phenomena in the form of erythema, edema, infiltration, papules, vesicles, depending on the degree of their severity.

The results of a positive reaction are assessed:

– erythema – +;

– erythema and swelling – ++;

– erythema, edema, onset of vesiculation – +++;

– erythema, edema, vesicles or ulcers – ++++.

Scarification tests are often carried out with various groups of non-bacterial allergens. This test is specific and less dangerous than the intradermal test.

The test is performed on the inner surface of the forearm: 0.5 cm long incisions are made with a scarifier at a distance of 3 cm from each other, and an allergen or control examination is applied to the damaged skin. Up to 20–25 allergens are used in a single examination. The results of the reaction are assessed after 15–20 minutes.

The reaction is considered positive if a blister larger than 5 mm in diameter appears at the scarification site.

In the light of the problem under consideration, allergic reactions of the immediate type (or humoral) and delayed type (or cellular) are distinguished. Humoral reactions are characterized by very rapid development(within a few seconds or minutes after the interaction of the sensitized organism and the allergen antigen). The mechanism for the development of such reactions is based on surface serous inflammation, which disappears without a trace after a few hours. In this case, antihistamines provide an excellent therapeutic effect.

May have antigenic properties various substances protein nature (proteins of animal and plant origin). They are capable of causing the induction (formation) of antibodies or specific cellular reactions. Exists great amount substances that come into contact with antibodies, after which no further synthesis of antibodies follows. These are haptens.

By combining with body proteins, they acquire antigenic properties. The stronger the antigen, the higher and more rigid its molecular structure and the greater the mass of the molecule. Strong antigens are soluble allergens, weak antigens are insoluble, corpuscular, bacterial cells. There are endogenous allergens, which are present or formed in the body itself, and exogenous, which enter the human body from the environment. A.D. Ado proposed to classify exogenous allergens by origin into non-infectious and infectious. Non-infectious include:
1) simple chemical compounds (detergents, perfumes, gasoline);
2) household (pollen, house dust);
3) food allergens of animal and plant origin (citrus fruits, egg whites, etc.);
4) epidermal (dandruff, wool);
5) medicinal (aspirin, sulfonamides, antibiotics
and etc.).

Non-infectious allergens are divided according to their source into: industrial (wool, flour dust); household (dust, wool) and natural (pollen from flowers, cereals and plants).

Infectious allergens are represented by fungi, viruses, bacteria and the products of their metabolism (life activities).

Exogenous allergens enter the body in various ways, for example parenterally, enterally, inhalation and percutaneously (through skin).
Endogenous allergens, or autoallergens, are divided into primary (natural) and secondary (acquired).

Natural antigens are found in colloid thyroid gland, gray matter of the brain, lens of the eye, testes.

In some pathologies, due to the increased permeability of physiological barriers (blood-brain or histohematic), the so-called dystopia of these antigens from the above tissues and organs occurs, followed by their contact with immunocompetent cells, as a result of which autoantibodies begin to be produced. As a result, damage to the corresponding organ occurs.
Acquired (secondary) autoallergens are synthesized from the proteins of one’s own body under the influence of certain harmful agents (ionizing radiation, low or high temperature, etc.). In particular, these mechanisms underlie radiation and burn illness.

Low temperature, cold - this, of course, is not an allergen, but this factor contributes to the agglutination (sticking together) of red blood cells during active participation anti-erythrocyte antibodies. The resulting agglutinins (clumped formations) trigger the activation of the complement system, which leads to the death of red blood cells.

Such phenomena can occur, for example, in alcoholic cirrhosis of the liver, infectious mononucleosis, mycoplasma infections.
It should be noted that under the influence of microorganisms, the proteins of the macroorganism form complex endoallergens and intermediate ones. Complex ones appear as a result of contact of the body’s own tissues with microorganisms or their toxins, which promotes the production of antibodies, their interaction with antigens and ultimately tissue damage.

Intermediate endoallergens are formed due to the combination of microorganisms with body tissues, but in this case a structure with completely new antigenic properties is formed.

There are thymus-independent antigens (when the immune response does not require the participation of T-lymphocytes-helpers) and thymus-dependent antigens (when the response of the immune system is possible with the obligatory participation of T-lymphocytes, B-lymphocytes and macrophages).

The classification of immediate allergic reactions includes:
1) anaphylactic (atopic) reactions;
2) cytotoxic reactions;
3) immune complex pathology.

1. Anaphylactic reactions are most often caused by allergens such as house and industrial dust, pollen and fungal spores, cosmetical tools and perfumes, epidermis and animal hair. These are called local anaphylactic reactions (urticaria, angioedema, atopic bronchial asthma, allergic conjunctivitis and rhinitis). Sources of generalized allergic reactions (anaphylactic shock) are hormone allergens, antitoxic serums, blood plasma proteins, medications, X-ray contrast agents. Thus, local anaphylactic reactions occur when the antigen enters naturally into the body and are found in places of fixation (mucous membranes, skin, etc.). Aggressor antibodies are isolated, belonging to the class of immunoglobulins E and G4, which have the ability to attach, for example, to mast cells, macrophages, platelets, basophils, neutrophils, eosinophils. In this case, there is a release of allergy mediators, in particular eosinophils produce cationic proteins, phosphatase D, histominase, arylsulfatase B; platelets release serotonin, mast cells and basophils - histamine, heparin arylsulfatase A, galactosidase, chemotrypsin, leukotrienes, prostaglandins, superoxide dismutase, neutrophil and eosinophil chemotoxic factors.
2. Also platelets, neutrophils, basophils, lymphocytes and endothelial cells are sources of platelet-activating factor. Allergy mediators are biologically active substances, with their help the so-called slow-reacting substance of anaphylaxis (MRS-A) is activated, which, in fact, causes anaphylaxis (a type of allergic reaction).

The development of such allergic reactions is represented by three stages:
1) immunological;
2) pathochemical;
3) pathophysical.

The stage of immune reactions, or immunological, begins with the accumulation of antibodies in the body after the introduction of a foreign antigen, which leads to the development of sensitization, or increased sensitivity of the body to this allergen. At this time, a clone of sensitized (sensitive) T-lymphocytes is formed. During the latent (hidden) period of sensitization, recognition and absorption of the allergen by the macrophage takes place, as a result of which most of the antigen is destroyed under the influence of hydrolytic enzymes. The remaining part of the antigen is fixed on the A-cell membrane in complex with proteins. This complex is called a superantigen; it has a certain immunogenicity and is capable of activating the production of antibodies. This process is influenced by T-helpers and T-suppressors. It has been proven that even minor changes in their ratio can lead to serious disorders immunogenesis. The formation and release of allergy mediators constitutes the next stage of immune reactions - the pathochemical stage, in which special meaning for the synthesis of mediators has the energy reserve of cells. The body becomes sensitized after about two weeks. When the allergen is re-entered, antigen-antibody complexes are formed. This moment is the trigger. Metabolism increases, new media are synthesized and released. There are two types of mediators that are released during immediate reactions.
Primary - this group is represented by serotonin, histamine, they are formed at the time of the antigen-antibody reaction.

Secondary - synthesized during the action of other cells and enzymes (for example, the mediator bradykinin).

In its own way biological activity And chemical structure mediators are divided into:
1) chemotactic (attracting certain cells
blood);
2) proteoglycans;
3) enzymes;
4) acting on smooth muscles and blood vessels.

1. Chemotactic mediators include the chemotaxis factor of neutrophils (a type of leukocyte) (FCN) and eosinophils (a type of leukocyte) (PCE). Neutrophil chemotaxis factors are responsible for terminating the local action of mediators and take part in modulating the release of biologically active substances. The most significant is histamine, which enhances or inhibits neutrophil chemotaxis, acting indirectly through H2 receptors or H2 receptors, respectively. The oxidation products of arachnoidic acid (leukotriene B4) also play an important role. After the start of the “antigen-antibody” contact, the release of a high-molecular neutrophil chemotaxis factor is observed within 5-15 minutes. Eosinophils migrate and accumulate in the lesion due to the eosinophil hemotaxis factor. The chemotaxis of eosinophils is also enhanced by other metabolic products, in particular arachnoidic acid, leukotriene B4, mono and hydroxy fatty acids, and histamine.

2. Proteoglycans. After the antigen is introduced into the body, a mediator is released that modulates (changes) the activity of trypsin (a destructive enzyme) and inhibits the functioning of the blood coagulation system. This is heparin, which is found in the granules of mast cells in the human skin and lungs and is closely related to histamine. Heparin contributes to the inhibition of complement functions. Proteoglycans such as chondrotin sulfates, found in basophils, have anticoagulant properties similar to heparin, but are approximately five times less active.

3. Enzymes as mediators of allergies are represented by neit; ral proteases (break down proteins) (active bradykinin, pulmonary Hageman factor, tryptase) and acidic (peroxidase and hydrolase). Increased inflammatory processes, fibrin deposition near mast cells, inhibition of blood clotting - all this is controlled by enzymes such as acid hydrolases, in particular arylsulfatase, superoxide dismutase, peroxidase, beta-glucuronidase, beta-hexaminase.

4. Mediators acting on smooth muscles and blood vessels. A prominent representative is histamine, which is found in mast cells of the skin, lungs, and submucosal layer of the intestine. Histamine is in close ionic bond with heparin. Histamine is also found in basophils (a type of white blood cell), but in smaller quantities. The greater the concentration of antigen that enters the body, the higher the rate of histamine release. In small doses, it affects β-receptors, which, in turn, leads to a narrowing of the bronchi, pulmonary and coronary vessels, increased chemotaxis of eosinophils and neutrophils, increased synthesis of prostaglandins F2-alpha, E2, thromboxane and other products of arachnoidic acid metabolism. Activation of H receptors increases mucus secretion in the upper respiratory tract, increases the concentration of cGMP inside the cell, increases the permeability of blood vessels and their dilation, and finally, stimulation of H receptors causes partial disconnection of connections between cells, which causes the development of urticaria or edema.

H2-histamine receptors are mostly located in the heart. Stimulation of these receptors is accompanied by dilation of the coronary vessels of the heart. Under their influence, secretion also increases of hydrochloric acid in the stomach. Normal level in the blood of this mediator should be 0.6 ± 0.2 ng/ml. Increasing it to 1.6 ng/ml leads to an increase in heart rate by 30%, to 2.4 ng/ml - headache, redness of the skin, to 4.6 ng/ml - an even greater increase in the rate of contraction of the left ventricle and moderate hypotension, and above 30 ng/ml leads to cardiac arrest. It is necessary to take into account the fact that when introducing any intravenous drug in 10-30% of individuals, several ng of histamine may be released into the blood. The combination of such drugs sometimes leads to a total increase in histamine levels, which sometimes causes various complications.
In some cases, with an increase in histamine levels, activation of H2 receptors located on T-suppressors is observed, which is a trigger for the occurrence of attacks in patients with atopic bronchial asthma.

Another mediator that plays an important role is serotonin, which also affects blood vessels and smooth muscles. Serotonin is involved in the migration of sensitized leukocytes through vascular endothelium(inner layer). Serotonin ensures platelet aggregation (sticking together) and also stimulates the secretion of lymphokines by T lymphocytes. In the presence of serotonin, permeability increases vascular wall and the smooth muscles of the bronchi contract.

In the third pathophysiological stage of immediate allergic reactions, after the formation and release of allergy mediators (in the pathochemical stage), the biological effects of these mediators develop and clinical manifestations. The most serious and dangerous manifestation of allergies is anaphylactic shock, in the development of which metabolites of arachnoidic acid play an important role. They are classified into:
1) cycloxygenase products: prostacyclin, thromboxanes,
prostaglandins;
2) lipoxygenase products: leukotrienes.

Prostaglandins are mediators that are synthesized
from arachnoidic acid with the participation of the enzyme cycloxygenase, the process occurs in most cases in mast cells of the parenchyma (tissue) of the lungs. These are mediators inflammatory reactions, bronchospasm, hypertension in the pulmonary artery system.
Leukotrienes are formed from fatty acids under the influence of the enzyme lipoxygenase. Three of them: C4, D4 and E4 constitute a slow-reacting substance (MRS-A). The effect of leukotriene C4 appears within ten minutes after the antigen enters the body and disappears after twenty-five to thirty minutes. This mediator increases the permeability of the microvasculature, causes bronchospasm, reduces cardiac output and increases systemic and pulmonary hypertension, accompanied by leukopenia and hemoconcentration. Leukotriene D4 is much stronger in its histamine characteristics, especially in its ability to constrict small bronchi, coronary vessels and vessels of the pulmonary circulation. Leukotriene E4 activates the formation of thromboxane in the bronchi, causing their swelling, increased mucus secretion and thereby causing prolonged bronchospasm.

Allergy (Greek “allos” - another, different, “ergon” - action) is a typical immunopathological process that occurs against the background of the influence of an allergen antigen on the body with a qualitatively altered immunological reactivity and is accompanied by the development of hyperergic reactions and tissue damage.

There are immediate and delayed allergic reactions (humoral and cellular reactions, respectively). Allergic antibodies are responsible for the development of allergic reactions of the humoral type.

For manifestation clinical picture An allergic reaction requires at least 2 contacts of the body with the allergen antigen. The first dose of allergen exposure (small) is called sensitizing. The second dose of exposure - large (resolving) is accompanied by the development of clinical manifestations of an allergic reaction. Allergic reactions of the immediate type can occur within a few seconds or minutes, or 5 to 6 hours after repeated contact of the sensitized organism with the allergen.

In some cases, long-term persistence of the allergen in the body is possible and, in connection with this, it is almost impossible to draw a clear line between the effects of the first sensitizing and repeated resolving doses of the allergen.

Classification of immediate allergic reactions:

• 1) anaphylactic (atopic);
• 2) cytotoxic;
• 3) immune complex pathology.

Stages of allergic reactions:

I - immunological

II - pathochemical

III - pathophysiological.

Allergens that induce the development of humoral allergic reactions

Antigens-allergens are divided into antigens of bacterial and non-bacterial nature.

Non-bacterial allergens include:

• 1) industrial;
• 2) household;
• 3) medicinal;
• 4) food;
• 5) vegetable;
• 6) of animal origin.

There are complete antigens (determinant groups + carrier protein), capable of stimulating the production of antibodies and interacting with them, as well as incomplete antigens, or haptens, consisting only of determinant groups and not inducing the production of antibodies, but interacting with ready-made antibodies. There is a category of heterogeneous antigens that have similar structures of determinant groups.

Allergens can be strong or weak. Strong allergens stimulate the production of large amounts of immune or allergic antibodies. Soluble antigens, usually of a protein nature, act as strong allergens. An antigen of a protein nature is stronger, the higher its molecular weight and the more rigid the structure of the molecule. Weak are corpuscular, insoluble antigens, bacterial cells, antigens of damaged cells of the body's own.

There are also thymus-dependent and thymus-independent allergens. Thymus-dependent antigens are those that induce an immune response only with the obligatory participation of 3 cells: macrophage, T-lymphocyte and B-lymphocyte. Thymus-independent antigens can induce an immune response without the participation of helper T lymphocytes.

General patterns of development of the immunological phase of immediate-type allergic reactions

The immunological stage begins with exposure to a sensitizing dose of the allergen and the latent period of sensitization, and also includes the interaction of the resolving dose of the allergen with allergic antibodies.

The essence of the latent period of sensitization lies, first of all, in the macrophage reaction, which begins with the recognition and absorption of the allergen by the macrophage (A-cell). During the process of phagocytosis, most of the allergen is destroyed under the influence of hydrolytic enzymes; the non-hydrolyzed part of the allergen (determinant groups) is exposed on the outer membrane of the A-cell in complex with Ia proteins and macrophage mRNA. The resulting complex is called a superantigen and has immunogenicity and allergenicity (the ability to induce the development of immune and allergic reactions), many times greater than that of the original native allergen. During the latent period of sensitization, following the macrophage reaction, a process of specific and nonspecific cooperation of three types of immunocompetent cells occurs: A-cells, T-helper lymphocytes and antigen-responsive clones of B-lymphocytes. First, the allergen and Ia proteins of the macrophage are recognized by specific receptors of T-lymphocyte helpers, then the macrophage secretes interleukin-1, which stimulates the proliferation of T-helper cells, which, in turn, secrete an inducer of immunogenesis, stimulating the proliferation of antigen-sensitive clones of B-lymphocytes, their differentiation and transformation into plasma cells - producers of specific allergic antibodies.

The process of antibody formation is influenced by another type of immunocytes - T-suppressors, whose action is opposite to the action of T-helpers: they inhibit the proliferation of B-lymphocytes and their transformation into plasma cells. Normally, the ratio of T-helpers to T-suppressors is 1.4 - 2.4.

Allergic antibodies are divided into:

• 1) aggressor antibodies;
• 2) bystander antibodies;
• 3) blocking antibodies.

Each type of allergic reaction (anaphylactic, cytolytic, immunocomplex pathology) is characterized by certain aggressor antibodies that differ in immunological, biochemical and physical properties.

When a permissive dose of antigen penetrates (or in the case of persistence of the antigen in the body), the active centers of antibodies interact with determinant groups of antigens at the cellular level or in the systemic bloodstream.

The pathochemical stage consists of the formation and release in environment in a highly active form of allergy mediators, which occurs during the interaction of an antigen with allergic antibodies at the cellular level or fixation of immune complexes on target cells.

The pathophysiological stage is characterized by the development of biological effects of immediate-type allergy mediators and clinical manifestations of allergic reactions.

Anaphylactic (atonic) reactions

There are generalized (anaphylactic shock) and local anaphylactic reactions (atopic bronchial asthma, allergic rhinitis and conjunctivitis, urticaria, Quincke's edema).

Allergens that most often induce the development of anaphylactic shock:

• 1) allergens of antitoxic serums, allogeneic preparations?-globulins and blood plasma proteins;
• 2) allergens of hormones of protein and polypeptide nature (ACTH, insulin, etc.);
• 3) medications (antibiotics, in particular penicillin, muscle relaxants, anesthetics, vitamins, etc.);
• 4) radiopaque agents;
• 5) insect allergens.

Local anaphylactic reactions can be caused by:

• 1) allergens of plant pollen (polynoses), fungal spores;
• 2) allergens from house and industrial dust, epidermis and animal hair;
• 3) allergens of cosmetics and perfumes, etc.

Local anaphylactic reactions occur when an allergen enters the body naturally and develops in places of entry and fixation of allergens (conjunctival mucosa, nasal passages, gastrointestinal tract, skin, etc.).

The aggressor antibodies in anaphylaxis are homocytotropic antibodies (reagins or atopens), belonging to immunoglobulins of classes E and G4, capable of fixing on various cells. Reagins are fixed primarily on basophils and mast cells - cells with high-affinity receptors, as well as on cells with low-affinity receptors (macrophages, eosinophils, neutrophils, platelets).

With anaphylaxis, two waves of release of allergy mediators are distinguished:

• The 1st wave occurs after approximately 15 minutes, when mediators are released from cells with high-affinity receptors;
• 2nd wave - after 5 - 6 hours, the sources of mediators in this case are carrier cells of low-affinity receptors.

Mediators of anaphylaxis and sources of their formation:

• 1) mast cells and basophils synthesize and secrete histamine, serotonin, eosinophilic and neutrophilic factors, chemotactic factors, heparin, arylsulfatase A, galactosidase, chymotrypsin, superoxide dismutase, leukotrienes, prostaglandins;
• 2) eosinophils are a source of arylsulfatase B, phospholipase D, histaminase, and cationic proteins;
• 3) leukotrienes, histaminase, arylsulfatases, prostaglandins are released from neutrophils;
• 4) from platelets - serotonin;
• 5) basophils, lymphocytes, neutrophils, platelets and endothelial cells are sources of the formation of platelet-activating factor in the case of activation of phospholipase A2.

Clinical symptoms of anaphylactic reactions are due to biological effect allergy mediators.

Anaphylactic shock is characterized by the rapid development of general manifestations of pathology: a sharp drop in blood pressure up to a collaptoid state, disorders of the central nervous system, disorders of the blood coagulation system, spasm of smooth muscles respiratory tract, gastrointestinal tract, increased vascular permeability, skin itching. Death may occur within half an hour with symptoms of asphyxia, severe damage to the kidneys, liver, gastrointestinal tract, heart and other organs.

Local anaphylactic reactions are characterized by increased permeability of the vascular wall and the development of edema, the appearance of skin itching, nausea, abdominal pain due to spasm of smooth muscle organs, sometimes vomiting, and chills.

Cytotoxic reactions

Varieties: blood transfusion shock, Rh incompatibility of mother and fetus, autoimmune anemia, thrombocytopenia and other autoimmune diseases, a component of transplant rejection.

The antigen in these reactions is a structural component of the membrane of the body's own cells or an antigen of an exogenous nature (bacterial cell, medicinal substance, etc.), firmly fixed on the cells and changing the structure of the membrane.

Cytolysis of the target cell under the influence of a resolving dose of the allergen antigen is ensured in three ways:

• 1) due to activation of complement - complement-mediated cytotoxicity;
• 2) due to the activation of phagocytosis of cells coated with antibodies - antibody-dependent phagocytosis;
• 3) through activation of antibody-dependent cellular cytotoxicity - with the participation of K-cells (null, or neither T- nor B-lymphocytes).

The main mediators of complement-mediated cytotoxicity are activated complement fragments. Complement refers to a closely related system of serum enzyme proteins.

DELAYED TYPE HYPERSENSITIVITY REACTIONS

Delayed-type hypersensitivity (DTH) is one of the forms of pathology of cellular immunity carried out by immunocompetent T-lymphocytes against cell membrane antigens.

For the development of HRT reactions, previous sensitization that occurs upon initial contact with the antigen is necessary. HRT develops in animals and humans 6–72 hours after penetration of the resolving (repeated) dose of the allergen antigen into the tissue.

Types of HRT reactions:

• 1) infectious allergy;
• 2) contact dermatitis;
• 3) transplant rejection;
• 4) autoimmune diseases.

Antigens-allergens that induce the development of the HRT reaction:

The main participants in HRT reactions are T lymphocytes (CD3). T lymphocytes are formed from undifferentiated stem cells of the bone marrow, which proliferate and differentiate in the thymus, acquiring the properties of antigen-reactive thymus-dependent lymphocytes (T lymphocytes). These cells settle in the thymus-dependent areas of the lymph nodes, spleen, and are also present in the blood, providing cellular immune responses.

Subpopulations of T lymphocytes

• 1) T-effectors (T-killers, cytotoxic lymphocytes) - destroy tumor cells, genetically foreign cells of transplants and mutated cells of one’s own body, performing the function of immunological surveillance;
• 2) T-producers of lymphokines - participate in HRT reactions, releasing HRT mediators (lymphokines);
• 3) T-modifiers (T-helpers (CD4), amplifiers) - promote differentiation and proliferation of the corresponding clone of T-lymphocytes;
• 4) T-suppressors (CD8) - limit the strength of the immune response, blocking the proliferation and differentiation of T- and B-series cells;
• 5) Memory T cells - T lymphocytes that store and transmit information about the antigen.

General mechanisms for the development of delayed-type hypersensitivity reactions

When an allergen antigen enters the body, it is phagocytosed by a macrophage (A-cell), in whose phagolysosome, under the influence of hydrolytic enzymes, part of the allergen antigen is destroyed (about 80%). The unfragmented part of the allergen antigen, in complex with Ia protein molecules, is expressed on the A-cell membrane in the form of a superantigen and is presented to antigen-recognizing T lymphocytes. Following the macrophage reaction, there is a process of cooperation between the A-cell and T-helper, the first stage of which is the recognition of a foreign antigen on the surface of the A-cell by antigen-specific receptors on the T-helper membrane, as well as the recognition of Ia proteins of the macrophage by specific T-helper receptors. Next, A cells produce interleukin-1 (IL-1), which stimulates the proliferation of T-helper cells (T-amplifiers). The latter secrete interleukin-2 (IL-2), which activates and supports blast transformation, proliferation and differentiation of antigen-stimulated T-producers of lymphokines and T-killers in regional lymph nodes.

When T-lymphokine producers interact with the antigen, more than 60 soluble mediators of HRT-lymphokines are secreted, which act on various cells in the lesion allergic inflammation.

Classification of lymphokines.

I. Factors affecting lymphocytes:

• 1) Lawrence transfer factor;
• 2) mitogenic (blastogenic) factor;
• 3) a factor that stimulates T- and B-lymphocytes.

II. Factors influencing macrophages:

• 1) migration inhibitory factor (MIF);
• 2) factor that activates macrophages;
• 3) a factor that enhances the proliferation of macrophages.

III. Cytotoxic factors:

• 1) lymphotoxin;
• 2) a factor inhibiting DNA synthesis;
• 3) a factor that inhibits hematopoietic stem cells.

IV. Chemotactic factors for:

• 1) macrophages, neutrophils;
• 2) lymphocytes;
• 3) eosinophils.

V. Antiviral and antimicrobial factors - β-interferon (immune interferon).

Along with lymphokines, other biologically active substances also play a role in the development of allergic inflammation during HRT: leukotrienes, prostaglandins, lysosomal enzymes, and kelones.

If T-producers of lymphokines realize their effect remotely, then sensitized T-killers have a direct cytotoxic effect on target cells, which occurs in three stages.

Stage I - target cell recognition. The killer T cell attaches to the target cell through cellular receptors for a specific antigen and histocompatibility antigens (H-2D and H-2K proteins - products of the D and K genes of the MHC loci). In this case, a close membrane contact between the T-killer and the target cell occurs, which leads to the activation of the metabolic system of the T-killer, which subsequently carries out lysis of the “target cell”.

Stage II - lethal blow. The killer T cell has a direct toxic effects on the target cell due to the activation of enzymes on the membrane of the effector cell.

Stage III - osmotic lysis of the target cell. This stage begins with a series of sequential changes in the membrane permeability of the target cell and ends with rupture of the cell membrane. Primary damage to the membrane leads to the rapid entry of sodium and water ions into the cell. The death of the target cell occurs as a result of osmotic lysis of the cell.

Phases of delayed-type allergic reactions:

I - immunological - includes the period of sensitization after the introduction of the first dose of the allergen antigen, proliferation of the corresponding clones of effector T-lymphocytes, recognition and interaction with the target cell membrane;

II - pathochemical - phase of release of HRT mediators (lymphokines);

III - pathophysiological - manifestation of the biological effects of HRT mediators and cytotoxic T-lymphocytes.

Selected forms of HRT

Contact dermatitis

Allergies of this type most often occur to low molecular weight substances of organic and inorganic origin: various chemicals, paints, varnishes, cosmetics, antibiotics, pesticides, arsenic, cobalt, platinum compounds that affect the skin. Contact dermatitis can also be caused by substances of plant origin - cotton seeds, citrus fruits. Allergens, penetrating the skin, form stable covalent bonds with the SH- and NH2-groups of skin proteins. These conjugates have sensitizing properties.

Sensitization usually occurs as a result of prolonged contact with an allergen. With contact dermatitis, pathological changes are observed in surface layers skin. Infiltration by inflammatory cellular elements, degeneration and detachment of the epidermis, and loss of integrity are noted basement membrane.

Infectious allergy

HRT develops in chronic bacterial infections caused by fungi and viruses (tuberculosis, brucellosis, tularemia, syphilis, bronchial asthma, streptococcal, staphylococcal and pneumococcal infections, aspergillosis, blastomycosis), as well as for diseases caused by protozoa (toxoplasmosis), and for helminthic infestations.

Sensitization to microbial antigens usually develops during inflammation. The possibility of sensitization of the body by some representatives cannot be ruled out. normal microflora(Neisseria, Escherichia coli) or pathogenic microbes when they are carried.

Graft rejection

During transplantation, the recipient's body recognizes foreign transplantation antigens (histocompatibility antigens) and carries out immune reactions leading to transplant rejection. Transplantation antigens are present in all nucleated cells, with the exception of adipose tissue cells.

Types of grafts

• 1. Syngeneic (isograft) - the donor and recipient are representatives of inbred lines that are antigenically identical (monozygotic twins). The syngeneic category includes an autograft when tissue (skin) is transplanted within the same organism. In this case, transplant rejection does not occur.
• 2. Allogeneic (homograft) - the donor and recipient are representatives of different genetic lines within the same species.
• 3. Xenogeneic (heterograft) - the donor and recipient belong to different species.

Allogeneic and xenogeneic transplants are rejected without the use of immunosuppressive therapy.

Dynamics of skin allograft rejection

In the first 2 days, the transplanted skin flap merges with the recipient's skin. At this time, blood circulation is established between the tissues of the donor and recipient and the graft looks like normal skin. On the 6th - 8th day, swelling, infiltration of the graft with lymphoid cells, local thrombosis and stasis appear. The graft becomes bluish and hard, and degenerative changes occur in the epidermis and hair follicles. By the 10th - 12th day the graft dies and does not regenerate even when transplanted to a donor. When a graft is re-transplanted from the same donor, pathological changes develop faster - rejection occurs on the 5th day or earlier.

Mechanisms of graft rejection

• 1. Cellular factors. The recipient's lymphocytes, sensitized by donor antigens, migrate into the graft after vascularization of the graft, exerting a cytotoxic effect. As a result of the influence of T-killers and under the influence of lymphokines, the permeability of the membranes of target cells is disrupted, which leads to the release of lysosomal enzymes and cell damage. For more late stages Macrophages also participate in the destruction of the graft, enhancing the cytopathogenic effect, causing cell destruction according to the type of antibody-dependent cellular cytotoxicity due to the cytophilic antibodies present on their surface.
• 2. Humoral factors. During allotransplantation of skin, bone marrow, and kidney, hemagglutinins, hemolysins, leukotokeins, and antibodies to leukocytes and platelets are often formed. During the antigen-antibody reaction, biologically active substances are formed that increase vascular permeability, which facilitates the migration of killer T cells into the transplanted tissue. Lysis of endothelial cells in the graft vessels leads to activation of blood coagulation processes.

Autoimmune diseases

Diseases of an autoimmune nature are divided into two groups.

The first group consists of collagenoses - systemic diseases connective tissue, in which autoantibodies are detected in the blood serum without strict organ specificity. So, with SLE and rheumatoid arthritis autoantibodies are detected to antigens of many tissues and cells: connective tissue of the kidneys, heart, lungs.

The second group includes diseases in which organ-specific antibodies are detected in the blood (Hashimoto’s thyroiditis, pernicious anemia, Addison's disease, autoimmune hemolytic anemia etc.).

There are several possible mechanisms in the development of autoimmune diseases.

• 1. Formation of autoantibodies against natural (primary) antigens - antigens of immunologically barrier tissues (nervous, lens, thyroid gland, testes, sperm).
• 2. Formation of autoantibodies against acquired (secondary) antigens formed under the influence of the damaging effects on organs and tissues of pathogenic factors of non-infectious (heat, cold, ionizing radiation) and infectious (microbial toxins, viruses, bacteria) nature.
• 3. Formation of autoantibodies against cross-reacting or heterogeneous antigens. The membranes of some varieties of streptococcus are antigenically similar to cardiac tissue antigens and glomerular basement membrane antigens. In this regard, antibodies to these microorganisms during streptococcal infections react with tissue antigens of the heart and kidneys, leading to the development of autoimmune damage.
• 4. Autoimmune lesions can occur as a result of a breakdown of immunological tolerance to one’s own unchanged tissues. Failure of immunological tolerance can be caused by somatic mutations of lymphoid cells, which leads either to the appearance of mutant forbidden clones of T-helpers, ensuring the development of an immune response to their own unchanged antigens, or to a deficiency of T-suppressors and, accordingly, an increase in the aggressiveness of the B-lymphocyte system against native ones antigens.

The development of autoimmune diseases is caused by a complex interaction of allergic reactions of cellular and humoral types with the predominance of one or another reaction depending on the nature of the autoimmune disease.

Principles of hyposensitization

For allergic reactions of the cellular type, methods are usually used nonspecific hyposensitization, aimed at suppressing the afferent link, the central phase and the efferent link of delayed-type hypersensitivity.

The afferent link is provided by tissue macrophages - A-cells. Synthetic compounds suppress the afferent phase - cyclophosphamide, nitrogen mustard, gold preparations

To suppress the central phase of cell-type reactions (including the processes of cooperation between macrophages and various clones of lymphocytes, as well as the proliferation and differentiation of antigen-reactive lymphoid cells), various immunosuppressants are used - corticosteroids, antimetabolites, in particular, analogues of purines and pyrimidines (mercaptopurine, azathioprine), antagonists folic acid(amethopterin), cytotoxic substances (actinomycin C and D, colchicine, cyclophosphamide). allergic antigen medical electrical injury

To suppress the efferent link of cellular hypersensitivity reactions, including the damaging effect on target cells of killer T cells, as well as delayed-type allergy mediators - lymphokines, anti-inflammatory drugs - salicylates, antibiotics with a cytostatic effect - actinomycin C and rubomycin, hormones and biological active substances are used , in particular corticosteroids, prostaglandins, progesterone, antisera.

It should be noted that most of the used immunosuppressive drugs does not cause a selective inhibitory effect only on the afferent, central or efferent phases of allergic reactions of the cellular type.

It should be noted that in the vast majority of cases, allergic reactions have a complex pathogenesis, including, along with the dominant mechanisms of delayed (cellular) type hypersensitivity reactions, and auxiliary mechanisms of humoral type allergies.

In this regard, to suppress the pathochemical and pathophysiological phases of allergic reactions, it is advisable to combine the principles of hyposensitization used for allergies of humoral and cellular types.

(1) Cytotropic (cytophilic) type reactions . The following substances act as initiators of a generalized anaphylactic reaction (anaphylactic shock) of this type of allergy:

allergens of antitoxic serums, allogeneic preparations of γ-globulins and blood plasma proteins;

allergens of hormones of protein and polypeptide nature (ACTH, insulin and others);

medications [antibiotics (penicillin), muscle relaxants, anesthetics, vitamins and others];

radiopaque agents;

insect allergens.

Local anaphylactic reactions - atopic bronchial asthma, allergic rhinitis and conjunctivitis, urticaria, Quincke's edema) - can occur under the influence of such antigens as:

allergens of plant pollen (hay fever), fungal spores);

house and industrial dust allergens;

epidermal allergens of pets;

allergens contained in cosmetics and perfumes, etc.

As a result of primary contact with the allergen, the ICS organizes an immune response in the body, the specificity of which lies in the synthesis of Ig E- and/or Ig G 4-class immunoglobulins (reagins, atopenes) by B-lymphocytes and plasma cells. The production of Ig G 4 and E-class immunoglobulins by B lymphocytes depends on the presentation of the allergen by APC and cooperation between T and B lymphocytes. Locally synthesized E-class Ig initially sensitizes mast cells at the site of its formation, after which the antibody spreads through the bloodstream to all organs and tissues of the body (Fig. 1;).

Rice. 1. Schematic representation of reactino-

vogo (cytotropic, cytophilic) mechanism

immediate hypersensitivity

Subsequently, the bulk of the Ig E- and Ig G 4 classes interact with high-affinity receptors and their subsequent fixation at the site of localization of Fc receptors on the cytoplasmic membranes of first-order target cells - mast cells (mast cells) and basophils. The remaining immunoglobulins of the Ig E and Ig G 4 classes interact with low-affinity receptors of second-order target cells - granulocytes, macrophages, lymphocytes, platelets, Langerhans cells of the skin and endothelial cells, also using a fragment of the Fc receptor. For example, on each mast cell or basophil, from 3,000 to 300,000 Ig E molecules can be fixed. Here they are able to remain for several months, and during this entire period of time, increased sensitivity to the allergen of first- and second-order target cells remains.

When the allergen re-enters, which can occur at least a week or more after the initial contact, an immune complex Ag+AT is formed at the site of localization of the IgE class, which is also fixed on the membranes of target cells of the first and second order. This leads to the withdrawal of receptor proteins for Ig E from the surface of the cytoplasmic membrane and subsequent activation of the cell, which is expressed in increased synthesis, secretion and release of HNT mediators. Maximum cell activation is achieved by binding of several hundred or thousands of receptors by immune complexes Ag+AT. The degree of activation of target cells depends on the content of calcium ions, the energy potential of the cell, as well as the ratio of cyclic adenosine monophosphate (cAMP) and guanosine monophosphate (cGMP) - a decrease in cAMP and an increase in cGMP.

As a result of the formation of the AG + AT complex and the activation of target cells (for example, mast cells), their cytolemma is destroyed, and the contents of the cytoplasmic granules are poured into the pericellular space. Mast cells, or mast cells, belong to the components of connective tissue and are localized mainly in those structures that directly or indirectly interact with the environment - skin, respiratory tract, digestive tract, along the nerve fibers and blood vessels.

In the process of destruction of the cytoplasmic and intracellular membranes, a large number of presynthesized biologically active substances are poured into the pericellular space, which are called immediate-type allergy mediators - vasoactive amines (histamine, serotonin), arachidonic acid metabolites (prostaglandins, leukotrienes, thromboxane A 2), cytokines that mediate local and systemic tissue damage [interleukins-1-6, IL-8, 10, 12, 13, platelet activating factor - PAF, neutrophil and eosinophil chemotaxis factors, TNF-α, γ-INF, eosinophil proteins, eosinophil neurotoxins, adhesins, selectins (P and E), granulocyte-monocyte colony-stimulating factor, lipid peroxidation products) and many other biologically active substances (heparin, kinins, arylsulfatases A and B, galactosidase, superoxide dismutase, histaminase, phospholipases A  and D, chymotrypsin, lysosomal enzymes, cationic proteins )]. Most of them are found in granules, primarily basophils, mast cells, as well as neutrophils, eosinophils, macrophages and others, and the process of releasing granules from first- and second-order target cells containing HNT mediators is called degranulation. Mediators of immediate allergic reactions have both protective and pathogenic effects. The latter is manifested by symptoms of various diseases. The classic way of releasing allergy mediators leads to immediate reactions that develop in the first half hour - the so-called first wave of mediator release. It is caused by the release of allergy mediators from cells with high affinity receptors (mast cells and basophils).

An additional pathway associated with the formation of a second wave of release of reagin allergy mediators initiates the development of the so-called late, or delayed, phase of HNT, associated with the release of biologically active substances from second-order target cells (granulocytes, lymphocytes, macrophages, platelets, endothelial cells). It appears after 6-8 hours. The severity of the late reaction may vary. Most HNT mediators have a predominant effect on vascular tone, the permeability of their walls and the state of smooth muscle fibers of hollow organs (relaxation or spasm). For example, the spasmogenic effect of leukotriene D 4 is hundreds of times higher than that of histamine.

This type of reaction is called cytotropic, or cytophilic, due to the high affinity (affinity) of Ig E for target cells. Degranulation of mast cells can occur under the influence of non-immunological activators - ACTH, substance P, somatostatin, neurotensin, ATP, as well as activation products of granulocytes and macrophages: cationic proteins, myeloperoxidase, free radicals. Some drugs (eg, morphine, codeine, radiocontrast agents) have a similar ability.

Genetic aspects of reagin allergy. It is well known that atopy (reaginic or anaphylactic type of allergy) occurs only in a certain category of patients. In such subjects, a noticeably larger amount of E-class immunoglobulins is synthesized, a higher density of Fc receptors and their higher sensitivity to Ig E are detected on first-order target cells, and a deficiency of suppressor T lymphocytes is detected. In addition, the skin and airways of such patients have a higher sensitivity to the action of specific and nonspecific stimuli compared to those of other subjects. In families where one of the parents suffers from allergies, atopy in children occurs in 30-40% of cases. If both parents suffer from a similar form of allergy, then anaphylaxis (or the reagin form of GNT) is detected in children in 50-80% of cases. Predisposition to atopy is determined by a group of genes that control the immune response, the synthesis of anti-inflammatory cytokines, the development of hyperreactivity of the smooth muscles of blood vessels, bronchi, hollow organs, etc. It has been proven that these genes are localized on chromosomes 5, 6, 12, 13, 20 and possibly other chromosomes.

(2) Cytotoxic type reactions . This mechanism began to be called cytotoxic because when a type II allergic reaction occurs, damage and death of target cells are observed, against which the action of the ICS was directed (Fig. 2;).

Rice. 2. Schematic representation of cytotoxic

(cytolytic) mechanism of hypersensitivity

immediate type. Designations: C – complement, K –

activated cytotoxic cell.

The reasons for the development of cytotoxic type of reactions may be:

firstly, antigens that are part of their own modified cytoplasmic membranes (most often, blood cells, kidney cells, liver, heart, brain and others);

secondly, exogenous Ags, secondarily fixed on the cytoplasmic membrane (drugs, metabolites or components of microorganisms, and others);

thirdly, non-cellular tissue components (for example, AG of the glomerular basement membrane, collagen, myelin, etc.).

There are three known mechanisms of cytotoxic (cytolytic) tissue damage in this type of allergy.

Complement mediated cytotoxicity;

Activation of phagocytosis of cells marked with antibodies;

Activation of antibody-dependent cellular toxicity;

The next stage is that this immune complex adsorbs on itself and activates complement components according to the classical type. Activated complement forms a membrane attack complex, which perforates the membrane, followed by lysis of the target cell. Therefore, this type of reaction was called cytolytic. Th 1 takes part in the induction of cytolytic reactions, producing IL-2 and γ-IFN. IL-2 ensures autocrine activation of Th, and γ-IFN – switches the synthesis of immunoglobulins from Ig M to Ig G.

Many autoimmune diseases develop through this mechanism - autoimmune and drug-induced hemolytic anemia, thrombocytopenia, leukopenia, Hashimoto's thyroiditis, autoimmune aspermatogenesis, sympathetic ophthalmopathy, transfusion shock when transfused with incompatible blood group or Rh factor, Rh conflict of mother and fetus, etc. P. The main mediators of complement dependent type allergies are

activated complement components (C4b2a3b, C567, C5678, C56789, etc.),

oxidants (O - , OH - and others),

lysosomal enzymes.

2. Another mechanism of cytolytic damage to target cells (cells with altered membrane properties) is associated with the activation of a subpopulation of cytotoxic cells and their attachment through the Fc receptor and Ig G- or Ig M classes to the cytoplasmic membrane with altered antigenic properties. Such cytotoxic cells can be natural killer cells (NK cells), granulocytes, macrophages, platelets, which recognize target cells to be destroyed through immunoglobulins fixed on them and their own Fc receptors, attach to them and inject toxic principles into the target cell, destroying her. It is assumed that Abs can act as “bridges” between the target cell and the effector cell.

3. The third mechanism of a type II allergic reaction is considered to be the destruction of the target cell through phagocytosis carried out by macrophages. Fc receptors of macrophages recognize antibodies fixed on the target cell and through them attach to the cell, followed by phagocytosis. This mechanism of destruction of target cells is typical, for example, in relation to platelets with ATs fixed on them, as a result of which the blood platelets become the object of phagocytosis, passing through the sinuses of the spleen.

In general, the mechanisms of type II allergic reactions include autoimmune hemolytic anemia and thrombocytopenia, diabetes mellitus, bronchial asthma, allergic drug agranulocytosis, post-infarction and post-commissurotomy myocarditis, endocarditis, encephalitis, thyroiditis, hepatitis, drug allergies, myasthenia gravis, components of the transplant rejection reaction and others.

(3) Immune complex formation reactions . Immune complex pathology has a certain place in the mechanisms of development of diseases such as glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, scleroderma, arteritis, endocarditis and others. This type of reaction occurs when the following allergens enter the sensitized body in a known high dose and in soluble form:

allergens of antitoxic serums,

allergens of certain medications (antibiotics, sulfonamides and others),

allergens of food proteins (milk, eggs, etc.),

household allergens,

bacterial and viral allergens,

cell membrane antigens,

allogeneic γ-globulins,

Precipitating (Ig G 1-3) and complement-fixing (Ig M) immunoglobulins synthesized for these allergens interact equivalently with a specific allergen and form medium-sized circulating immune complexes (CIC) of Ag + Ab, soluble in plasma and other body fluids. Such complexes are called precipitins (Fig. 3). Th 1 takes part in the induction of the immune response. Exogenous and endogenous Ags are constantly detected in the human body, which initiate the formation of immune complexes Ag+Abs. These reactions are an expression of the protective, or homeostatic, function of the immune system and are not accompanied by any damage. Immune complexes are required for rapid and efficient phagocytosis. However, under certain conditions they can acquire aggressive properties and destroy the body's own tissues. The damaging effect is usually caused by soluble complexes medium-sized, appearing with a slight excess of AG. Important role The occurrence of this pathology is attributed to disturbances in the system of elimination of complexes (deficiency of complement components, Fc fragments of antibodies or receptors on erythrocytes for immune complexes, disturbances in the macrophage reaction), as well as the presence of chronic infection. In such cases, their damaging effect is realized through the activation of complement, the kallikrein-kinin system, the release of lysosomal enzymes, and the generation of superoxide radical.

Rice. 3. Schematic representation

immune complex mechanism of hypersensitivity

immediate type. Designations as in Fig. 1.

Precipitins can be found either in the blood, where they are localized on the inner wall of small vessels, or in tissues. Deposits, which include Ig G, penetrate the vascular wall, stratify endothelial cells and accumulate in its thickness on the basement membrane, resulting in the formation of larger and larger conglomerates of immune complexes. Unlike the CEC, they can activate not only complement components, but also the kinin, coagulation and fibrinolytic systems of the blood, as well as granulocytes, mast cells and platelets. As a result, at the site of their precipitation, for example, in the lumen of peripheral vessels, accumulations of leukocytes and other blood cells are formed, thrombosis is formed, and the permeability of the vascular wall increases. All this leads to the development of allergic (hyperergic) inflammation with a predominance of alteration and exudation processes. Being activated, fixed complement components enhance inflammatory reactions, causing the formation of anaphylotoxins (C3a and C5a), and inflammatory and allergic mediators (in particular, chemotactic factors) attract more and more leukocytes to the lesion site. Anaphylotoxins C3a and C5a cause the release of histamine by mast cells, contraction of smooth muscles and increase vascular permeability, promoting the further development of inflammation.

This type is a generalized form of allergy, for example, serum sickness. It is characterized by the development of systemic vasculitis, hemodynamic disorder, edema, rash, itching, arthralgia, hyperplasia lymphoid tissue(see also below).

Glomerulonephritis of immunocomplex origin is characterized by impaired filtration, reabsorption and secretory functions of the kidneys.

Rheumatoid arthritis is accompanied by the formation of rheumatoid factor (IgM19S, IgG7S), autoantigens of inflammatory origin and autoantibodies, immune complexes and the involvement of synovial membranes in the pathological process with the development of systemic vasculitis (cerebral, mesenteric, coronary, pulmonary).

The formation of systemic lupus erythematosus is accompanied by the formation of immune complexes consisting of native DNA and nuclear proteins, antibodies to them and complement, which are subsequently fixed on the basement membrane of the capillaries, causing damage to the joints (polyarthritis), skin (erythema), serous membranes (exudative and adhesive process up to proliferation), kidneys (glomerulonephritis), nervous system (neuropathy), endocardium (Liebman-Sachs endocarditis), blood cells (anemia, leukopenia, thrombocytopenia, pancytopenia), and other organs.

If immune complexes are fixed in individual organs or tissues, then subsequent damaging processes are localized precisely in these tissues. For example, during vaccination, the antigen is fixed at the injection site with the subsequent development of a local allergic reaction similar to the Arthus phenomenon. The main mediators in this type of allergic reactions are

activated complement,

lysosomal enzymes,

• histamine,

  serotonin,

  superoxide anion radical.

The formation of immune complexes, their activation of leukocytes and other cellular elements, as well as their direct damaging effect, cause secondary reactions of immunoallergic origin. These include the development of allergic inflammation, cytopenias, intravascular coagulation, thrombus formation, immunodeficiency states and others. As mentioned above, specific manifestations of allergic diseases occurring in this type of HNT are serum sickness, glomerulonephritis, arteritis, exogenous allergic alveolitis (“farmer’s lung”, “poultry farmer’s lung” and others), rheumatoid arthritis, endocarditis, anaphylactic shock, systemic red lupus, bacterial, viral and protozoal infections (eg, streptococcal diseases, viral hepatitis B, trypanosomiasis and others), bronchial asthma, vasculitis and others.

(4) Receptor-mediated reactions . This type IV allergic reaction mechanism is called antireceptor. It is associated with the presence of antibodies (mainly Ig G) to physiologically important determinants of the cell membrane, causing stimulating or inhibitory effects on the target cell through its receptors. As a result, for example, blockades are switched off from active functioning of numerous receptors of target cells, with the help of which they exchange molecular material with the pericellular space, including biologically active substances (ligands) necessary for normal cell activity (β-adrenergic receptors, acetylcholine, insulin and others receptors). An example of such a blocking effect is myasthenia gravis, which develops as a result of the formation of Ig G to the receptors of the neurotransmitter acetylcholine, localized on the postsynaptic membrane of skeletal muscle myocytes. The binding of AT to acetylcholine receptors blocks them, preventing the connection of acetylcholine with them and the subsequent formation of the muscle plate potential. Ultimately, the transmission of impulses from the nerve fiber to the muscle and its contraction are disrupted.

An example of a receptor-mediated stimulating type of allergic reaction is the development of a hyperthyroid state when AT antibodies imitate the effects of thyroid-stimulating hormone. Thus, in hyperthyroidism (allergic thyrotoxicosis), which is an autoimmune disease, autoantibodies activate receptors for thyroid-stimulating hormone. The latter stimulate thyrocytes of the thyroid follicles, which continue to synthesize thyroxine, despite the limited production of thyroid-stimulating hormone by the pituitary gland.

General patterns of development of delayed-type allergic reactions

Immunological stage of HRT . In cases of HRT, active sensitization is associated with the formation of an antigen–nonspecific receptor complex on the surface of the APC—macrophage, in which most of the antigens are destroyed during endocytosis. Passive sensitization is achieved by introducing pre-sensitized T-lymphocytes into the blood or transplanting lymphoid tissue of lymph nodes from an animal pre-sensitized with this AG. . Determinant allergen groups (epitopes) in combination with MHC class I and II proteins are expressed on the APC membrane and presented to antigen-recognizing T lymphocytes.

CD4 lymphocytes take part in the induction of HRT, i.e. Th 1 cells (helpers). The main effector cells are CD8 lymphocytes, among which are T-cytotoxic lymphocytes and T-lymphocytes that produce lymphokines. CD4 lymphocytes recognize allergen epitopes in complex with MCH class II glycoproteins, while CD8 lymphocytes recognize them in complex with MCH class I proteins.

Next, APCs secrete IL-1, which stimulates the proliferation of Th 1 and TNF. Th 1 secretes IL-2, γ-IFN and TNF. IL-1 and IL-2 promote differentiation, proliferation and activation of Th 1 and T-cytotoxic lymphocytes. γ-IFN attracts macrophages to the site of allergic inflammation, which, through phagocytosis, increase the degree of tissue damage. γ-IFN, TNF and IL-1 enhance the generation of nitric oxide and other reactive oxygen-containing radicals at the site of inflammation, thereby exerting a toxic effect.

T-cytotoxic lymphocytes and T-killer cells destroy genetically foreign cells of the transplant, tumor and mutated cells of their own body, performing immunological surveillance functions. T-producers of lymphokines participate in HRT reactions, releasing numerous (more than 60) HRT mediators (lymphokines).

Pathochemical stage of HRT . Since during HRT sensitized lymphocytes come into contact with the allergen, the BAS they produce - lymphokines - determine the further course of pathological reactions. Among the lymphokines, the following groups are distinguished:

lymphokines acting on macrophagocytes: macrophage migration inhibitory factor, macrophage aggregation factor, chemotactic factor for macrophages and others;

lymphokines that determine the behavior of lymphocytes: helper factor, suppression factor, blast transformation factor, Lawrence transfer factor, IL-1, IL-2 and others;

lymphokines affecting granulocytes: factors of emigration of neutrophils and eosinophils, factor inhibiting granulocyte migration and others;

lymphokines that influence cell cultures: interferons, factor inhibiting the proliferation of tissue culture cells and others;

lymphokines acting in the whole organism: a factor causing skin reaction, a factor that increases vascular permeability, an edema factor and others.

Pathophysiological stage of HRT . Structural and functional lesions during HRT are caused mainly by the development of an inflammatory reaction with a pronounced emigration of predominantly mononuclear cells - lymphocytes, monocytes and macrophages, followed by cellular infiltration by them and other tissue phagocytes.

(5) Response mediated by cellular immune mechanisms . This type of reaction is provided by sensitized T-lymphocytes belonging to a special category of helper cells - first-order T-helpers, which exert a cytotoxic effect directed against cell membrane antigens using two known mechanisms: they can attack the target cell with its subsequent destruction or influence it indirectly through the lymphokines they synthesize (Fig. 4).

Rice. 4. Schematic representation of cells

indirect mechanism of allergy development (HRT).

Designations: T – cytotoxic lymphocyte.

The action of lymphokines in HRT reactions is aimed at activating certain target cells - macrophages, monocytes, neutrophils, lymphocytes, fibroblasts, bone marrow stem cells, osteoclasts and others. The target cells activated by lymphokines, mentioned above, damage or destroy the altered cells on which antigens are fixed, already with their mediators (for example, lysosomal enzymes, peroxide compounds and others). This type of reaction develops when the following allergens-antigens enter the body:

foreign protein substances (for example, collagen), including those contained in vaccine solutions for parenteral administration;

haptens, for example medicines(penicillin, novocaine), simple chemical compounds (dinitrochlorophenol and others), herbal preparations that can be fixed on the membranes of their own cells, changing their antigenic structures;

protein histocompatibility antigens;

specific tumor antigens.

The mechanisms of HRT are fundamentally similar to other mechanisms of the formation of cellular immunity. The differences between them are formed at the final stage of reactions, which in delayed-type allergic reactions reduce to damage to one’s own organs and tissues.

The entry of an allergen antigen into the body forms an ICS immune response associated with the activation of T-lymphocytes. The cellular mechanism of immunity is activated, as a rule, in cases of insufficient efficiency of humoral mechanisms, for example, when the antigen is intracellularly localized (mycobacteria, Brucella, and others) or when the cells themselves are the antigens (microbes, protozoa, fungi, transplant cells, and others). Cells of one's own tissues can also acquire autoallergic properties. A similar mechanism may be activated in response to the formation of autoallergens when a hapten is introduced into the protein molecule (for example, in cases of contact dermatitis and others).

Typically, T-lymphocytes, sensitized to a given allergen and arriving at the site of an allergic reaction, are formed in a small amount - 1-2%, however, other non-sensitized lymphocytes change their functions under the influence of lymphokines - the main mediators of HRT. More than 60 different lymphokines are now known, which demonstrate a wide variety of their effects on various cells at the site of allergic inflammation. In addition to lymphokines, lysosomal enzymes, components of the kinin-kallikrein system and other mediators of allergic reactions that enter the site of damage from polymorphonuclear leukocytes, macrophages and other cells take part in damaging reactions, although to a lesser extent.

Manifestations of HRT in the form of cell accumulation, cellular infiltration, etc. appear 10-12 hours after repeated administration of a specific allergen and reach their maximum after 24-72 hours. It is important to note that during the formation of HRT reactions, tissue swelling is practically absent due to the limited participation of histamine in it. But an integral part of HRT is the inflammatory process, which occurs at the second, pathochemical stage of this reaction due to the destruction of target cells, their phagocytosis, and the action of allergy mediators on tissue. The inflammatory infiltrate is dominated by mononuclear cells (lymphocytes, macrophages, monocytes). The inflammation that develops during HRT is both a factor of damage and dysfunction of the organs where it occurs, and it plays a major pathogenetic role in the formation of infectious-allergic, autoimmune and some other diseases.

The inflammatory reaction is productive and usually normalizes after the allergen is eliminated. If the allergen or immune complexes are not excreted from the body, then they are fixed at the site of introduction and delimited from the surrounding tissues by forming a granuloma (see above). The granuloma may include various mesenchymal cells - macrophages, fibroblasts, lymphocytes, epithelioid cells. The fate of the granuloma is ambiguous. Typically, necrosis develops in its center, followed by the formation of connective tissue and sclerosis. Clinically, HRT reactions manifest themselves as

autoallergic diseases,

infectious and allergic diseases (tuberculosis, brucellosis and others),

contact allergic reactions (contact dermatitis, conjunctivitis and others),

transplant rejection reactions.

The division of allergic reactions into 5 types is schematic and is intended to facilitate understanding of the complex processes of allergy. All types of allergic reactions can be observed in a patient simultaneously or follow each other.

Now let’s make a final comparison of the changes that are characteristic of HNT and HRT. The GNT is characterized by the following:

rapid type of reaction development (in minutes and hours);

the presence in the blood of freely circulating immunoglobulins to this allergen, the synthesis of which is due to the activation of the ICS B-subsystem;

antigens are, as a rule, non-toxic substances;

occurs during active and passive sensitization by parenteral administration of sera containing ready-made antibodies (immunoglobulins) to a given antigen;

an important role is played by biologically active substances – HNT mediators: histamine, serotonin, bradykinin and others, including cytokines;

manifestations of HNT are suppressed by antihistamines (diphenhydramine, pipolfen, suprastin, tavegil and others), as well as glucocorticoids;

local reactions are accompanied by pronounced vascular components (hyperemia, exudation, edema, emigration of leukocytes) and alteration of tissue elements.

The manifestations of HRT are characterized by the following:

the response occurs after 12-48 hours or more;

antigens are in most cases toxic substances;

sensitization is associated with activation of cellular immunity;

sensitized T-lymphocytes, interacting with antigen, destroy it or induce other phagocytes to do so with their cytokines;

passive sensitization is achieved by parenteral administration of sensitized lymphocytes or tissue transplantation of lymph nodes removed from the body of a sensitized animal;

there is no histamine release reaction, and lymphokines act as allergy mediators;

the reaction is inhibited by glucocorticoids;

local reactions are mild;

The inflammatory reaction is most often accompanied by proliferation processes and the appearance of granulomas.