Immunodeficiency states

IMMUNODEFICIENCY STATES

ALLERGY. CONCEPT ABOUT HYPO– AND DESENSITIZATION

 

Immunodeficiency states

Organization and development of immune system

The organs of the immune system can be thought of as central or peripheral. The primary function of the central organs is the generation of new lymphocytes to populate and repopulate the peripheral organs, in which immune responses actually take place.

Here the immune system is intimately connected with the mononuclear system. By birth the main central lymphocyte-producing organs are the bone marrow and the thymus as part of the blood system they derive from a pluripotential hematopoietic stem cell, and it in turn gives rise to two types of precursors, pre-B- and pre-T-cells.

 

T–lymphocytes and cell immunity

 

Pre-T-cells also arise within the bone marrow but must travel to the thymus to their complete maturation. Whether the thymus stroma elaborates maturation hormones thymosin, thymopoietin, thymulin and other.

The selected cells that are exported from the thymus home to particular areas of the peripheral lymphoid tissues. They are deployed so that interaction are optimized between the antigen-trapping macrophages and reticular cells on the one hand and T- and B-cells on the other. They travel in the blood until they reach a lymphatic node.

The central cell in antigen response is the helper T-cell (Th). The helper T-cell role in the immune response is to help other lymphocytes get activated by antigen. It does so by secreting a variety of growth and differentiation factor (lymphokines) to which they respond.

The Th-cell seems to need two signals to become activated; binding antigen plus MHC provides the first signal , and the antigen-presenting cell provides the second in the form of a soluble or membrane-associated growth factor called interleukin1 (IL-1). Together these activate the helper cell, which begins to produce other growth factors, including interleukin 2 (IL-2). Help, in the form of growth and differentiation factors like IL-2,is nearly obligatory for most immune responses, and an individual with deficient Th will be severely impaired, even if the other components of the immune system are intact (the situation in AIDS). Among the lymphokines are factors that attract and activate macrophages. Such phagocytes will ingest and destroy the antigen.

The other important class of effector T-lymphocyte is the “killer” or cytotoxic T-cell (Tc). Cells of this type are selected for seeing antigen in the context of class I MHC product. They are specialized for killing the body’s own cells. There are at least two circumstance under which this would be desirable: when the cell in question has undergone a change, possibly malignant ; and when the cell is infected by a virus. Viruses are not really living, so they are hard to “kill”; the tactic of the immune system is to destroy the infected cell before the viruses can multiply. They need to be in physical contact with their target cell for about 5 minutes, after which the target is programed to die and the killer can go on another cell. The killer may deposit some toxic molecule or structure on the target cell surface, it signal the target to self-destruct by activating a “death program”.

Less is known about the last subpopulation of T-lymphocytes, the suppressor T-cells (Ts). These cell can be shown to oppose the activation or expression of all the other cells of immune system. It is assumed that they are a part of the normal regulation of immunity.

 

B–lymphocytes and humoral immunity

B-lymphocytes (B-cells) have receptors or antigens as do T-cells, but the structure is different: B-cells use a membrane-bound version of the antibody they will later secrete. This receptor antibody is of the IgM and IgD classes. As with T-cells, each B-cell has many copies of one particular receptor. B-cell receptors see antigen alone and do not require the joint recognition of self markers so characteristic of T-cells. There are some antigens that can activate a B-cell that has appropriate receptors directly. The B-cells begins to grow and divide, and its daughters eventually differentiate into highrate, antibody-secreting cells (plasma cells). Antibodies are immunoglobulins (Ig), and occur in five structurally and functionally distinct classes: IgG, IgM, IgD, IgA and IgE. Any particular specificity will occures in more than one class.

 

Natural killer cells

Cytotoxic T-cells appear in the tissues in response to an appropriate antigen. There is another class of killer that do not seem to depend upon prior immunization and so are called natural killer (NK) cells. They kill certain types of tumor cells, primarily of the hematopoietic system. Their activity is significantly increased by interferon. NK-cells look line large, granular lymphocytes but, for the most part, are distinct from mature T- or B-cells.

 

 

Pathology of immune system

 

Immunity means protection or security from diseases or poisons. Immunopathology is the study of diseases caused by immune mechanisms. The word immunopathology illustrates the paradox of immune reactions. On one hand, immune reactions provide efficient organisms protection against infections; on other hand, they may destroy the host’s own tissues and cause disease.

Specific immune protection is mediated by products generated as a result of an immune response, which involve proliferation and differentiation of cell in the lymphoid system. This specific protection depends on previous exposure of the individual to the particular noxious agent or organisms (antigen). As a result of this primary exposure to antigen, there develop serum proteins (antibodies) or altered cells (specifically sensitized cells) that have the capacity to recognize, react with and neutralize the noxious agent or infecting organism.

Essential to an immune response is the capacity of the individual’s immune system to recognize an antigen. Most natural antigen are other organisms (bacteria, viruses, fung). Experimental of therapeutic procedures provide contact with other potential antigens, such as exogenous macromolecules (drugs), serum proteins, blood cells, or tissues (grafts) from individuals of the same or other species. An antigen that can induce an immune response is termed as immunogen. The capacity of an individual to respond to a given immunogen depends on several factors, such as dose, route, form, degree of foreignness, and number of previous exposure to the immunogen. The products of the immune response are humoral (immunoglobin) antibody and cellular (specifically sensitized cells).

 

Immune deficiency

Immune deficiency diseases may be classified as primary or secondary. Primary immune deficiencies result from genetic or development abnormalities in the acquisition of immune maturity. Secondary deficiencies result from diseases or drugs that interfere with the expression of a mature immune system.

Multiple levels of defensive reactions must be considered in the evaluation of resistance to infection. Infections may occur with increased frequency in elderly individuals, in debilitated patients, or wheatural nonimmune barriers are affected. The depression of pulmonary clearing mechanisms because of the loss of ciliary activity of bronchial lining cells found associated with exposure to cigarette smoke is an example. In addition there is a genetic disorder resulting in a microtubule defect that affects the mobility of cilia, the immobile ciliar syndrome. Affected patient also have immobile sperm and chronic respiratory infections, frequent homophilus influenzae infection and abundant mucus secretions. Because of the complexity of immune deficiencies and the diverse clinical presentation of deficiency states, a careful systematic diagnostic work up must be carried out in order to select appropriate therapy.

 

Primary immune deficiency

 

Primary immune deficiencies may be understood as defects in the development of the immune system and classified into the following four general groups depending on the stage in development of which the defect occurs:

1.   Combined (T- and B-cell) deficiencies

2.   B-cell deficiencies

3.   T-cell deficiencies

4.   Deficiency of stem cells.

The type infection observed is determined by the kind of immune abnormality present. Deficiencies in T-cell immunity usually result in fatal viral, fungal, or mycobacterial infections. Defects in B-cell immunity (humoral antibody) are associated with fatal bacterial infections. Defects in production of inflammatory cells, particularly polymorphonuclear leukocytes (agranulocytosis) are also associated with bacterial infections.

Defects in purine metabolism are responsible for a small number of immune deficiencies. Such deficiencies may result in a loss of T-cell (purine nucleoside phosphorylase deficiencies) or T- and B-cell (adenosine deaminase, ADP deficiency) function because of accumulation of toxic metabolites. Other purine metabolizing enzyme deficiencies are hypoxanthine-guanine phosphoribosyl transferase (Lesch-Nyhan syndrome) and ceto-5′-nucleotidase, which may be associated with a B-cell deficiency.

 

Secondary immune deficiency

 

 Secondary immune deficiencies occur after full development of the immune system. Some of these are secondary to immunosuppressive therapy or infections (such as AIDS). Secondary immune deficiencies are associated with debilitating diseases, such as cancer.

The most common immune deficiencies are those that are secondary to immune suppressive therapy, as in graft recipients or cancer patients. Less common are immune deficiencies secondary to infections, such as AIDS or infection with virus. Many chemotherapeutic agents for cancer are antimetabolites also suppress the immune system. Frequently cancer patients die from infections that are treatment related. Particularly important are steroids, which are used for therapy of diseases variety of. High doses of steroids are particularly dangerous because they are directly toxic for lymphocytes and suppress phagocytosis.

Defect may also occur in the accessory inflammatory systems activated by immune effector mechanisms.

There are very rare but may be associated with particular infections. Also rare, but more severe, are disorders in phagocytosis.

 

Іmmune deficiency associated with predominanty T-cell

Di George’s syndrome. This appears to be one of series of similar multiorgan developmental defect reflecting abnormal embryogenesis at 4-6 weeks of gestation. There are probably a variety of causes for these anomalies. The characteristic manifestations include multiple anomalies of the third and fourth bronchial arch derivabires, type 1 truncus arteriosus, dysmorphic facies with micrognathia low-set ears, a shortened filtrum of the upper lip, thymic and parathyroid hypoplasia or aplasia. Neonatal tetany is observed in most affected infants. About 20 % of those involved have decreased number and function of T-lymphocytes. The lymph nodes and spleen show poorly developed T-cell-dependent zones and usually expanded B-cell-depended areas.

Immune deficiency T-cell associated with puriucleoside phosphorylase (PNP) deficiency. This autosomal recessive disease results from defects in the gene located on chromosome 9. In the absence of PNP, toxic metabolites, in this case d-GTP, accumulate within the cell and impair proliferation. T-lymphocytes are particularly sensitive to the accumulation of d-GTP, and they are affected to a greater degree than B-lymphocytes. There are such immunologic differences between ADP and PNP deficiency.

 

IMMUNE DEFICIENCY ASSOCIATED WITH PREDOMINANTY B-CELL

 

Bruton’s X-linked agammaglobulinemia. This is the prototypic antibody deficiency. Affected males present in infancy or early childhood with recurrent pyogenic infections. Criteria for diagnosis include profound in ability to make antibody and resultant extremely low concentrations of all immunoglobulin isotypes. There is a profound decrease in circulating B-lymphocytes (usually less than 5/1000 lymphocytes); plasma cells are absent from lymph nodes and bone marrow. The number and function of T-lymphocytes (including cell-mediated immunity) are unaffected. Pre-B-cell are found in the bone marrow. The gene defect has been localized to the long arm of the X chromosome. In female carriers the defective chromosome is preferentially lionized during B-lymphocyte proliferation, permitting carrier defection.

 

Selective IgA deficiency. IgA deficiency is more frequent in patients with chronic lung disease than in a normal agematched population.

 

In complete IgA deficiency. The defect is presumed to result from maturational failure of IgA-producing lymphocytes. Autosomal recessive in heritance has been shown in some families. A fixed haptotype of MHC genes is frequently associated with IgA deficiency.

IgA is the characteristic antibody class in the secretion associated with mucous membranes. The helper T-cells found in the lymphoid tissues of the gastrointestinal and respiratory tracts seem to be specialized for driving B-cells to switch from IgM to IgA secretion. The B-cells also make a joining chain that allows two IgA subunits to from a dimer. In passing through epithelial cells on their way to the lumen, the IgA molecules acquire another polypeptide chain called secretory component, which is necessary for secretion and may provide some resistance to proteolytic digestion. Thus the IgA class of antibodies function primarily on the interface between the body and outside world and forms the first line of defense against invaders at the mucous membranes.

 

Selective IgG deficiencies with IgA deficiency. Criteria for diagnosis should include normal total serum IgG levels are frequently, but not invariably decreased.

IgG is the predominant antibody class in blood. It is useful in the defense against bacterial invaders: when it binds antigen it becomes able to activate a series of precursor proteins in blood collectively called complement. Activated complement components are chemotaxic for polymorphonuclear neutrophils, and so an inflamatory process is set up that helps get rid of the pathogens. Certain activated complement components are lytic and can destroy some bacteria directly. Other complement components adhere to the bacterial surface, and this is desirable since phagocytes have receptors for one of them (C3b), as indeed they do for IgG, which has bound antigen. This results in the bacterium being coated with “handles” for the phagocytes to seize (opsonized) and increases the effeciency of phagocytosis several numdred fold.

Immunoglobulin deficiency with increased IgM. This syndrome apparently represents a group of distinct entities with similar clinical expression. Some of the families reported have been clearly X-linked in inheritance; others have been autosomal recessive. Diagnostic criteria include impacted antibody formation. Thus, serum M, levels are elevated while IgG (and IgA) levels are diminished of irculating B-lymphocytes. Most patients have reccurent of persistent neutropenia; it is not clear whether this caused by IgM autoantibodies to granulocytes or by myeloid maturation arrest.

 

SEVERE COMBINED IMMUNE DEFICIENCY DISEASES

 

Swiss type of agammaglobulinemia. This group of diseases is characterized clinically and immunologically by defects in both T- and B-lymphocytes. Criterie for diagnosis generally include presentation in infancy with severe, potentially lethal infections, profound abnormalities of T-cell-mediated immunologic reactivity and antibody deficiency, and lymphopenia, particularly of T-lymphocytes. The clinical presentation usually includes failure to thrive and unusually persistent infections with low-virulence opportunistic organisms. These findings require differentiation from infants with AIDS.

 

Immune deficiency with ataxia and telangiectasia (Louis-Bare’s syndrome). This autosomal recessive syndrome is characterized by combination of progressive cerebellar ataxia and fine telangiectases, especially on the earlobes and conjunctival selera. Raised levels of serum a-fetoprotein and immunodeficiency are regularly present. Serum immunoglobulins are frequently low or absent. Antibody responses are decreased. Circulating numbers of T-lymphocytes are often decreased, and T-cell-mediated immunologic reactivity is diminished. Cells from patients with ataxia telangiectasia have defective DNA repair-processing mechanisms and express hypersensitivity to ionizing radiation. Lymphocytes show frequent chromosomal breaks, inversions, and translocations involving sites of the T-cell receptor genes in T-cells and immunoglobulin gene complexes in B-cells. Death usually occurs in early adult life after years of increasing disability, often from lymphoreticular malignancy.

The disease has many genetic variants, and at least five complementation groups have been identified. The chromosome locus of the defective gene for the complementation group A, C, and D.

 

Immunodeficiency with thrombocytopenia eczema (Wiskott-Aldrich’s syndrome). The Wiskott-Aldrich’s syndrome (WAS) is an X-linked monogenic disease. Affected males have small platelets and severe thrombocytopenia, eczema, and undue susceptibility to both pyogenic and opportunistic infections. Their T-cell function declines with age.

Obligate female heterozygotes who bear the WAS gene are immunologically normal. However, all their peripheral white blood cells exhibit nonrandom inactivation of the X chromosome, and this implies that all the nucleated blood cells as well as platelets are affected by the defect. The basic defect in WAS is not known. The platelets are invariably small. Platelets related sialoglycoprotein of the T-cells, CD43, is also defective. However, the genes of neither othese sialoglycoprotein map to the X chromosome and the defects appear to be secondary to some unknown cytosceletal abnormality in the blood cells of these males. The characteritic eczematous dermatitis is clinically and histologically identical to that of ordinary atopic dermatitis.

 

PHAGOCYTOSIS AND IT DISORDERS

 

Many cells possess the ability to ingest material by engulfment. The ingested matter is usually particulate, such as bacteria, protozoal parasites or other microorganisms, tissue cells (usually necrotic), dust, pigment and other foreign material. When engulfment involves such particulate matter, the process is termed phagocytosis.

Phagocytes comprise two main classes of cell: those that are capable of migrating to the site where their phagocytic ability is required (such as neutrophilic and eosinophilic leycocytes and circulating mononuclear phagocytes) and those that are fixed in tissues during all or most of their life and therefore depend on chance encounter with foreign materials (such as Kupffer cell in liver and liking sinusoid of lymphatic node). In the act of phagocytosis, small particle such as a grain of charcoal may be ingested in an instant. Larger objects such as tissue cell, clumps of bacteria, or a single large bacterium are ingested by the more active response. This process is similar for neutrophils (microphages), monocytes and tissue macrophages. The process of phagocytosis involves four stages: 1. The approach stage or chemotaxis. 2. The attachment stage, in which the particle becomes found to the surface of the phagocyte. 3. The ingestion stage, involving invagination of the surface membrane and the surrounding of the particle. 4. The digestion stage.

Сhemotaxis – the phenomenon being defined as a response in which the direction of locomotion of a cell is determined by a substance in its environment. Chemotaxis ensures that, rather than wandering at random the leukocytes move toward the site of injury or foreing material and therefore concentrate in the infected or injured tissues tissues. Factor chemotic for monocytes overlap with those for neutrophils and include cleavage products of C3 and C5 and soluble bacterial products. Lymphocytes stimulate with antigen. Mononuclear phagocytes able to play a key role in various types of immunologic injury. Many examples are known in which the leukocytes contribute to the breakdown of the host’s own tissue.

The fate of ingested particulate matter is closely related to the process of degranulation and the discharge of granule contents into the newly formed digestive pouch or phagosome. The nature of the surface of the object to be ingested (whether bacterium, cell, or foreign body) determines whether there can be firm fixation to the neutrophils surface as the necessary prelude to phagocytosis. Since both bacteria and neutrophils usually have a net surface charge that is negative and therefore repellent, some form of physical or chemical bond must be established between particle and cell membrane. Opsonins (such as plasma fibronectin) are factors that act on the surface of many bacteria, presumably by absorption and render them susceptible to phagocytosis.

In the absence of opsonins (as in serum), ingestion of most microorganisms by neutrophils proceeds slowly or not all. (film 1), (film 2).

 

The physical nature of the environmental influence upon phagocytosis by neutrophils. Phagocytosis is accompanied by degranulation of the macrophags, resulting in the liberation of digestive enzymes and antibacterial substances. The degranulation stees to result from contact of the membranes of the cytoplasmic granules with the membranes of the “phagocytic pouch” surrounding the ingested particle. The hydrolases released by the granules are discharged into the pouch, and so the cell cytoplasm is protected from its own ferments. The antibacterial substances released include lysosome, hydrogen peroxide, basic peptides (leukins), and a basic protein (phagocytin) that kills a wide range of organisms without lyzing them.

 

Chediak-Higashi syndrome. The Chediak-Higashi syndrome is inherited as an autosomal recessive trait. Precise mapping of the gene has not yet been accomplished. The disease is characterized by abnormally large granules in the cytoplasm of several cell types. Affected children have recurrent bacterial infections, particularly with the staphylococcus aurens. This has been attributed to their abnormal granulocyte function. Partial oculocutaneous albinism and a variety of central and peripheral neuropathies are observed in the Chediak-Higashi syndrome. The diagnosis is established by the presence of giant peroxidase-positive granules in peripheral blood granulocytes or, more reliably, in bone marrow myelocytes . The abnormality of the bone marrow myelocytes also leads to ineffective myelopoiesis so that many patiets are neutropenic. Chemotaxis and degranulation are abnormal. The monocytes, lymphocytes and natural killer cells are also abnormal in morphology and function, and all contain abnormally large granules in their cytoplasm. Although thrombocytopenic does not occur in Chediak-Higashi syndrome, the platelets contain large granules also and do not aggregate normally. The outcome is usually fatal. The pathological hallmark of Chediak-Higashi syndrome is the presence of large memrane-bound intracellular inclusious. Although these structures are most easily demonstrated in leukocytes, they are also present in renal tubular epithelial cells, gastric mucose, pancreas, thyroid , neural tissue, and melanocytes. The leukocytes inclusions are 2 to 4 µm in diameter and stain violet to blue with routine Romanowsky agents.

 

Chronic granulomatous disease. Chronic granulomatous disease (CGD) is an inherited defect in phagocytic cells so that they are unable to produce superoxide and related toxic metobolites. CGD results from an abnormality in phagocyte-specific cytochrome b. This enzymatic activity has many component parts, one of which is encoded on the X chromosome and the others on outosomes. Consequently CGD may be inherited as an X-linked or as an autosomal recessive trait. The phagocytes in CGD have normal chemotaxis, ingestion, and degranulation , but the intracellular killing of microbial pathogens is abnormal. Patients with CGD have chronic and recurrent bacterial infections. The most common sites of infection are the lung, skin, lymphatic nodes, liver, and bone. Abscess formation occurs most frequently at these sites because of intracellular persistence of catalase-producing microorganisms. The most common of these encountered in CGD are staphilococcus aureus, Aspergillus and Nocardia species. Hystologically the abscesses contain poorly formed granulomas with necrosis and many neurophils. A distinctive feature of these inflammatory lesions is the presence of macrophages containing a light yellow-brown pigment.

 

ALLERGY. CONCEPT ABOUT HYPO– AND DESENSITIZATION

 

Allergy is an immune response, which is followed by damage of own tissues. If damage is followed by such changes in organism, that are typical for a disease, than allergic diseases arise. Allergic diseases – is a group of diseases, in development base of which damage lies, caused by an immune reaction on allergens. Allergic diseases are widely spread among people. It is considered that they cover about 10 % of earth population. In different countries these sizes vacillate from 1 to 50 % and more.

 

General etiology of allergic diseases

 

The cause of allergic diseases is the allergen, the conditions of their appearing are the specific peculiarities of the environment and state of organism reactivity.

Allergen – is a substance that causes development of an allergic reaction.

Allergens have all properties of antigens (macromolecularity, mainly proteiature, foreign for a particular organism). However allergic reactions can be caused by substances of not only antigen nature, but also substances, not possessing these properties. To this group belong many officinal preparations, bacterial products, polysaccharides, simple chemical substances (bromine, iodine, chrome, nickel). These substances are called haptens. While entering the organism they become antigens (allergens) only after binding with tissues proteins. Herewith complex antigens, which sensitize the organism are formed.

All allergens are divided into two groups – exogenous and endogenous allergens (autoallergens). Exogenous allergens come into the organism from outside, endoallergens are formed in the organism. There are few allergens classifications. According to the origin exogenous allergens are divided into following groups: a) allergens of noninfectious origin: home, epidermal, pollen, food, industrial and officinal; b) allergens of infectious origin: bacterial, fungous, viral.

 

Domestic allergens. Main role among them domestic dust plays, which includes particles, bed-clothes, furniture, bacteria.

 

Epidermal allergens. To this group refer: scurf, wool, birds, fur, fish, scales. Professional sensitization by epidermal allergen is observed in sheepmen, horsemen, poultry farms workers, hairdressers.

 

Officinal allergens. Any officinal preparation with a little exception causes the development of an officinal allergy. Medicines or their metabolites are, as usual, haptens. In case of sensitization of the organism to one preparation, allergic reactions to other medicines, having alike chemical structure can arise.

 

Pollen allergens. Allergic diseases are caused by shallow plants, pollen. It is called pollinosis. The diverse types of pollen can have the general allergens, therefore in people, sensitive to one type of pollen, a reaction on its other kinds is possible.

 

Food allergens. Many food products can be by allergens. They are usually fish, wheat, beans, tomatoes, milk, eggs. Chemical substances added to food products (dye-stuffs, antioxidants, aromatic and other substances) may also be allergens.

 

Industrial allergens. The industrial allergens for the most are haptens. In each industrial production a particular admission of chemical matters is used. These are: resin, glue and covering materials, plastics, dye-stuffs, metals and their salts, wood products, latex, perfumer substances, washing means, synthetic cloths and others.

 

 

Allergens of infectious origin. All the different causative agents of infectious diseases and products of their life activity cause the development of allergic processes. Those infectious diseases, in pathogenesis of which allergy plays a leading role, were named infectiously allergic. These are all the chronic infections (tuberculosis, lepra, brucellosis, syphilis, rheumatism, chronic candidosis etc.). The widespread allergens are the fungi. Many nonpathogenic fungi while entering the organism cause sensitization and development of diverse allergic diseases (bronchial asthma). Such fungi are contained in atmospheric air, dwellings, domestic dust, food products. With biotechnological development a possibility of sensitization on enterprises on production of stern squire, vitamins, antibiotics, enzymes arises.

 

 

Pathogenesis of allergic reactions

There are different classifications of allergic reactions. R.A.Cook picked out allergic reactions of immediate type and allergic reactions of delayed-type or hypersensitization of delayed-type. In the base of classification the time of appearing of reaction after contact with allergen has been placed. The reactions of immediate type developed during 15-20 minutes, delayed-type – after 1-2 days. However it does not envelop all the variety of allergy displays. For example, some reactions develop over 4-6 or 12-18 hours. Therefore the distinctions between allergic reactions were interconnected with different mechanisms of their development and the classifications based on pathogenic principle were put together.

The classification by P.Gell, R.Coombs is widely spread in the world. It is based on pathogenic principle. The peculiarities of immune mechanisms lay in its base. In accordance to this classification there are 4 types of allergic reactions: anaphylaxic, cytotoxic, immune-complex, delayed hypersensitivity.

 

CLASSIFICATION OF ALLERGY

by R.A. Cook

 

 

CLASSIFICATION OF ALLERGY

by P. Gell and R. Coombs

 

Type I — anaphylaxis

 

Type II — cytotoxic

 

Type ІІІ — immune–complex

 

Type IV— delayed–type hypersensitivity

 

Type V — stimulating allergy

 

Allergy development stages. Entering into the organism antigen causes its sensitization. Sensitization is an immunological rising of organism sensitiveness to antigens (allergens) of exogenous or endogenous origin. According to method of receiving there are active and passive sensitizations. Active sensitization develops in artificial introduction or natural penetration of the allergen into the organism. Passive sensitization is reproduced in the experiment by introduction of blood plasma or lymphoid cells of an actively sensitized donor to an intact recipient. In the development of allergic reaction there are three stages:

 

1. Immunological stage. It covers all the changes in immune system during the penetration of an allergen into the organism, formation of antibodies or sensitized lymphocytes and their binding with the repeatedly entering allergen.

 

2. Pathochemical stage. Its sense is in formation of biological active substances. The stimulus to their formation is the binding of allergen to antibodies or sensitized lymphocytes at the end of immunological stage.

 

3. Pathophysiological stage. It is described by pathogenic action of formed mediators onto cells, organs and tissues of the organism with a clinical display.

 

In this way the immunological mechanisms lay in development base of allergic processes. Central cell of immune system is a lymphocyte. Lymphocytes are heterogenic according to their functions, markers, receptors. They develop from a stem cell. A lymphoid stem cell will form from it, from which T- and B-lymphocytes develop. The T-lymphocytes acquire the specific antigen receptors, with the help of which they identify an antigen and other markers. There are 3 types of T-cells: T-helpers, T-suppressors, T-effectors. The last ones form sensitized lymphocytes or killers, which participate in realization of allergic reaction of delayed-type and realize cytotoxic action on cell-target. The B-lymphocytes produce 5 classes of immunoglobulins IgG, IgM, IgA, IgE, IgD. These cells during ripening acquire the receptors for antigen on their membranes. During binding of such B-cells with proper allergens and after the signal, received from T-helper, they become activated, and proliferation and differentiation into antibody producing cells starts.

The correlation between two groups of subpopulations of T-helpers (T_h-1 and T_h-2) plays an important role in the development of immune reaction. They are both formed of T_h-0 and differ form each other by the set of secreted lymphokines and quantity of Fc-receptors for immune globulins on their surface. On T_h-2 there are many receptors for immune globulins A, M, E, and on T_h-1 there are a few of them or they are absent. During the activation of T_h-1 the formation of IL-2 increases, it stimulates the secretion of immune globulins A, M and G by B-cells and turns on cellular mechanism of immunity. Activation of T_h-2 leads though IL-4 to changing of synthesis of IgE by B-cells to proliferation of fat cells and through IL-5 to increasing and proliferation of eosinophiles. There are antagonistic relationship between these two ways. The choice of way of activation depends on character of allergen. Besides that the form of allergen, conditions on introduction into organism and its quantity play role.

 

ANAPHYLACTIC TYPE OF ALLERGY REACTIONS

 

According to anaphylactic type a group of atopic diseases (atopic bronchial (film 4) asthma, pollinosis,

 

 atopic dermatitis, nettle-rash, food and officinal allergy, Quinke’s edema(pic.1, (pic.2.)

 

pic.1

pic.2

URTICARIA, HIVES, NETTLE RASH

 

URTICARIA, HIVES, NETTLE RASH

 

 

Immunological stage. IgE and IgG₄ are formed as an answer to penetrating of allergen into the organism. They get fixed on the mast cells and basophiles of blood. These cells have on their surface Fc receptors for immune globulin. The state of sensitization of the organism appears. If the same allergen again gets into the organism or it still stays in the organism after the first penetration, connection of antigen with IgE-antibodies occurs. The same thing is observed with IgG₄. they bind with their receptors on basophiles, macrophages, eosinophiles, trombocytes. Depending on the quantity of molecules of IgE-antibodies connected to antigen, quantity of antigen we can observe either inhibition of activity of the cell or its activation and transfer of the process to the next, pathochemical stage.

 

Pathochemical stage. Activation of the most and basophile cells leads to releasing of different mediators. The process of secretion of mediators need energy, that’s why blocking of energy-formation blocks also releasing of mediators. A certain role in this process play cyclic nucleotides of the cells – cAMP and cGMP. Secretion of one of the main mediators – histamine depends on their correlation. Many different mediators have been excluded from the most cells and basophile leucocytes. Some mediators are in the cell in ready form and are easily secreted (histamine, serotonin, eosinophiles chemotaxic factors). Some mediators are formed after stimulation of the cell (leukotriens, trombocyte activating factors). This mediators act on vessels and target-cells, including in the development of allergic reaction eosinophiles, trombocytes and other cells. As a result eosinophiles, neutrophiles, which start also to release mediators – phosrholipase D, histaminase, leukotriens and others come to the place of activation of the most cells.

Histamine is localized in ready form in granules of the most cells and basophile leucocytes. In the blood of healthy people histamine almost totally stays in basophile leucocytes. Histamine acts on the tissues cells through the receptors of two types – H₁ and H₂. Their correlation and spreading on the cells of different cells is different. Stimulation of H₁ promotes to contraction of smooth muscles, endothelial cells and postcapillary part of microcirculation. This leads to increasing of permeability of vessels, development of edema and inflammation. Stimulation of H₂ causes the opposite effects. Besides this releasing of histamine from basophile leucocytes and from the lungs is diminished through them, the function of the lymphocytes modulates, formation of migration ingibitory factor (MIF) by T-lymphocytes gets oppressed, releasing of lysosome enzymes by neutrophile leucocytes diminishes as well. In many cases the increasing of quantity of histamine in blood is observed in the intensive stage of bronchial asthma, nettle-rash, officinal allergy.

Heparin is activated after releasing out of the most cells. It possesses an antitrombine and anticomplementar activity. Trombocyte activating factor (TAF) is secreted by basophiles, lymphocytes, trombocytes and endothelial cells. TAF acts on target-cells through corresponding receptors: 1) it causes the aggregation of trombocytes and releasing of histamine and serotonin out of them; 2) it helps to chemotaxis and secretion of granular content of eosinophiles and neutrophiles; 3) it causes spasm of smooth muscles; 4) it increases permeability of vessels.

Metabolites of arachidone acid. It is metabolized in two different ways: cyclooxygenic and lipooxygenic. Under the influence of cyclooxygenase prostaglandins, tromboxans and prostacycline are formed from arachidone acid. Under the influence of lipooxygenase leukotriens are formed from it. In allergy prostaglandins of F group possess the ability to cause contraction of smooth muscles, including bronchi, and prostaglandins of E group provide the relaxing action. Leukotriens cause the spasm of smooth muscles, increase secretion of mucous, decrease coronary blood flow and power of heart contractions, increase chemotaxis of polymorphic-nuclear leukocytes, lead to development of prolonged bronchial spasm.

 

Pathophysiological stage. Under the influence of mediators the permeability of vessels and chemotaxis of neutrophiles and eosinophiles increase, which leads to development of inflammatory reaction. The increasing of permeability of vessels promotes the exit of fluid, immunoglobulins and complement into tissues. With the help of mediators and also through the IgE-antibodies, the cytotoxic effect of macrophages is activated, secretion of enzymes, prostaglandins and leukotriens, trombocyte activating factor is stimulated. The released mediators cause also a damaging action onto cells and connective tissue structures. Bronchospasm develops in respiratory organs. These effects are clinically manifested by attacks of bronchial asthma , rhinitis, conjunctivitis, nettle-rash, skin itch, diarrhea. Anaphylactic shock develops in severe complication. Spasm of smooth muscles of internal organs with clinical manifestation of bronchospasm (cough, expiratory breathlessness), spasm of gastro-intestinal tract muscles (spastic pain in the whole abdomen, nausea, vomiting, diarrhea), spasm of uterus in women (pain below abdomen) are observed. Spastic phenomena are worsened by edemas of mucous covers of internal organs, during the edema of larynx the picture of asphyxia may develop. The arterial pressure is sharply decreased, the heart insufficiency, ischemia of brain, seizes paralysis develop, danger for the life of the patient appears.

 

FILM

 

Cytotoxic type of allergy

Immunological stage. It is called cytotoxic because the antibodies that developed to antigen of the cell bind to cells and cause their damage or even lysis (cytolytic action). For turning on of this mechanism cells of tissues have to acquire autiallergen properties. Than the formation of autoantibodies starts. In this process action of chemical substances, usually medicines, viruses, microbes onto the cell plays a big role. They may change the antigen structure of cell membranes. The formed autoantibodies belong to IgG and IgM. They connect to corresponding antigens of the cells by their Fab-fragments.

 

 

Pathochemical stage. The main mediator of cytotoxicity is the activated enzymes of complement. Phagocytes release some lyzosome enzymes and generate superoxide anion-radical.

 

Pathophysiological stage. The damage of the cell with the antigen properties may be caused by three reasons: due to activation of complement, the components of which damage the cell membrane; due to activation of phagocytosis of the cells covered with antibodies; due to activation of T-lymphocytes, natural killers, K-lymphocytes.

Cytotoxic type of the allergy can be a manifestation of officinal allergy with the development of leucocytopenia, trombocytopenia, hemolytic anemia etc. This may also happen in blood transfusion and also in rhesus incompatibility of mother and fetus.

Immune complex type

 

Immunological stage. Many exogenous and endogenous antigens participate in formation of immune complexes. Among them there are officinal preparations (penicillin, sulfanilamides,), antitoxic vaccines, allogen gamma-globulins, food product (milk, egg white), inhalation allergen (home dust, fungi). In case of penetration of soluble antigen into the organism

 

 

IgG and IgM antibodies are formed. These antibodies can cause the formation of precipitate and connection to antigen. Immune complex can be formed in tissues or in blood flow.

 

 

Patochemical stage. Under the influence of immune complexes the following mediators are formed: fragments C3a, C5a, C4a of the complement, lyzosomal enzymes of phagocytes, kinines, superoxyde anion-radical.

Pathophysiological stage. Usually immune complexes are placed on vessels of cannalicular apparatus of kidneys, inflammation with alteration, exudation and proliferation (glomerulonephritis) develops, in case if the complexes are placed in the lungs alveolitis appears, in skin – dermatitis. The inflammation may lead to formation of ulcers, hemorrhages, thrombosis is possible in the vessels. This type of allergic reactions is the prominent one in development of serum , some cases of officinal and food allergy, some autoallergic diseases (rheumatoid arthritis, systemic red lupus erythematosus). In case of massive activation of complement anaphylactic shock, bronchial asthma may develop.

 

Delayed allergy

Immunological stage. The cellular mechanism of immunity is usually activated in cases of insufficiency of effectiveness of humoral mechanisms, for example, in case of intracellular localization of the antigen (mycobacterium, brucella, histoplasma etc.) or when cells are antigen themselves. They may microbes, fungi and their spores, which get into the organism from the outside. The cells of own tissues also may acquire the auto allergen properties.

This mechanism may turn on as a response to formation of complex allergens, in case of including haptens into proteins, for example, in case of contact dermatitis, which appears during the contact of the skin with different medicinal, industrious and other allergens. The foreign antigen is phagocyted by macrophages and get to T-helpers. At the same time macrophages secrete IL-1, which stimulates T-helpers. The latest excrete the growth factor pro-T-lymphocytes – IL-2, which activates and supports proliferation of antigen stimulated T-cells. This process leads to formation of sensitized lymphocytes. They belong to T-lymphocytes and in the cell membrane they have receptors of the antibody type, which are able to connect with the antigen. In case of repeated penetration of the allergen into the organism it binds with the sensitized lymphocytes.

 

Mechanisms of delayed type allergy

Pathochemical stage. This leads to morphological, biochemical and functional change in lymphocytes. They are presented by blast transformation and proliferation, increasing of synthesis of DNA, RNA and proteins and secretion of different mediators, which are called lymphokines. With the help of lymphokines (MIF, interleukines, chemotaxic factors, factor of transfer) mobilization of different cells (macrophages, polymorph-nuclear), increasing of chemotaxic activity and placing in the site of allergen occur.

MIF promotes accumulation of macrophages in the site of allergic damage, increases their activity and phagocytosis. It takes part in formation of granulems during infectious-allergic diseases, increase the ability of macrophages to destroy certain kinds of bacteria.

There are several kinds of chemotaxic factors, each of which is called chemotaxis of leukocytes – macrophages, neutrophiles, eosinophiles and basophiles. Lymphotoxins cause damage and destroying of all different target-cells.

Interferon is secreted by lymphocytes and under the influence of α-interferon and nonspecific mitogens. It acts a modulating influence on cellular and humoral mechanisms of immune reaction.

Besides lymphokines, lizosome enzymes also provide a damaging activity. They are released during phagocytosis and destroying of cells. Kallikreine-kinine system is also activated. Histamine doesn’t play a big role in this type of allergic reactions.

 

Pathophysiological stage. A particular form of lymphokines (lymphotoxin, interferon) shows a cytotoxic action and decreases activity of cell. In allergic reaction of delayed type damaging action may develop in several ways: 1) direct cytotoxic action of sensitized T-lymphocytes on target-cells, which acquired autoallergen properties; 2) cytotoxic activity of T-lymphocytes, mediated by lymphotoxin; 3) releasing of lysosome enzyme, which damage tissue structures during phagocytosis.

 

 

Inflammation that is associated to immune reaction by action of mediators is a component of allergic reaction of delayed-type. Nevertheless inflammation is at the same time a factor of damage of function of the organs. Allergic reactions of delayed type make the base of development of infectious-allergic diseases (tuberculosis, lepra, brucellosis, syphilis), rejection of transplant, and autoallergic diseases (disturbance of nervous system, endocrine glands etc.).

 

Mechanisms of allergy development

 

 

PSEUDOALLERGIC REACTIONS

Pseudoallergy is a pathological process, which is clinically similar to allergy but doesn’t have an immune stage of its development. Pseudoallergy differs from a simple one by the absence of first (immune) stage. The rest two stages – releasing of mediators (pathochemical) and pathophysiological (stage of clinical manifestations) are the same both in pseudoallergy and a real one. To pseudoallergic reactions refer only processes in the development of which the leading role play mediators, which are formed also in pathochemical stage of true allergic reactions.

The reason of pseudoallergy is any substance that acts directly on effector cells (fat cells, basophiles etc.) or biological fluids and cause releasing of mediators from the cells or production of them in the fluids. Practically most of the allergens can lead to development of both allergic and pseudoallergic reactions. This depends oature of the substance, its phase, frequency of introduction into the organism and reactivity of the organism. Pseudoallergic reactions usually occur in officinal and food intolerance. Many remedies more usually lead to development of pseudoallergy than true allergy.

Clinical picture of pseudoallergic diseases is close to one of allergic diseases. Development of such pathological processes as increasing of permeability of vessels, edema, inflammation , spasm of smooth muscles, destroying of blood cells lay in the base of this clinical picture. These processes may be local, organic and systemic. They are presented by rhinitis, nettle-rash, Kvinke’s edema, periodical headaches, disturbance of gastro-intestinal tract, bronchial asthma, vaccine disease, anaphylactic shock and also damaging of certain organs.

 

PREVENTING OF ALLERGY. HYPOSENSITIZATION

 

Prophylaxis of an allergic disease depends on its character and group of the allergens. It consists of measures of preventing of penetration of given allergen into the organism and preventing of the influence of different irritating factors on the organism. If sensitization has already occurred and allergic diseases has already started, the following measures are appropriate.

Skin reaction onto allergen

 

1. Suppression of antibodies and sensitized lymphocytes production with the help of immune depressants, ionizing radiation, cytostatics, specific lymphocyte vaccines and monoclonal antibodies.

 

2. Specific desensitization by Bezredka. (film 5) Desensitization is provided by little doses of the antigen, which do not cause severe reactions. The doses are introduced repeatedly after certain intervals of time, during which produced mediators get inactivated in the organism. The main dose of the antigen is introduced after antibodies binding. This method is effective in introduction of foreign medical vaccines.

3. Inactivation of biological active substances. For this purpose antihistamine preparations, inhibitors of proteolytic enzymes etc. are introduced.

4. Protection of the cells from the influence of biological active substance and also normalizing of functional disorders in organs and systems (narcotic, spasmolytic substances, receptor blockers etc.).