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Immunodeficiency - what is it?

Doctors note that recently patients are increasingly diagnosed with serious illness difficult to treat. Immunodeficiency or, scientifically, immunodeficiency is pathological condition in which the immune system does not work properly. The described violations are faced by both adults and children. What is this state? How dangerous is it?

Immunodeficiency is characterized by a decrease in activity or the inability of the body to create a protective reaction due to the loss of a cellular or humoral immune link.

This condition may be congenital or acquired. In many cases, IDS (especially if left untreated) is irreversible, however, the disease can also be transitive (temporary) form.

Causes of immunodeficiency in humans

The factors causing IDS are not yet fully understood. However, scientists are constantly studying this issue to prevent the onset and progression of immunodeficiency.

Immunodeficiency, causes:

The cause can only be identified with the help of a comprehensive hematological diagnosis. First of all, the patient is sent for blood donation to evaluate the indicators of cellular immunity. During the analysis, the relative and absolute number of protective cells is calculated.

Immunodeficiency can be primary, secondary and combined. Each disease associated with IDS has a specific and individual severity of the course.

When pathological signs It is important to contact your doctor in a timely manner to receive recommendations for further treatment.

Primary immunodeficiency (PID), features

It is the most complex genetic disease that manifests itself in the first few months after birth (40% of cases), in early infancy (up to two years - 30%), in childhood and adolescence (20%), less often - after 20 years (10%).

It should be understood that patients do not suffer from IDS, but from those infectious and comorbidities that the immune system is unable to suppress. As a result, patients may experience the following:

• polytopic process. This is a multiple lesion of tissues and organs. Thus, the patient can simultaneously experience pathological changes, for example, in the skin and urinary system.
• Difficulty in the treatment of a single disease. Pathology often becomes chronic with frequent relapses (repetitions). Diseases are rapid and progressive.
• High susceptibility to all infections, leading to polyetiology. In other words, one disease can cause several pathogens at once.
• The usual therapeutic course does not give the full effect, so the dosage of the drug is selected individually, often in loading doses. However, it is very difficult to cleanse the body of the pathogen, so carriage and a latent course of the disease are often observed.

Primary immunodeficiency is a congenital condition, the beginnings of which were formed in utero. Unfortunately, screening during pregnancy does not detect a severe anomaly at the initial stage.

This state develops under the influence of an external factor. Secondary immunodeficiency is not a genetic abnormality; it is diagnosed for the first time with the same frequency both in childhood and in adults.

Factors causing acquired immunodeficiency:

• deterioration of the ecological environment;
• microwave and ionizing radiation;
• acute or chronic poisoning with chemicals, heavy metals, pesticides, low-quality or expired food;
• long-term treatment with drugs that affect the functioning of the immune system;
• frequent and excessive mental stress, psycho-emotional overstrain, experiences.

The above factors negatively affect immune resistance, therefore, such patients, in comparison with healthy ones, will more often suffer from infectious and oncological pathologies.

Main reasons, due to which secondary immunodeficiency may develop are listed below.

Errors in nutrition - The human body is very sensitive to the lack of vitamins, minerals, proteins, amino acids, fats, carbohydrates. These elements are essential for making a blood cell and maintaining its function. In addition, for normal operation immune system It takes a lot of energy that comes with food.

All chronic diseases negatively affect the immune defense, worsening the resistance to foreign agents that penetrate from the external environment into the body. At chronic course infectious pathology the function of hematopoiesis is inhibited, so the production of young protective cells is significantly reduced.

Adrenal hormones. An excessive increase in hormones inhibits the function of immune resistance. Failure of work is observed in violation of material exchange.

A short-term state, as a protective reaction, is observed due to severe surgical procedures or receiving severe injury. For this reason, patients who have undergone surgery are susceptible to infectious diseases for several months.

Physiological features of the body:

• prematurity;
• children from 1 year to 5 years;
• pregnancy and lactation;
• old age

Features in people of these categories are characterized by inhibition of the immune function. The fact is that the body begins to work intensively in order to transfer an additional load to perform its function or survive.

Malignant neoplasms. First of all, we are talking about blood cancer - leukemia. With this disease, there is an active production of protective non-functional cells that cannot provide full-fledged immunity.

Also, a dangerous pathology is the defeat of the red bone marrow, which is responsible for hematopoiesis and the replacement of its structure with a malignant focus or metastases.

Along with this, all other oncological diseases deal a significant blow to the protective function, but disturbances appear much later and have less pronounced symptoms.

HIV is the human immunodeficiency virus. By suppressing the immune system, it leads to a dangerous disease - AIDS. All lymphoid nodes increase in the patient, oral ulcers often recur, candidiasis, diarrhea, bronchitis, pneumonia, sinusitis, purulent myositis, meningitis are diagnosed.

The immunodeficiency virus affects the defense reaction, so patients die from those diseases that a healthy body can hardly prevent, and weakened by HIV infection - even more so (tuberculosis, oncology, sepsis, etc.).

Combined immunodeficiency (CID)

is the heaviest and rare disease which is very difficult to cure. CID is a group of hereditary pathologies that lead to complex disorders of immune resistance.

As a rule, changes occur in several types of lymphocytes (for example, T and B), while in PID only one type of lymphocyte is disturbed.

KID manifests itself in early childhood. The child is poorly gaining weight, lags behind in growth and development. These children have a high susceptibility to infections: the first attacks may begin immediately after birth (for example, pneumonia, diarrhea, candidiasis, omphalitis).

As a rule, after recovery, a relapse occurs in a few days or the body is affected by another pathology of a viral, bacterial or fungal nature.

Treatment of primary immunodeficiency

To date, medicine has not yet been invented universal medicine which helps to completely overcome all types of immunodeficiency states. However, therapies aimed at removing and eliminating negative symptoms, increased lymphocytic protection and improved quality of life.

This is a complex therapy, selected on an individual basis. The life expectancy of the patient, as a rule, depends entirely on the timely and regular intake of medical products.

Treatment of primary immunodeficiency is achieved by:

• prevention and concomitant therapy of infectious diseases in the early stages;
• improving protection by bone marrow transplantation, immunoglobulin replacement, neutrophilic mass transfusion;
• increased function of lymphocytes in the form of treatment with cytokines;
  the introduction of nucleic acids (gene therapy) to prevent or stop the development of the pathological process at the chromosomal level;
• vitamin therapy to support immunity.

If the course of the disease is aggravated, this should be reported to the attending physician.

Treatment of secondary immunodeficiency

As a rule, the aggressiveness of secondary immunodeficiency states is not serious. Treatment is aimed at eliminating the cause that caused the IDS.

Therapeutic focus:

• with infections - elimination of the focus of inflammation (with the help of antibacterial and antiviral drugs);
• for increase immune protection- immunostimulants;
• if the IDS was caused by a lack of vitamins, then a long course of treatment with vitamins and minerals is prescribed;
• human immunodeficiency virus - treatment consists of highly active antiretroviral therapy;
• at malignant formations- surgical removal of a focus of atypical structure (if possible), chemo-, radio-,
• tomotherapy and others modern methods treatment.

In addition, with diabetes, you should carefully monitor your health: follow a hypocarbohydrate diet, regularly test your sugar level at home, take insulin tablets or subcutaneous injections in a timely manner.

CHID treatment

Therapy for primary and combined forms of immunodeficiency is very similar. The most effective method of treatment is bone marrow transplantation (in case of damage to T-lymphocytes).

• Today, transplantation is successfully carried out in many countries, helping to overcome an aggressive genetic disease.

Prognosis: what the patient expects

The patient must be provided with high-quality medical care even at the first stages of the development of the disease. If we are talking about a genetic pathology, then it should be identified as early as possible by passing many tests and undergoing a comprehensive examination.

Children who are born with PID or CID and do not receive appropriate therapy have a low survival rate up to two years.

At HIV infection it is important to regularly test for antibodies to the human immunodeficiency virus in order to control the course of the disease and prevent sudden progression.

Age features of the immunological status of animals

In the embryonic period, the immunological status of the fetal organism is characterized by the synthesis of its own protective factors. At the same time, the synthesis of natural resistance factors outstrips the development of specific response mechanisms.

Of the factors of natural resistance, cellular elements are the first to appear: first monocytes, then neutrophils and eosinophils. In the embryonic period, they function as phagocytes, possessing an exciting and digesting ability. Moreover, the digestive capacity prevails and does not change significantly even after the intake of colostrum by newborn animals. By the end of the embryonic period, lysozyme, properdin and, to a lesser extent, complement accumulate in the fetal circulation. As the fetus develops, the level of these factors gradually increases. In the prefetal and fetal periods, immunoglobulins appear in the fetal blood serum, mainly of the M class and less often of the class G . They have the function of predominantly incomplete antibodies.

In newborn animals, the content of all protection factors increases, but only lysozyme corresponds to the level of the maternal organism. After taking colostrum in the body of newborns and their mothers, the content of all factors, with the exception of complement, levels off. The complement concentration does not reach the maternal level even in the serum of 6-month-old calves.

Saturation of the bloodstream of newborn animals immune factors occurs only in a colostral way. Colostrum contains in decreasing amounts IgG1, IgM, IgA, IgG 2. Immunoglobulin Gl Approximately two weeks before calving, it selectively passes from the bloodstream of cows and accumulates in the udder. The remaining colostral immunoglobulins are synthesized by the mammary gland. Lysozyme and lactoferrin are also formed in it, which, together with immunoglobulins, represent humoral factors of local udder immunity. Colostrum immunoglobulins pass into the lymph and then the bloodstream of a newborn animal by pinocytosis. In crypts thin department intestines, special cells selectively transport molecules of colostrum immunoglobulins. Immunoglobulins are most actively absorbed when drinking colostrum to calves in the first 4..5 hours after birth.

The mechanism of natural resistance changes in accordance with the general physiological state of the animal organism and with age. In old animals, there is a decrease in immunological reactivity due to autoimmune processes, since during this period mutant forms of somatic cells accumulate, while immunocompetent cells themselves can mutate and become aggressive against normal cells of their body. A decrease in the humoral response was established due to a decrease in the number of plasma cells formed in response to the introduced antigen. It also reduces the activity of cellular immunity. In particular, with age, the number of T-lymphocytes in the blood is much less, there is a decrease in reactivity to the injected antigen. With regard to the absorption and digestion activity of macrophages, no differences have been established between young animals and old ones, although the process of freeing blood from foreign substances and microorganisms is slowed down in old ones. The ability of macrophages to cooperate with other cells does not change with age.

Immunopathological reactions .

Immunopathology studies pathological reactions and diseases, the development of which is due to immunological factors and mechanisms. The object of immunopathology is a variety of violations of the ability of immunocompetent cells of the body to distinguish between "own" and "alien", own and foreign antigens.

Immunopathology includes three types of reactions: reaction to self antigens, when immunocompetent cells recognize them as foreign (autoimmunogenic); a pathologically strongly pronounced immune reaction to an allergen, a decrease in the ability of immunocompetent cells to develop an immune response to foreign substances (immunodeficiency diseases, etc.).

Autoimmunity.It has been established that tissue breakdown occurs in some diseases, accompanied by the formation of autoantigens. Autoantigens are components of one's own tissues that occur in these tissues under the influence of bacteria, viruses, drugs, and ionizing radiation. In addition, the introduction of microbes into the body that have common antigens with mammalian tissues (cross-antigens) can serve as the cause of autoimmune reactions. In these cases, the animal's body, reflecting the attack of a foreign antigen, simultaneously affects the components of its own tissues (often the heart, synovial membranes) due to the common antigenic determinants of micro- and macroorganisms.

Allergy. Allergy (from the Greek. alios - other, ergon - action) - altered reactivity, or sensitivity, of the body in relation to a particular substance, more often when it is re-entered into the body. All substances that change the reactivity of the body are called allergens. Allergens can be various substances of an animal or plant origin, lipoids, complex carbohydrates, medicinal substances and others. Depending on the type of allergens, infectious, food (idiosyncrasy), drug and other allergies are distinguished. Allergic reactions are manifested due to the inclusion of specific defense factors and develop, like all other immune reactions, in response to the penetration of the allergen into the body. These reactions can be increased compared to the norm - hyperergy, can be lowered - hypoergy or completely absent - anergy.

Allergic reactions are subdivided according to their manifestation into immediate-type hypersensitivity (IHT) and delayed-type hypersensitivity (DTH). NHT occurs after re-introduction of the antigen (allergen) after a few minutes; HRT appears after several hours (12...48), and sometimes even days. Both types of allergies differ not only in the speed of clinical manifestations, but also in the mechanism of their development. GNT includes anaphylaxis, atopic reactions, and serum sickness.

Anaphylaxis(from Greek ana - against, phylaxia - protection) - a state of increased sensitivity of a sensitized organism to repeated parenteral administration foreign protein. Anaphylaxis was first discovered by Portier and Richet in 1902. The first dose of antigen (protein) that causes hypersensitivity is called sensitizing(lat. sensibilitas - sensitivity), the second dose, after the introduction of which anaphylaxis develops, - permissive, moreover, the resolving dose should be several times higher than the sensitizing one.

Passive anaphylaxis. Anaphylaxis can be artificially reproduced in healthy animals in a passive way, i.e., by introducing the immune serum of a sensitized animal. As a result, the animal develops a state of sensitization after a few hours (4...24). When administered to such an animal specific antigen passive anaphylaxis occurs.

Atopy(Greek atopos - strange, unusual). Atopy refers to HNT, which is a natural hypersensitivity that occurs spontaneously in people and animals predisposed to allergies. Atopic diseases more studied in humans is bronchial asthma, allergic rhinitis and conjunctivitis, urticaria, food allergy to strawberries, honey, egg white, citrus, etc. Food allergy has been described in dogs and cats for fish, milk and other products; in cattle, an atopic reaction such as hay fever was noted when transferred to other pastures. AT last years very often register atopic reactions caused by drugs - antibiotics, sulfonamides, etc.

Serum sickness . Serum sickness develops 8-10 days after a single injection of foreign serum. The disease in humans is characterized by the appearance of a rash resembling hives, and is accompanied by severe itching, increased body temperature, impaired cardiovascular activity, swelling lymph nodes and progresses without death.

Delayed type hypersensitivity (DTH). For the first time this type of reaction was discovered by R. Koch in 1890 in a patient with tuberculosis with subcutaneous injection of tuberculin. Later it was found that there are a number of antigens that stimulate predominantly T-lymphocytes and mainly determine the formation of cellular immunity. In an organism sensitized by such antigens, on the basis of cellular immunity, a specific hypersensitivity is formed, which manifests itself in the fact that after 12–48 hours an inflammatory reaction develops at the site of repeated administration of the antigen. Its typical example is the tuberculin test. Intradermal administration of tuberculin to an animal with tuberculosis causes edematous painful swelling at the injection site, an increase in local temperature. The reaction reaches a maximum by 48 hours.

Hypersensitivity to allergens (antigens) of pathogenic microbes and their metabolic products is called infectious allergies. It plays an important role in the pathogenesis and development of such infectious diseases as tuberculosis, brucellosis, glanders, aspergillosis, etc. When the animal recovers, the hyperergic state persists for a long time. Specificity of infectious allergic reactions allows them to be used for diagnostic purposes. Various allergens are prepared industrially in biofactories - tuberculin, mallein, brucellohydrolyzate, tularin, etc.

It should be noted that in some cases there is no allergic reaction in a sick (sensitized) animal, this phenomenon is called anergy(reactivity). Anergy can be positive or negative. Positive anergy is noted when the immunobiological processes in the body are activated and the contact of the body with the allergen quickly leads to its elimination without development inflammatory response. Negative anergy is caused by the unresponsiveness of body cells and occurs when defense mechanisms suppressed, which indicates the defenselessness of the body.

When diagnosing infectious diseases accompanied by allergies, the phenomena of paraallergy and pseudoallergy are sometimes noted. Paraallergy - the phenomenon when a sensitized (sick) organism reacts to allergens prepared from microbes that have common or related allergens, such as Mycobacterium tuberculosis and atypical mycobacteria.

Pseudoallergy(heteroallergy) - the presence of a nonspecific allergic reaction as a result of autoallergization of the body by tissue decay products during the development of a pathological process. For example, an allergic reaction to tuberculin in cattle with leukemia, echinococcosis or other diseases.

There are three stages in the development of allergic reactions:

· immunological - the combination of an allergen with antibodies or sensitized lymphocytes, this stage is specific;

· pathochemical - the result of the interaction of the allergen with antibodies and sensitized cells. Mediators, a slowly reacting substance, as well as lymphokines and monokines are released from the cells;

· pathophysiological - the result of the action of various biologically active substances on fabric. It is characterized by circulatory disorders, spasm of smooth muscles of the bronchi, intestines, changes in capillary permeability, swelling, itching, etc.

Thus, in allergic reactions, we observe clinical manifestations that are not characteristic of direct action antigen (microbes, foreign proteins), but rather the same type of symptoms characteristic of allergic reactions.

Immunodeficiencies

Immunodeficiency states are characterized by the fact that the immune system is not able to respond with a full immune response to various antigens. The immune response is not just the absence or decrease in the immune response, but the inability of the body to carry out one or another link of the immune response. Immunodeficiencies are manifested by a decrease or complete absence of an immune response due to a violation of one or more parts of the immune system.

Immunodeficiencies can be primary (congenital) or secondary (acquired).

Primary immunodeficiencies characterized by a defect in cellular and humoral immunity (combined immunodeficiency), either only cellular or only humoral. Primary immunodeficiencies arise as a result of genetic defects, as well as as a result of inadequate feeding of mothers during pregnancy, primary immunodeficiencies can be observed in newborn animals. Such animals are born with signs of malnutrition and are usually not viable. With combined immunodeficiency note the absence or hypoplasia of the thymus, bone marrow, lymph nodes, spleen, lymphopenia and low maintenance immunoglobulins in the blood. Clinically, immunodeficiencies can manifest themselves as a delay in physical development, pneumonia, gastroenteritis, sepsis, caused by an opportunistic infection.

Age-related immunodeficiencies observed in young and old organisms. In young people, humoral immunity deficiency is more common as a result of insufficient maturity of the immune system during the neonatal period and up to the second or third week of life. In such individuals, there is a lack of immunoglobulins, B-lymphocytes in the blood, a weak phagocytic activity of micro- and macrophages. There are few secondary lymphoid follicles with large reactive centers and plasma cells in the lymph nodes and spleen. Animals develop gastroenteritis, bronchopneumonia, caused by the action of opportunistic microflora. Deficiency of humoral immunity during the neonatal period is compensated by full-fledged colostrum of the mother, and at a later time - by full-fledged feeding and good living conditions.

In old animals, immunodeficiency is caused by age-related involution of the thymus, a decrease in the number of T-lymphocytes in the lymph nodes and spleen. These organisms often develop tumors.

Secondary immunodeficiencies arise in connection with the disease or as a result of treatment with immunosuppressants. The development of such immunodeficiencies is observed in infectious diseases, malignant tumors, prolonged use of antibiotics, hormones, inadequate feeding. Secondary immunodeficiencies are usually accompanied by impaired cellular and humoral immunity, i.e. are combined. They are manifested by involution of the thymus, devastation of the lymph nodes and spleen, a sharp decrease in the number of lymphocytes in the blood. Secondary deficiencies, unlike primary ones, can completely disappear when the underlying disease is eliminated.Against the background of secondary and age-related immunodeficiencies, drugs may be ineffective, and vaccination does not create strong immunity against infectious diseases. Thus, immunodeficiency states must be taken into account in the selection, development of therapeutic and preventive measures in the economy. In addition, the immune system can be manipulated to correct, stimulate, or suppress certain immune responses.Such an effect is possible with the help of immunosuppressants and immunostimulants.

Secondary (acquired) immunodeficiencies

Secondary (acquired) immunodeficiencies are more common than congenital immunodeficiencies. Acquired immunodeficiencies may be the result of exposure to environmental factors and endogenous substances. The factors responsible for the induction of secondary immunodeficiencies include pathogens of infectious and parasitic diseases, pharmacological substances, and endogenous hormones. They can be the result of splenectomy, aging, malnutrition, the development of tumors and radiation exposure.

infectious agents. Canine distemper virus, canine parvovirus, feline panleukopenia virus, feline leukemia virus, feline immunodeficiency virus and other viruses induce suppression of the cellular link of the immune response. Diseases such as demodicosis, ehrlichiosis and systemic fungal diseases are also accompanied by profound immunosuppression.

pharmacological substances. Corticosteroids and various anticancer drugs are the most common pharmacological agents that induce immunosuppression. Drugs such as chloramphenicol, sulfamethoxypyridazine, clindamycin, dapsone, lincomycin, griseofulvin have also been associated with immunosuppression.

endogenous hormones. Hyperadrenocorticism, growth hormone deficiency, diabetes mellitus, and hyperestrogenism are associated with acquired immunodeficiency diseases. Hyperadrenocorticism is manifested by suppression of immune functions due to an increase in glucocorticoids, while growth hormone deficiency causes an immunodeficiency state associated with inhibition of maturation of T-lymphocytes due to suppression of thymus development. Patients with diabetes mellitus show a predisposition to skin, systemic and urinary tract infections, which can be directly related to a decrease in serum insulin concentration or to glycemia. The immunosuppressive effect of hyperestrogenism is similar to that of leukopenia.

3.1. VIRUS-INDUCED IMMUNOSUPPRESSION

That viruses can affect immune responses was discovered by von Pirquet as early as 1908, when he showed that measles infection delayed the development of delayed-type hypersensitivity in patients who had a normal response to mycobacterial antigens. Thus, von Pirquet was the first to introduce an immunological aspect of the explanation for the manifestation of hypersensitivity to superinfections in patients with viral diseases. The next message (1919), which confirmed this hypothesis, was that the influenza virus also suppresses the body's response to tuberculin. For the next 40 years, there were no publications on the effect of viruses on the immune system. Since the early 1960s, evidence has emerged that oncogenic viruses have an immunosuppressive effect. Old and colleagues were the first to do so, and then five years later, Good et al presented the first systematic assessment of antibody suppression caused by murine leukemia virus. During the late 1960s and early 1970s, there was a boom in this field, with a large number of reports supporting the concept of immune suppression by oncogenic viruses. Moreover, it was shown that both humoral and cellular immunity are inhibited. Studies of many non-oncogenic viruses have shown that they also exhibit immunosuppressive activity. Many investigators have considered viral immunosuppression as an important factor in causing persistent infections leading to chronic disease and tumor formation. However, in the mid-70s, the number of studies in this area of ​​virology declined sharply, and their revival dates back to the 80s. At the same time, the authors tried to find out molecular mechanisms causing virus-induced immunosuppression. Thus, the "science" of studying the relationship between virus and immunity is not new. Intensification of research in this area has been outlined in recent years. This was facilitated by the discovery and study of the human immunodeficiency virus.

Viruses can interfere with the development of an immune response in several ways:

• directly lyse lymphoid cells (eg, measles virus and canine distemper virus);
• infect lymphocytes and disrupt their functions in various ways (for example, bovine leukemia virus);
• produce viral substances that can directly interfere with antigenic recognition or cellular cooperation (for example, feline leukemia virus);
• secondarily induce immunosuppression by producing a large number immune complexes (for example, feline infectious peritonitis virus).

Canine distemper virus (CDV), feline leukemia virus (FeLV), parvoviruses cause virus-induced immune dysfunction through various mechanisms.

Viral measles infection in humans can induce a temporary state of immunosuppression due to the destruction of T-lymphocytes in T-dependent zones of lymphoid structures. This is due to the presence of specific measles virus receptors on the surface of T cells.

Canine distemper virus is closely related to the measles virus, and although the presence of equivalent viral receptors on the surface of canine T cells has not been proven, there is strong clinical and experimental evidence showing that this virus also induces a state of transient immunosuppression. As a result of infection of gnotobiote dogs with it, atrophy of the thymus is observed with generalized lymphoid depletion, leading to lymphopenia. This disrupts the blast transformation of lymphocytes in vitro, but the ability to reject an allogeneic skin graft does not change. The degree of lymphoid depletion, and hence the occurrence of T-cell immunosuppression, correlates with disease outcome. Animals that do not respond to intradermal administration of PHA are more severely affected; they quickly die from encephalitis, while animals that retain a T-cell immune response often recover.

Vpruz dog plague causes immunosuppression primarily due to the cytotoxic effect during early replication of the virus in the lymphoreticular tissue. As a result, lymphocyte necrosis occurs in the lymph nodes, spleen, thymus and lymphopenia. In addition, there is a decrease in the T-cell response to mitogens in vitro and a decrease in the humoral immune response in infections associated with CDV. This is observed at an early stage of the disease with subsequent secondary development of bacterial infections.

Other mechanisms underlie immunosuppression caused by feline leukemia virus.

The disease caused by FeLV is probably the most studied in veterinary medicine. Infection of kittens leads to virus-induced destruction of lymphoid tissues, followed by their atrophy and increased sensitivity to infections. At the same time, most of the immune parameters are reduced, and the ability of the animals to reject the allogeneic skin graft is impaired. Usually, infection leads to immunosuppression without overt destruction of lymphoid tissues. This is due to the production of excessive amounts of the viral envelope protein p15E. The exact mechanism of action of this excess is unclear, but it has been suggested that it interferes with lymphocyte activation and antigen recognition. The literature describes immunosuppression caused by a defect-replicated feline leukemia virus mutant that occurred during natural illness. Although FeLV is often referred to as AIDS in cats due to its similarity to HIV infection, the described feline T-lymphotropic lentivirus may be a more appropriate animal model.

FeLV infection is characterized by thymic atrophy, lymphopenia, low blood complement, and high levels of immune complexes. At the same time, cats have hypersensitivity to various infections including infectious peritonitis, herpesvirus rhinitis, viral panleukopenia, hemobartonellosis and toxoplasmosis. Further development of these diseases causes a fundamental defect in T cells, which manifests itself in vitro as a pronounced decrease in the T cell response to mitogens. A primary T-cell defect is accompanied by a secondary functional B-cell defect. But the B cell defect may not be related to the T cell defect. B cells are unable to produce IgG antibodies in the absence of T helper cells, but may retain the ability to synthesize IgM antibodies through T cell independent mechanisms. Therefore, B cell activity is only partially impaired in FeLV infection.

The manifestation of a defect in T cells is associated with the lack of the required stimulation for T cell activation. A related problem is a disruption in the production of interleukin-2, a lymphokine essential for maintaining and maintaining T-cell activation, proliferation, and T-helper production, which favorably influences B-cell antibody production. Two serum factors seem to be involved in the immunosuppressive effect of FeLV infection. The viral envelope protein p15E directly causes immunosuppression of lymphocytes and abolishes the response of lymphocytes to various mitogenic stimuli in vitro. This action may be due to its ability to block the response of T-41 lymphocytes to interleukin-1 and interleukin-2 and to abolish the synthesis of interleukin-2. When p15E is administered to cats at the same time as the FeLV vaccine, there is no formation of protective antibodies to the feline oncornavirus membrane cell antigen. Thus, p15E plays a central role in FeLV-induced immunosuppression both in vivo and in vitro. In addition, affected cats have high levels of circulating immune complexes, which are themselves immunosuppressive.

FeLV can directly interfere with the migration of T cells from the bone marrow to peripheral lymphoid tissues, reducing the number of normal T cells in the thymus, spleen, and lymph nodes. It appears that several different mechanisms of B and T cell damage may contribute to the immunosuppression of FeLV-infected cats.

Parvovirus infection in many animal species leads to immunosuppression due to the mitolytic effect of the virus on stem cell division in the bone marrow. Therefore, lymphopenia and granulocytopenia are a direct consequence of the infection caused by this virus. Canine parvovirus infection is also associated with immunosuppression, and distemper vaccination-associated encephalitis has been described in dogs experimentally infected with parvovirus.

feline panlepkopenpp virus, like parvovirus, has a less potent immunosuppressive effect, which limits the temporary depletion of T cells to a greater extent. The possible immunosuppressive effect of a live attenuated vaccine, in particular canine parvovirus, is questionable, but simultaneous immunization with attenuated parvovirus and distemper virus is considered safe and effective.

Infection of foal mares, conditioned equine herpesvirus, can cause abortions in the last third of pregnancy. If the foal is born to term, it is prone to severe infections, which are caused by virus-induced atrophy of all lymphoid structures.

Viral diarrhea of ​​cattle - another example of virus-induced immunosuppression, which is accompanied by damage to T- and B-cell immunity. This contributes to the development of a chronic wasting syndrome with persistent infection. This virus is also able to pass through the placenta, causing immunological tolerance and reduced immune response in calves.

Bovine leukemia virus- shows tropism for B cells, in which it causes proliferation and sometimes neoplastic transformation. Its influence on immunological parameters depends on the type and stage of the disease. Usually there is lymphocytosis with an increase in the number of B cells expressing surface immunoglobulins.

3.2. IMMUNOSUPPRESSION CAUSED BY BACTERIA

Compared to viral infections, in which the immunosuppressive effect is usually associated with direct infection of lymphoid tissues, the mechanism of secondary immunosuppression in bacterial diseases insufficiently studied.

In Ione's disease, a paradox is observed in which, despite a pronounced cellular immune response to the pathogen, the corresponding reaction to other antigens may be impaired or not manifest at all. So affected cattle do not develop a skin reaction to tuberculin. The same situation is observed in chronic mycobacterial diseases in humans, in which there is a state of anergy. At the same time, lymphocytes do not undergo transformation in response to PHA in vitro, the number of suppressor cells increases in the presence of a soluble factor that prevents the manifestation of cellular reactions.

By the end of the last decade, it became apparent that the lack of in vitro stimulation of lymphocytes is associated with many chronic diseases of infectious and non-infectious origin. Lymphocytes are unable to respond to mitogens in the presence of homologous normal serum or fetal bovine serum. In other cases, lymphocytes show a reaction that occurs when they are isolated from autologous serum. Suppression in this case is associated with the action of suppressive serum immunoregulatory factors. The involvement of these substances in the in vivo immune response remains unclear. It is only known that substances with such properties are found in many sera obtained from normal and sick animals, but the nature of these substances has not been established. It is also unclear whether they are the cause of the disease, or are formed in the course of it, participating in the mechanism by which the microbial agent manifests its pathogenicity in the future. Experiments are needed to show the increase in pathogenicity of microorganisms under the influence of these factors, since it is possible that they do not play any role in these cases.

3.3. IMMUNODEFICIENCY ASSOCIATED WITH DEMODECOSIS IN DOGS

The special genetic sensitivity of dogs, which predetermines the development of demodicosis, is determined by their inability to develop delayed-type hypersensitivity during intradermal injection of tick-borne antigen. The molecular basis of this defect remains unclear.

Many investigators are investigating the role of immunosuppression as an etiological factor in canine demodicosis with varying results that are far from conclusive and each side has its own opponents. In defense of the hypothesis that demodicosis is the result of T-cell immunodeficiency, the following observations support:

• lymphocytes obtained from animals with demodicosis show in vitro a weak reaction of blast transformation under the influence of PHA;
• The intradermal test with PHA in Doberman Pinschers severely affected by demodicosis is significantly reduced in comparison with healthy animals of the same age.

Other evidence argues against the putative role of immunodeficiency in demodicosis:

• immunosuppression disappears when the tick population is destroyed;
• immunostimulation of animals with levamisole leads to reversal of immunosuppression;
• factors that suppress blastogenesis are found in demodicosis only in the presence of a secondary staphylococcal infection, and are not found in the serum of dogs with a squamous form of the disease, in which there is no association with secondary bacterial infections. Therefore, the suppression of T-cell function is not associated with the proliferation of Demodex mites, but rather is the result of a secondary staphylococcal infection.

Most evidence suggests that the immunosuppression observed in demodicosis is the result of secondary pyoderma and has no etiological role in the proliferation of Demodex mites. If in fact the immune response is related to the etiology of demodicosis, there is one hypothesis that there is a primary defect in antigen-specific T cells, which gives rise to the initial proliferation of ticks.

Despite the likelihood that immunosuppression is not the cause of demodicosis, it must be remembered that in animals with a generalized form of the disease, nevertheless, a state of immunosuppression is noted. As a result, immunoprophylactic measures are not effective enough for them.

Generalized canine demodicosis leads to the development of immunosuppression. The functions of T-cells, as shown by the results of studies of blast transformation of lymphocytes under the influence of mitogens in vitro, and the delayed-type hypersensitivity reaction to concavalin A are sharply reduced. Interestingly, suppression of the lymphocyte response to mitogens in vitro occurs only in the presence of sera from affected dogs. If lymphocytes from the patient are washed and incubated with normal dog serum, then the process of blast transformation proceeds normally. These results suggest the presence of a suppressor factor induced by the tick population in serum. Supporting this position is the fact that lymphocytes from normal dogs have a reduced response to mitogens when incubated with sera from demodicosis dogs. The suppressor factor is located in the beta-globulin fraction of the patient's serum, and some researchers suggest that it really represents an antigen-antibody complex consisting of a mite antigen and host antibodies. Therefore, the immunosuppressive effect of circulating immune complexes is expressed in a decrease in T-cell function, which is characteristic of many diseases like feline leukemia virus. If this situation arises, the defect in T cells should be considered as a result of the disease, or it is associated with the formation of pyoderma. It is unlikely that there are any other reasons. This position is confirmed by observations when the destruction of the population of mites and the pyodermal effects caused by them, restores the ability to a normal T-cell response to mitogens. Humoral immunity, neutrophil function, and T-cell counts remain normal in dogs with demodicosis.

In conclusion, demodicosis is most likely the result of a congenital T-cell defect that allows the Demodex canis mite to infect the host. The presence of a large number of ticks contributes to an additional decrease in the function of T cells through the formation of a serum suppression factor, leading to generalized immunodeficiency.

3.4. DISTURBANCE IN PASSIVE ANTIBODY TRANSFER

Impaired passive transmission of maternal antibodies is one of the most common examples of acquired immunodeficiency in veterinary medicine, which is a major cause of neonatal infection and early mortality predominantly in foals, calves, kids, lambs and piglets. Violation in the receipt of colostrum causes omphalophlebitis, septic arthritis, septicemia, pneumonia and diarrhea in newborns. The increased susceptibility to infection is the result of the absence of maternal immunoglobulins, which are necessary for direct bactericidal action on pathogens and for their opsonization.

The importance of this provision depends on the cognate assistance of placental versus colostral transmission of antibodies in neonatal protection, which is a reflection of placental formation. The placenta of mares, donkeys, cows, sheep and pigs prevents the transfer of immunoglobulins from mother to offspring, while the endotheliochorial placenta in dogs and cats provides their limited transplacental transfer. Intestinal absorption of immunoglobulins is believed to take place only in the first 24 hours, and one of the authors notes that no absorption occurs in dogs after this time. Absorption is most effective in the first 6 hours.

Maternal colostrum deficiency does not significantly affect puppies as long as hygienic conditions are maintained, however, there are reports that suggest that colostrum deficiency in cats contributes to increased morbidity and mortality in kittens. Of course, the lack of passive transfer of antibodies with colostrum is important in cows, horses, sheep and pigs, and it is very difficult to raise newborn calves, foals, lambs and piglets even under ideal conditions in the complete absence of colostrum.

Foals are usually born essentially agammaglobulinemic with only a small amount of IgM found in their serum. On the other hand, lambs are able to form low levels of IgG1 and IgM in late stage pregnancy, but deprived of IgG2 and IgA at birth. In both cases, the protection of newborns depends on the provision of colostrum. The absence of maternal antibodies in newborns prevents the body from fighting the infectious agents it encounters during early life.

Reception of colostrum by newborns leads to intestinal absorption of large amounts of intact maternal immunoglobulins during the first 6-8 hours of life. Trypsin inhibitors in colostrum prevent the breakdown of globulins in the stomach of the newborn. The absorption of these globulins occurs through receptors for the Fc fragment of immunoglobulin located on the surface of intestinal epithelial cells. These properties of cells that allow intestinal absorption of maternal antibodies decline rapidly after 12 hours; between 24 and 48 hours after birth, the intestines are unable to absorb immunoglobulins, despite the high concentration of immunoglobulins in the intestinal contents. The cessation of absorption is associated with the replacement of specialized immunoabsorptive enterocytes with mature epithelium. Usually, absorbed maternal antibodies gradually disappear over the course of 6-8 weeks of life, once newborns begin to synthesize their own antibodies.

Impaired passive transmission of maternal antibodies can occur in any type of domestic animal, but is most documented in horses. Reports indicate that impaired transmission of maternal antibodies can be as high as 24% of foals. Transmission failure can be determined by maternal factors, as well as by the state of the newborns themselves and environmental factors. In some mothers, the production of colostrum with a sufficient concentration of immunoglobulins may be impaired, mainly due to a genetic deficiency. On the other hand, mothers with normal colostrum production lose immunoglobulins due to premature lactation. Premature lactation is a major cause of impaired passive transmission and has been associated with placentitis, twin pregnancy, and premature separation of the placenta in the horse. A colostral immunoglobulin concentration lower than 1mg/ml, indicative of abnormal production or premature lactation, causes a disturbance in passive transmission.

The foal must receive adequate colostrum during the first 12 hours of life. Weak or unadapted foals may not receive the required amount. Slippery floors make it difficult to take colostrum. In these cases, it is necessary to feed him from a bottle. Some newborn foals are not designed to drink well from a bottle, so they may not get enough colostrum. If the foal has received an adequate amount of colostrum, the intestinal epithelium should absorb the immunoglobulins, with the rate of absorption varying from foal to foal. Endogenous production of glucocorticoid associated with stress can lead to a decrease in IgG absorption by specialized immunoabsorptive enterocytes. Thus, impaired passive transmission may occur for the following reasons: the quantity and quality of maternal colostrum, the foal's ability to consume sufficient colostrum, and the foal's ability to absorb immunoglobulins.

In recent years, the literature has widely presented data on immunodeficiencies in calves, piglets and lambs associated with untimely and insufficient colostrum after birth. It has been shown that the process of absorption of immunoglobulins by the intestines of newborn animals is influenced by various environmental and economic factors. At the same time, the incidence and mortality of young animals are directly dependent on the time of receipt of the first colostrum.

The diagnosis of impaired passive transmission of antibodies is based on the determination of the concentration of IgG in the blood serum of newborn animals during the first 12 hours of life. For this, 3 methods are used: turbidity test with zinc sulfate, radial immunodiffusion or latex agglutination. The turbidity test is a quick, simple method in which zinc sulfate (in foals), sodium sulfate (in calves), or ammonium sulfate (in piglets) is added to the test serum. The resulting immunoglobulin precipitates can be qualitatively measured colorimetrically at 485 nm. Foals that have more than 8 mg/ml of immunoglobulins in serum have good maternal transmission. A value between 4 and 8 mg/mL indicates a partial transmission disorder, and a level below 4 mg/mL indicates a significant impairment of colostral absorption. The values ​​for each type are different. Calves with an immunoglobulin content of more than 16 mg/ml have good absorption, levels between 8 and 16 mg/ml show reduced absorption, and maternal transmission is clearly impaired when the level is below 8 mg/ml. The zinc sulfate haze test is semi-quantitative and tends to overestimate serum IgG levels. Therefore, actual serum IgG concentrations below 4 mg/mL may appear higher in the turbidity test, and these immunologically deficient foals may not receive appropriate treatment. The reaction with zinc sulfate depends on factors such as temperature, shelf life and the preparation of the zinc sulfate solution.

A more accurate method by which the level of IgG in the blood serum of animals is determined is simple radial immunodiffusion. This test is commercially available, but the incubation time (18-24 hours) required to establish a reaction limits its use to diagnose passive transmission during the first critical 12 hours of life. Latex agglutination is a commercially available test in practice for diagnosing passive transmission and is more accurate than the turbidimetric test. The latex agglutination data are 90% consistent with the RID data in determining the level of IgG less than 4 mg/ml. The latex test requires a mixture of 5 µl of test serum with an appropriately diluted kit, followed by visual assessment of agglutination. The main disadvantage of this test is that it does not differentiate between 4 mg/mL and 8 mg/mL in foals.

Once a defect in passive transmission has been established, colostrum drinking from a bottle or intravenous administration of immunoglobulins (depending on the age of the newborn) is necessary to correct the deficiency. The introduction of 4 liters of plasma over 2-5 days is necessary to ensure a reliable level of IgG. Plasma donors should be free of antierythrocyte lysins and agglutinins and kept under the same conditions as foals for at least a few months. Commercially available equine plasma certified as negative for erythrocyte alloantibodies can also be used in equine practice in the treatment of passive transmission disorders.

3.5. PREGNANCY AND LACTATION

3.6. OTHER FACTORS CONTRIBUTING TO IMMUNOSUPPRESSION

Candidiasis of the skin and mucous membranes. The causative agent of candidiasis is the conditionally pathogenic yeast-like fungus Candida albicans. Immunodeficiencies, usually involving defects in T cells, may predispose to diseases that cause ulcerative lesions of the skin and mucosal surfaces. This condition is sometimes seen in dogs and should be distinguished from autoimmune skin diseases. It has not been determined in which cases this disease is the result of primary or secondary immunodeficiencies, or both. Experiments show that the immunological state changes under the influence of stimulation with levamisole.

Microelements and vitamins. Their role in the immune response is clear, although the influence of many agents and their mechanism of action is not always clear. Zinc is the most important micronutrient and its association with the lethal trait A46 (congenital immunodeficiency) has been established. In addition, vitamin E and selenium play an important role in the formation of a normal immune response, and the immunostimulatory action of vitamin E is used in adjuvants. Dogs consuming food deficient in vitamin E and selenium have severe damage to the immune system. The restoration of a normal immune response occurs as a result of the use of vitamin E supplements, but not selenium.

environmental contaminants. Environmental contaminants, including heavy metals such as lead, cadmium, mercury, various industrial chemicals and pesticides, bad influence to an immune response. Fungal metabolites that contaminate feed are also important; there is evidence of the immunosuppressive effect of aflatoxins secreted by Aspergillus spp.

Therapeutic drugs. The list of therapeutic substances that have an undesirable effect on the immune system is quite long. However, in general, their impact is insignificant, otherwise medicines will not be allowed on the market. The effect of painkillers on nonspecific defenses is known, and a marked impairment of the blastogenic response of lymphocytes in dogs after anesthesia with methoxyfluorane has been shown. Although this may not be of any practical importance, it at least implies that caution must be exercised in interpreting the results obtained from the study of lymphocyte function after anesthesia.

Table 2. Main Causes of Secondary Immunodeficiencies in Animals

PASSIVE ANTIBODY TRANSMISSION DISORDERS (mother-fetus-newborn) all kinds VIRUSES: canine distemper virus, canine parvovirus, feline leukemia virus, feline panleukopenia virus, equine herpesvirus 1, viral diarrhea cattle MEDICATIONS: immunosuppressive/cytotoxic therapy, amphotericin B METABOLISM DISORDERS: zinc deficiency, iron deficiency, vitamin E deficiency DIABETES, HYPERADRENOCORTICISM, UREMIA, PREGNANCY BACTERIA: Mycobacterium paratuberculosis (Jone's disease) TOXINS: mycotoxin bracken-fern trichlorethylene-soybean extract RADIATION ENDOCRINE DISTURBANCES: growth hormone deficiency, estrogen toxicity TUMORS: lymphoma, multiple myeloma

Table 4. Immunosuppressive action lymphoid tumors

Tumor	cell type	The manifestation of immunosuppression	Mechanism
Feline leukemia	T cells	lymphopenia, delayed skin graft rejection, increased susceptibility to infections, lack of response to mitogens	Viral suppressive proteins, p15E, cell suppression
Marek's disease	T cells	lack of response to mitogens, suppression of cellular cytotoxicity, suppression of IgG production	macrophage suppression
Avian lymphoid leukemia	B cells		lymphocyte suppression
Bovine leukemia	B cells	suppression of serum IgM synthesis	soluble suppressor factor
myeloma	B cells	increased susceptibility to infections	soluble tumor cell factor
Canine malignant lymphoma	B cells	Predisposition to infections accompanied by autoimmune disorders	unknown
Equine lymphosarcoma	T cells	increased susceptibility to infections	suppressor cell tumor

Antibodies to p24

Antibodies to gp120

Rice. 4.49. Dynamics of the content of the virus itself and antibodies to two of its proteins in the blood of those infected with the human immunodeficiency virus

T-cells, which allows them to avoid pressure from T-cell immunity. Thus, the cellular immune response is not able to eliminate the virus from the body due to the high adaptability of the virus based on variability. NK cells are also ineffective, although they are not the object of direct infection with the virus.

The dynamics of the content of viral antigens in the circulation serves as a reflection of the relationship between HIV infection and the macroorganism.

and antiviral antibodies (Fig. 4.49). Surge of antigenemia in the early period of development HIV infection (2–8 weeks after infection) reflects the intense replication of viruses that have invaded cells. With a intact immune system of the host, this causes the production of neutralizing antibodies (mainly to surface proteins gp120, gp41, group-specific gag antigen p17), which can be detected by the rise in serum antibody titer to these antigens, starting from the 8th week from the moment of infection. Such a change in the circulation of the antigen to the presence of antibodies in the bloodstream is referred to as " seroconversion". Antibodies to envelope (env) proteins persist throughout the disease, while gag-specific antibodies disappear at certain stages of its development, and viral antigens reappear in the bloodstream. Simultaneously with the accumulation of antibodies to viral antigens in the blood serum, the concentration of all serum immunoglobulins, including IgE, increases.

Circulating antibodies are able to neutralize free virus

and bind its soluble proteins. When responding to gp120, this is most relevant for antibodies specific to the immunodominant epitope. 303–337 localized in the 3rd hypervariable domain (V3) of the molecule. This is supported by the fact that passively administered antibodies can prevent HIV infection. Neutralizing antibodies, especially those directed against gp120, can block infections.

cells. This probably plays a role in the initial containment of HIV infection and to some extent determines the long latency period characteristic of this disease. At the same time, the effector activity of these antibodies is limited, and their protective role in HIV infection cannot be considered proven.

Formation of immunodeficiency in acquired immunodeficiency syndrome

(see table 4.20)

The main cause of immunodeficiency in AIDS is the death of CD4+ T cells. The obvious reason for the death of infected cells is the cytopathogenic effect of the virus. In this case, the cells die by the mechanism of necrosis due to a violation of the integrity of their membrane. Thus, when blood cells are infected with HIV, the number of CD4+ T-cells, starting from the 3rd day, sharply decreases simultaneously with the release of virions into the medium. The population of CD4+ T-cells of the intestinal mucosa suffers the most.

In addition to this mechanism of death of infected cells in AIDS, a high level of apoptosis is detected. The defeat of the T-cell link of the immune system significantly exceeds that expected based on the estimate of the number of infected cells. In lymphoid organs, no more than 10–15% of CD4+ T cells are infected, and in the blood this number is only 1%; however, a much larger percentage of CD4+ T lymphocytes undergo apoptosis. In addition to the infected, a significant part of the cells not infected with the virus, primarily CD4+ T-lymphocytes specific to HIV antigens, apoptates (up to 7% of these cells). Apoptosis inducers are the gp120 proteins and the Vpr regulatory protein, which are active in a soluble form. The gp120 protein lowers the level of the anti-apoptotic protein Bcl-2 and increases the level of the pro-apoptotic proteins p53, Bax, Bak. The Vpr protein disrupts the integrity of the mitochondrial membrane, displacing Bcl-2. There is an exit from the mitochondria of cytochromes and activation of caspase 9, which leads to apoptosis of CD4+ T cells, including those not infected, but HIV-specific.

The interaction of the viral protein gp120 with the membrane glycoprotein CD4+ of T-lymphocytes is the cause of another process that occurs during HIV infection and is involved in the death and functional inactivation of host cells - the formation of syncytium. As a result of the interaction of gp120 and CD4, cells merge with the formation of a multinuclear structure that is unable to perform normal functions and doomed to death.

Among cells infected with HIV, only T-lymphocytes and megakaryocytes die, being exposed to cytopathogenic action or entering into apoptosis. Neither macrophages nor epithelial or other cells infected with the virus lose viability, although their function may be impaired. Dysfunction can be caused not only by HIV as such, but also by its isolated proteins, for example, gp120 or the p14 genetat product. Although HIV is not capable of causing malignant transformation of lymphocytes (unlike HTLV-1, for example), the tat (p14) protein is involved in the induction of Kaposi's sarcoma in HIV infection.

A sharp decrease in the content of CD4+ T-lymphocytes is the most striking laboratory sign of HIV infection and its evolution into AIDS. Conditional

4.7. Immunodeficiencies

the limit of the content of these cells, which is usually followed by the clinical manifestations of AIDS, is 200–250 cells per 1 μl of blood (in relative terms, about 20%). The CD4/CD8 ratio at the peak of the disease drops to 0.3 or less. During this period, general lymphopenia appears with a decrease in the content of not only CD4+, but also CD8+ cells and B-lymphocytes. The response of lymphocytes to mitogens and the severity of skin reactions to common antigens continues to decline to complete anergy. Added to the various reasons for the inability of effector T cells to eliminate HIV is the high mutability of HIV with the formation of new epitopes that are not recognized by cytotoxic T cells.

Naturally, disorders of T-cell and T-dependent processes dominate among immunological disorders in AIDS. The factors that determine these violations include:

– reduction in CD4 count+ T-helpers due to their death;

– weakening of CD4 functions+ T-cells under the influence of infection and the action of soluble products of HIV, especially gp120;

– population imbalance T cells with a shift in the Th1/Th2 ratio towards Th2, while protection from the virus is promoted by Th1-dependent processes;

– regulatory induction T cells with gp120 protein and HIV-associated p67 protein.

A decrease in the body's ability to defend itself affects both its cellular and humoral factors. As a result, a combined immunodeficiency is formed, making the body vulnerable to infectious agents, including opportunistic pathogens (hence the development of opportunistic infections). Deficiency of cellular immunity plays a role in the development of lymphotropic tumors, and the combination of immunodeficiency and the action of certain HIV proteins plays a role in the development of Kaposi's sarcoma.

Clinical manifestations of immunodeficiency in human immunodeficiency virus infection and acquired immunodeficiency syndrome

The main clinical manifestations of AIDS are the development of infectious diseases, mainly opportunistic ones. The following diseases are most characteristic of AIDS: pneumonia caused by Pneumocystis carinii; diarrhea caused by cryptosporidium, toxoplasma, giardia, amoebas; strongyloidiasis and toxoplasmosis of the brain and lungs; candidiasis of the oral cavity and esophagus; cryptococcosis, disseminated or localized in the central nervous system; coccidioidomycosis, histoplasmosis, mucormycosis, aspergillosis of various localization; infections with atypical mycobacteria of various localization; salmonella bacteremia; cytomegalovirus infection of the lungs, CNS, digestive tract; herpetic infection of the skin and mucous membranes; Epstein-Barr virus infection; multifocal papovavirus infection with encephalopathy.

Another group of AIDS-related pathological processes constitute tumors, which differ from those not associated with AIDS in that they develop in more young age than usual (up to 60 years). With AIDS, Kaposi's sarcoma and non-Hodgkin's lymphomas often develop, localized mainly in the brain.

The development of the pathological process is facilitated by some macroorganism reactions provoked by HIV infection. Thus, the activation of CD4+ T cells in response to the action of viral antigens contributes to the implementation of the cytopathogenic effect, especially the apoptosis of T lymphocytes. Most of the cytokines produced by T cells and macrophages favor the progression of HIV infection. Finally, the autoimmune component plays an important role in the pathogenesis of AIDS. It is based on the homology between HIV proteins and some body proteins, for example, between gp120 and MHC molecules. However, these disorders, while aggravating immunodeficiency, do not form specific autoimmune syndromes.

Already at the preclinical stage of HIV infection, it becomes necessary to use immunological diagnostic methods. For this purpose, enzyme-linked immunosorbent assays are used to determine the presence of antibodies to HIV proteins in the blood serum. Existing test systems are based on solid phase immunosorbent antibody testing (ELISA). Initially, test kits were used using viral lysates as antigenic material. Later, recombinant HIV proteins and synthetic peptides reproducing epitopes that interact with serum antibodies of HIV-infected people began to be used for this purpose.

Due to the extremely high responsibility of clinicians making a conclusion about HIV infection based on laboratory tests, it is common practice to repeat tests for antibodies (sometimes using alternative methods, such as immunoblotting, see section 3.2.1.4), as well as detection of the virus using polymerase chain reaction.

Treatment of AIDS is based on the use of antiviral drugs, among which the most widely used is zidovudine, which acts as an antimetabolite. Successes have been achieved in the control of the course of AIDS, which significantly increases the life expectancy of patients. The main therapeutic approach is the use of nucleic acid antimetabolites in the variant of highly active antiretroviral therapy ( High active antiretroviral therapy- HAART). An effective adjunct to antiretroviral therapy is the use of interferon preparations, as well as the treatment of concomitant diseases and viral infections contributing to the progression of AIDS.

The mortality rate from AIDS is still 100%. Most common cause deaths are opportunistic infections, especially pneumocystis pneumonia. Other causes of death are associated tumors, damage to the central nervous system and the digestive tract.

4.7.3. Secondary immunodeficiencies

Secondary immunodeficiency states - these are violations of the body's immune defense due to the action of non-hereditary inductor factors (Table 4.21). They are not independent nosological forms, but only accompany diseases or the action of immunotoxic factors. To a greater or lesser extent, disorders of the immune

4.7. Immunodeficiencies

theta are associated with most diseases, and this significantly complicates the determination of the place of secondary immunodeficiencies in the development of pathology.

Table 4.21. The main differences between primary and secondary immunodeficiencies

Criterion	Primary	Secondary
	immunodeficiencies	immunodeficiencies
The presence of a genetic
defect with installed-
type of inheritance
The role of the inducing
early manifestation	Expressed	The time of manifestation of the immune
immune deficiency		nodeficiency determines-
		by the action of inducing
		factor
Opportunistic	Develop primarily	Develop after action
infections		Via inducing
	Substitutive, anti-	Elimination of induction
	infectious therapy.	driving factor.
	gene therapy	Substitutive, anti-
		infectious therapy

It is often difficult to differentiate the contribution of hereditary factors and inductive influences to the development of immune disorders. In any case, the response to immunotoxic agents depends on hereditary factors. An example of the difficulties in interpreting the basis of immunity disorders can be diseases classified as "frequently ill children". The basis of sensitivity to infection, in particular, respiratory viral, is a genetically (polygenically) determined immunological constitution, although specific pathogens act as etiological factors. However, the type of immunological constitution is influenced by environmental factors and earlier past illnesses. The practical significance of the exact isolation of the hereditary and acquired components of the pathogenesis of immunological deficiency will increase with the development of methods for a differentiated therapeutic effect on these forms of immunodeficiencies, including methods of adaptive cell therapy and gene therapy.

The basis of immunodeficiencies not caused by genetic defects can be:

– death of cells of the immune system - total or selective;

– dysfunction of immunocytes;

– unbalanced predominance of the activity of regulatory cells and suppressor factors.

4.7.3.1. Immunodeficiency states caused by the death of immunocytes

Classical examples of such immunodeficiencies are immune disorders caused by the action of ionizing radiation and cytotoxic drugs.

Lymphocytes are among the few cells that respond to the action of a number of factors, in particular DNA damage, by the development of apoptosis. This effect is manifested under the action of ionizing radiation and many cytostatics used in the treatment of malignant tumors (for example, cisplatin, which is introduced into the DNA double helix). The reason for the development of apoptosis in these cases is the accumulation of unrepaired breaks registered by the cell with the participation of the ATM kinase (see Section 4.7.1.5), from which the signal comes in several directions, including to the p53 protein. This protein is responsible for initiating apoptosis, the biological meaning of which is to protect a multicellular organism at the cost of the death of single cells that carry genetic disorders, fraught with the risk of cell malignancy. In most other cells (usually resting cells), this mechanism is counteracted by protection against apoptosis due to increased expression of Bcl-2 and Bcl-XL proteins.

Radiation immunodeficiencies

Already in the first decade after the discovery ionizing radiation their ability to weaken resistance to infectious diseases and selectively reduce the content of lymphocytes in the blood and lymphoid organs was discovered.

Radiation immunodeficiency develops immediately after irradiation of the body. The action of radiation is due mainly to two effects:

– violation of natural barriers, primarily mucous membranes, which leads to increased access to the body of pathogens;

– selective damage to lymphocytes, as well as to all dividing

cells, including progenitor cells of the immune system and cells involved in the immune response.

The subject of study of radiation immunology is mainly the second effect. Radiation cell death is realized by two mechanisms - mitotic and interphase. The cause of mitotic death is unrepaired damage to DNA and the chromosomal apparatus, which prevents the implementation of mitoses. Interphase death affects resting cells. Its cause is the development of apoptosis by p53/ATM-dependent mechanism (see above).

If the sensitivity of all cell types to mitosis is approximately the same (D0 is about 1 Gy), then lymphocytes are significantly more sensitive to interphase death than all other cells: most of them die when irradiated at doses of 1–3 Gy, while cells of other types die at doses of exceeding 10 Gy. The high radiosensitivity of lymphocytes is due, as already mentioned, to a low level of expression of the anti-apoptotic factors Bcl-2 and Bcl-XL. Different populations and subpopulations of lymphocytes differ insignificantly in their sensitivity to apoptosis (B cells are somewhat more sensitive than T lymphocytes; D0 for them is 1.7–2.2 and 2.5–3.0 Gy, respectively). In the process of lymphopoiesis, sensitive

4.7. Immunodeficiencies

The resistance to cytotoxic effects varies in accordance with the level of expression of anti-apoptotic factors in cells: it is highest during the periods of cell selection (for T-lymphocytes - the stage of cortical CD4+ CD8+ thymocytes, D0 - 0.5–1.0 Gy). Radiosensitivity is high in resting cells, it additionally increases at the initial stages of activation, and then sharply decreases. The process of proliferative expansion of lymphocytes is characterized by high radiosensitivity, and upon entry into proliferation, cells that have been exposed to radiation earlier and carry unrepaired DNA breaks can die. The formed effector cells, especially plasma cells, are resistant to radiation (D0 - tens of Gy). At the same time, memory cells are radiosensitive to approximately the same extent as naive lymphocytes. Innate immune cells are radioresistant. Only periods of their proliferation during development are radiosensitive. The exception is NK cells, as well as dendritic cells (they die at doses of 6–7 Gy), which, in terms of radiosensitivity, occupy an intermediate position between other lymphoid and myeloid cells.

Although mature myeloid cells and their mediated reactions are radioresistant, in early dates after irradiation, it is the insufficiency of myeloid cells, primarily neutrophils, that is most manifested, caused by radiation disturbance of hematopoiesis. Its consequences affect neutrophilic granulocytes the earliest and most severely, as the population of cells with the most rapid exchange of the pool of mature cells. This leads to a sharp weakening of the first line of defense, the load on which during this period increases significantly due to the violation of barriers and the uncontrolled entry of pathogens and other foreign agents into the body. The weakening of this link of immunity is the main cause of radiation death in the early stages after irradiation. In later periods, the consequences of damage to innate immunity factors are much weaker. The functional manifestations of innate immunity are themselves resistant to the action of ionizing radiation.

More than 90% of lymphoid cells die in mice 3–4 days after irradiation at doses of 4–6 Gy, and lymphoid organs become empty. The functional activity of surviving cells is reduced. Homing of lymphocytes is sharply disturbed - their ability to migrate in the process of recycling to secondary lymphoid organs. Adaptive immunity responses to these doses are attenuated according to the degree of radiosensitivity of the cells that mediate these responses. To the greatest extent, those forms of the immune response suffer from the action of radiation, the development of which requires the interaction of radiosensitive cells. Therefore, the cellular immune response is more radioresistant than the humoral one, and thymus-independent antibody production is more radioresistant than the thymus-dependent humoral response.

Radiation doses in the range of 0.1–0.5 Gy do not cause damage to peripheral lymphocytes and often have a stimulating effect on the immune response, due to the direct ability of radiation quanta,

generating reactive oxygen species, activate signaling pathways in lymphocytes. The immunostimulatory effect of radiation, especially in relation to the IgE response, naturally manifests itself during irradiation after immunization. It is believed that in this case the stimulating effect is due to the relatively higher radiosensitivity of regulatory T cells that control this form of immune response compared to effector cells. The stimulating effect of radiation on innate immunity cells is manifested even at high doses, especially in relation to the ability of cells to produce cytokines (IL-1, TNF α, etc.). In addition to the direct stimulating effect of radiation on cells, the manifestation of the amplifying effect is facilitated by the stimulation of these cells by the products of pathogens entering the body through damaged barriers. However, the increase in the activity of innate immunity cells under the influence of ionizing radiation is not adaptive and does not provide adequate protection. In this regard, the negative effect of irradiation prevails, manifested in the suppression (at doses exceeding 1 Gy) of the adaptive antigen-specific immune response (Fig. 4.50).

Already in the period of developing devastation lymphoid tissue turn on recovery processes. Recovery occurs in two main ways. On the one hand, the processes of lymphopoiesis are activated due to the differentiation of all types of lymphocytes from hematopoietic stem cells. In the case of T-lymphopoiesis, the development of T-lymphocytes from intrathymic precursors is added to this. In this case, the sequence of events is repeated to a certain extent,

7 Dendritic

Medullary 3 thymocytes

1 Cortical

thymocytes 0.5–1.0 Gy

Answer T: cells

IgM: antibodies to

in SKL - 1.25 Gy

EB - 1.0–1.2 Gy

Answer B: cells

Education

in vitro for LPS -

IgG: antibodies to

EB - 0.8–1.0 Gy

Rice. 4.50. Radiosensitivity of some cells of the immune system and reactions mediated by them. The values ​​D0 . EB - sheep erythrocytes

4.7. Immunodeficiencies

characteristic of T-lymphopoiesis in the embryonic period: first, γδT cells are formed, then αβT cells. The recovery process is preceded by rejuvenation of thymic epithelial cells, accompanied by an increase in their production peptide hormones. The number of thymocytes rapidly increases, reaching a maximum by the 15th day, after which secondary atrophy of the organ occurs due to the exhaustion of the population of intrathymic progenitor cells. This atrophy has little effect on the number of peripheral T-lymphocytes, since by this time the second source of restoration of the lymphocyte population is turned on.

This source is the homeostatic proliferation of surviving mature lymphocytes. The impetus for this mechanism of lymphoid cell regeneration is the production of IL-7, IL-15, and BAFF, which serve as homeostatic cytokines for T, NK, and B cells, respectively. Restoration of T-lymphocytes occurs most slowly, since the implementation of homeostatic proliferation requires contact of T-lymphocytes with dendritic cells expressing MHC molecules. The number of dendritic cells and the expression of MHC molecules (especially class II) on them after irradiation are reduced. These changes can be interpreted as radiation-induced changes in the microenvironment of lymphocytes - lymphocytic niches. Associated with this is a delay in the recovery of the pool of lymphoid cells, especially significant for CD4+ T cells, which is not fully realized.

T cells that form during homeostatic proliferation have the phenotypic features of memory cells (see section 3.4.2.6). They are characterized by recirculation pathways characteristic of these cells (migration to barrier tissues and non-lymphoid organs, weakening of migration to the T-zones of secondary lymphoid organs). That is why the number of T-lymphocytes in the lymph nodes practically does not recover to normal, while in the spleen it is completely restored. The immune response that develops in the lymph nodes also does not reach a normal level when it is fully normalized in the spleen. Thus, under the influence of ionizing radiation, the spatial organization of the immune system changes. Another consequence of T-lymphocyte phenotype conversion in the process of homeostatic proliferation is an increase in autoimmune processes due to an increase in the probability of recognition of autoantigens during migration to non-lymphoid organs, easier activation of memory T-cells, and a delay in the regeneration of regulatory T-cells compared to other subpopulations. Many changes in the immune system induced by radiation resemble the effects of normal aging; This is especially evident in the thymus, the age-related decrease in the activity of which is accelerated by irradiation.

Variation of the irradiation dose, its power, the use of fractionated, local, internal irradiation (incorporated radionuclides) gives a certain specificity to immunological disorders in the post-radiation period. However, the fundamentals radiation injury and post-radiation recovery in all these cases do not differ from those considered above.

The effect of moderate and low doses of radiation has acquired special practical significance in connection with radiation catastrophes, especially

but in Chernobyl. It is difficult to accurately assess the effects of low doses of radiation and to differentiate the effect of radiation from the role of confounding factors (especially such as stress). In this case, the already mentioned stimulating effect of radiation may appear as part of the hormesis effect. Radiation immunostimulation cannot be considered as a positive phenomenon, since, firstly, it is not adaptive, and secondly, it is associated with an imbalance in immune processes. So far, it is difficult to objectively assess the impact on the human immune system of that slight increase in the natural background of radiation, which is observed in areas adjacent to disaster zones or associated with production activities. In such cases, radiation becomes one of the adverse environmental factors and the situation should be analyzed in the context of environmental medicine.

Immunodeficiency states caused by non-radiation death of lymphocytes

The mass death of lymphocytes forms the basis of immunodeficiencies that develop in a number of infectious diseases of both bacterial and viral nature, especially with the participation of superantigens. Superantigens are substances capable of activating CD4+ T-lymphocytes with the participation of APCs and their MHC-II molecules. The effect of superantigens is different from that of conventional antigen presentation.

The superantigen is not cleaved into peptides and does not integrate into anti-

the gene-binding cleft, but connects to the “side surface” of the β-chain of the MHC-II molecule.

Superantigen is recognized T-cell, according to their affinity, not to the antigen-binding center of the TCR, but to the so-called 4th hypervariable

mu site - sequence 65-85, localized on the side surface of the β-chains of TCR belonging to certain families.

Thus, superantigen recognition is not clonal, but is due to TCR belonging to one or another β-family. As a result, superantigens involve in response a significant number of CD4+ T-lymphocytes (up to 20–30%). For example, mouse CD4+ T cells expressing TCRs belonging to the Vβ7 and Vβ8 families are involved in the response to staphylococcal exotoxin SEB. After a period of activation and proliferation accompanied by hyperproduction of cytokines, these cells undergo apoptosis, which causes a significant degree of lymphopenia, and since only CD4+ T cells die, the balance of lymphocyte subpopulations is also disturbed. This mechanism underlies T-cell immunodeficiency, which develops against the background of some viral and bacterial infections.

4.7.3.2. Secondary immunodeficiencies due to functional disorders of lymphocytes

Probably, this group of secondary immunodeficiencies is predominant. However, at present, there are practically no accurate data on the mechanisms of a decrease in the function of lymphocytes in various somatic diseases and exposure to harmful factors. Only in isolated cases is it possible to establish the exact mechanisms

- these are diseases of the immune system that occur in children and adults, not associated with genetic defects and characterized by the development of repeated, protracted infectious and inflammatory pathological processes that are difficult to treat etiotropically. Allocate acquired, induced and spontaneous form of secondary immunodeficiencies. Symptoms are due to a decrease in immunity and reflect a specific lesion of a particular organ (system). Diagnosis is based on the analysis of the clinical picture and data immunological research. Treatment includes vaccination, replacement therapy, immunomodulators.

General information

Secondary immunodeficiencies are immune disorders that develop in the late postnatal period and are not associated with genetic defects, occur against the background of an initially normal reactivity of the body and are due to a specific causative factor that caused the development of a defect in the immune system.

The causal factors leading to impaired immunity are diverse. Among them are long-term adverse effects external factors(environmental, infectious), poisoning, toxic effect drugs, chronic psycho-emotional overload, malnutrition, injuries, surgical interventions and severe somatic diseases that lead to disruption of the immune system, a decrease in the body's resistance, the development of autoimmune disorders and neoplasms.

The course of the disease can be hidden (complaints and clinical symptoms are absent, the presence of immunodeficiency is detected only when laboratory research) or active with signs of an inflammatory process on the skin and subcutaneous tissue, upper respiratory tract, lungs, genitourinary system, digestive tract and other organs. In contrast to transient changes in immunity, in secondary immunodeficiency, pathological changes persist even after the elimination of the causative agent of the disease and the relief of inflammation.

The reasons

A variety of etiological factors, both external and internal, can lead to a pronounced and persistent decrease in the body's immune defenses. Secondary immunodeficiency often develops with a general depletion of the body. Prolonged malnutrition with a deficiency in the diet of protein, fatty acids, vitamins and microelements, malabsorption and cleavage nutrients in the digestive tract lead to disruption of the processes of maturation of lymphocytes and reduce the body's resistance.

Severe traumatic injuries of the musculoskeletal system and internal organs, extensive burns, serious surgical interventions, as a rule, are accompanied by blood loss (along with plasma, complement system proteins, immunoglobulins, neutrophils and lymphocytes are lost), and the release of corticosteroid hormones designed to maintain vital functions (circulation, respiration, etc.) more depresses the immune system.

A pronounced disturbance of metabolic processes in the body in somatic diseases (chronic glomerulonephritis, renal failure) and endocrine disorders (diabetes, hypo- and hyperthyroidism) leads to inhibition of chemotaxis and phagocytic activity of neutrophils and, as a result, to secondary immunodeficiency with the appearance of inflammatory foci of various localization ( more often it is pyoderma, abscesses and phlegmons).

Immunity decreases with prolonged use of certain drugs that have an inhibitory effect on the bone marrow and hematopoiesis, disrupting the formation and functional activity of lymphocytes (cytostatics, glucocorticoids, etc.). Radiation has a similar effect.

In malignant neoplasms, the tumor produces immunomodulating factors and cytokines, resulting in a decrease in the number of T-lymphocytes, an increase in the activity of suppressor cells, and inhibition of phagocytosis. The situation is exacerbated by the generalization of the tumor process and metastasis to the bone marrow. Secondary immunodeficiencies often develop in autoimmune diseases, acute and chronic poisoning, in people of senile age, with prolonged physical and psycho-emotional overload.

Symptoms of secondary immunodeficiencies

Clinical manifestations are characterized by the presence in the body of a chronic infectious purulent-inflammatory disease resistant to etiotropic therapy against the background of a decrease in immune defense. The changes may be transient, temporary or irreversible. Allocate induced, spontaneous and acquired forms of secondary immunodeficiencies.

The induced form includes disorders that occur due to specific causative factors (X-ray radiation, long-term use of cytostatics, corticosteroid hormones, severe injuries and extensive surgical operations with intoxication, blood loss), as well as severe somatic pathology (diabetes mellitus, hepatitis, cirrhosis, chronic renal insufficiency) and malignant tumors.

In the spontaneous form, the visible etiological factor that caused the violation of the immune defense is not determined. Clinically, in this form, there is the presence of chronic, difficult to treat and often exacerbated diseases of the upper respiratory tract and lungs (sinusitis, bronchiectasis, pneumonia, lung abscesses), the digestive tract and urinary tract, skin and subcutaneous tissue (boils, carbuncles, abscesses and phlegmon) caused by opportunistic pathogens. Acquired immunodeficiency syndrome (AIDS) caused by HIV infection has been isolated in a separate, acquired form.

The presence of secondary immunodeficiency at all stages can be judged by the general clinical manifestations of the infectious and inflammatory process. It can be prolonged low-grade fever or fever, swollen lymph nodes and their inflammation, pain in muscles and joints, general weakness and fatigue, decreased performance, frequent colds, repeated tonsillitis, often recurrent chronic sinusitis, bronchitis, repeated pneumonia, septic conditions, etc. At the same time, the effectiveness of standard antibacterial and anti-inflammatory therapy is low.

Diagnostics

Identification of secondary immunodeficiencies requires an integrated approach and participation in the diagnostic process of various specialist doctors - an allergist-immunologist, hematologist, oncologist, infectious disease specialist, otorhinolaryngologist, urologist, gynecologist, etc. This takes into account the clinical picture of the disease, indicating the presence of a chronic infection that is difficult to treat and detection of opportunistic infections caused by opportunistic pathogens.

It is necessary to study the immune status of the body using all available methods used in allergology and immunology. Diagnosis is based on the study of all parts of the immune system involved in protecting the body from infectious agents. At the same time, the phagocytic system, the complement system, subpopulations of T- and B-lymphocytes are studied. Research is carried out by conducting tests of the first (indicative) level, which makes it possible to identify gross general violations immunity and the second (additional) level with the identification of a specific defect.

When conducting screening studies (level 1 tests that can be performed in any clinical diagnostic laboratory), you can get information about the absolute number of leukocytes, neutrophils, lymphocytes and platelets (both leukopenia and leukocytosis occur, relative lymphocytosis, elevated ESR), protein level and serum immunoglobulins G, A, M and E, complement hemolytic activity. In addition, the necessary skin tests can be performed to detect delayed-type hypersensitivity.

An in-depth analysis of secondary immunodeficiency (level 2 tests) determines the intensity of phagocyte chemotaxis, the completeness of phagocytosis, immunoglobulin subclasses and specific antibodies to specific antigens, the production of cytokines, T-cell inducers, and other indicators. The analysis of the obtained data should be carried out only taking into account the specific state this patient, concomitant diseases, age, the presence of allergic reactions, autoimmune disorders and other factors.

Treatment of secondary immunodeficiencies

The effectiveness of the treatment of secondary immunodeficiencies depends on the correctness and timeliness of identifying the etiological factor that caused the appearance of a defect in the immune system and the possibility of its elimination. If a violation of immunity has occurred against the background of a chronic infection, measures are taken to eliminate foci of inflammation using antibacterial drugs taking into account the sensitivity of the pathogen to them, adequate antiviral therapy, the use of interferons, etc. If the causative factor is malnutrition and beriberi, measures are taken to develop proper diet nutrition with a balanced combination of proteins, fats, carbohydrates, trace elements and the required calorie content. Existing metabolic disorders are also eliminated, normal hormonal status is restored, conservative and surgical treatment of the underlying disease (endocrine, somatic pathology, neoplasms) is carried out.

An important component of the treatment of patients with secondary immunodeficiency is immunotropic therapy using active immunization (vaccination), substitution treatment with blood products (intravenous administration of plasma, leukocyte mass, human immunoglobulin), as well as the use of immunotropic drugs (immunostimulants). The expediency of prescribing a particular therapeutic agent and the selection of dosage is carried out by an allergist-immunologist, taking into account the specific situation. With the transient nature of immune disorders, timely detection of secondary immunodeficiency and selection of the correct treatment, the prognosis of the disease can be favorable.