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Primary immunodeficiencies. Primary immunodeficiencies: treatment. Immunodeficiencies: diagnosis and immunotherapy
Secondary immunodeficiency, the treatment of this manifestation is important task modern medicine. Secondary immunodeficiency has nothing to do with poor heredity. It has a very complex origin, but its consequences are always the same:
- Increased susceptibility to infection.
- The course of the disease is clearly different from its classical forms.
- The disease is caused by various reasons, and can be localized quite arbitrarily.
- Sluggish reaction to the right treatment, aimed at the root cause of the disease.
- Mandatory presence of infections, purulent-inflammatory processes. And regardless. is this process the cause or consequence of infection and failure of the immune defense.
The full functioning of the body's immune defenses may become impossible due to a wide variety of factors from infections to man-made causes.
Etiology of secondary immunodeficiency
Traditional medicine distinguishes three possible forms secondary immunodeficiency:
- spontaneous;
- acquired;
- induced.
Induced immunodeficiency. What are the causes of such a disease? The induced form is entirely due to its appearance external reasons such as infections, effects of antibiotic treatment, X-ray exposure, surgical intervention and injury. Traditionally, this form of the disease also includes lesions of the immune defense, which are secondary to the underlying disease. This refers to immunity disorders caused by diabetes, hepatitis, nephritis, or developing oncology.
Acquired immunodeficiency. In the last century, for the first time in its history, man encountered viral infection defense system of the body, resulting in the development of AIDS. This disease is characterized by a high percentage deaths and a sort of list clinical symptoms. By the way, the treatment of this disease is also non-standard.
The immunodeficiency virus has an immunotropic nature and irreversibly destroys the body's lymphoid defenses. So there is a secondary immunodeficiency. The etiology of AIDS has not been fully elucidated, and the severity of its consequences is so great that it is customary to classify AIDS as a separate group of immunodeficiency.
Spontaneous immunodeficiency. This type of immunodeficiency is characterized by an unclear etiology of the failure of the defense system. What are the symptoms of secondary immunodeficiency?
- The clinical picture of this form is mainly reduced to frequently recurrent infectious and inflammatory diseases of the respiratory, genitourinary and digestive systems.
- Such processes are possible on the eyes, skin, soft tissues, in paranasal sinuses nose and the like, and the culprits of such a lesion are not the most dangerous microorganisms.
What are the causes of the disease? The group of patients with such a diagnosis is very heterogeneous due to the fact that the cause of this disease is unclear and all patients with an unclear diagnosis of immunodeficiency fall into this group of patients. This is one of the reasons for the constant reduction in the number of patients in this group.
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How to treat the disease
How is secondary immunodeficiency treated? Defeat immune system should be treated with maximum maintenance of weakened immunity. Modern medicine has three possible tools for such support:
- Timely vaccination of the patient.
- Medications that replace immunity, such as immunoglobulins, leukocyte mass and others.
- Medical preparations of an immunotropic nature, such as immunostimulants, granulocyte-macrophage preparations and other chemically pure and artificially synthesized preparations.
How to treat secondary immunodeficiency with immunotropic drugs depends entirely on the nature of the course of the disease.
The more acute the infectious-inflammatory process is, the more intensively it is necessary to use immunotropic drugs.
Vaccine therapy. This tool is applicable to preventive purposes, and is used exclusively during the period of all diseases in the patient. Any vaccine has its indications, contraindications and scheme of application.
Treatment with drugs that replace immunity - this method is applicable at any stage of the disease. Immunoglobulin preparations for intravenous use are especially popular. the basis of all similar drugs are a special kind of antibodies obtained from a large number of donors. Substitution treatment shows a good result when it is necessary to compensate for the loss of antibodies in secondary immunodeficiency, when the body is not able to produce a sufficient amount of immunoglobulins or is not capable of synthesizing them.
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Immunotropic treatment of secondary immunodeficiency
The basis therapeutic use This tool is supposed to use a wide variety of immunostimulants. With an integrated approach to the treatment of infectious and inflammatory processes without the use of immunomodulators, antimicrobial treatment will be ineffective.
The use of immunomodulators is subject to a number of simple rules:
- Immunomodulators are prescribed exclusively in conjunction with a drug intended for the treatment of the underlying disease. Separately, it is used only in case of remission of the underlying disease.
- The main factor in the choice of a particular drug is the severity of the course inflammatory process.
- An immunomodulator should be prescribed only when the body's torpid response to adequate treatment is observed, that is, with a pronounced immunodeficiency.
- The method of using such a drug must be within the framework of all instructions and prescriptions of the manufacturer. Changes to these schemes can only be made at the initiative of an experienced immunologist.
- The entire procedure for the use of such drugs must be carried out under the constant monitoring of a specialist.
- Diagnosis of any deviation of the immunity parameter from the norm in practically healthy person cannot be the reason for the appointment of treatment with immunoglobulins.
Immunostimulants. Given the multifactorial nature of the etiological component of secondary immunodeficiency, a positive result from treatment is completely in the hands of an immunologist. An experienced and qualified immunologist should choose immunotropic treatment in such a way that all the results of preliminary examinations are taken into account as much as possible. Such an approach to the treatment of secondary immunodeficiency will make the time spent by the patient in the hospital shorter, and the period of remission of the disease will be much longer. In some cases the right approach treatment can save a patient's life.
Anamnesis. characteristic feature immunodeficiency states are an infection caused by bacteria (especially with hypogammaglobulinemia), viruses and fungi (impaired cellular immunity), and, finally, general(combined immunodeficiencies). Infectious complications can appear already in the first weeks of a child's life, as well as at an older age. With an autosomal recessive type of inheritance, boys and girls are ill, parents are often related by blood. The sex-linked recessive form of immunodeficiency affects only boys. Observations have shown that the disease is transmitted to the child from a clinically healthy mother.
Methods for detecting immunodeficiencies
. In each specific case, it should be borne in mind that, in addition to special immunological tests to assess the T- and B-links of the immune system, phagocytosis and complement system disorders are determined, which manifest themselves in a number of diseases.Skin tests are performed mainly with bacterial antigens.
Methods in vitro. Quantification of peripheral blood lymphocytes. In severe combined immunodeficiencies, the content of lymphocytes is usually reduced. However normal performance do not exclude immunodeficiency.
T-lymphocytes: spontaneous rosette reaction with washed sheep erythrocytes (E-marker) or CD3 test. Identification of the T cell subpopulation using CD4 and CD8 markers, as well as the use of differentiation markers to determine the localization of the cell maturation block. It is necessary to take into account the discrepancy between the presence of the marker and possible dysfunction lymphocytes.
B-lymphocytes: Ig detection, rosette reaction with erythrocytes sensitized with Ig and complement.
A-cells: adhesion, phagocytosis.
Functional assessment of the T-link of immunity:
Stimulation of lymphocytes (non-specific) by mitogens PHA, ConA;
Specific stimulation with antigens of infectious agents and allogeneic antigens in a mixed culture of lymphocytes (unidirectional MLC);
Production of lymphokines (FUM, FUL); it is advisable to compare the data of RBTL and RTML, and when indicating circulating inhibitors, use the serum of other individuals in the tests.
Evaluation of the B-link immunity. quantitative and qualitative analysis 1. Conventional electrophoresis is not quite suitable for detecting immunodeficiency. Immunoelectrophoresis gives only quality assessment 1. The most common test is radial immunodiffusion (sensitivity limit - 10 μg / ml, method error 10%). More sensitive are radioimmunodiffusion (up to 100 ng/ml) and radioimmune test (1-10 ng/ml).
Determination of the level of natural antibodies, for example, isohemagglutinins of heterophile antibodies to sheep and rabbit erythrocytes (without absorption!), antibodies to E. coli.
Determination of the level of antibodies to antigens of infectious agents: typhoid - paratyphoid (agglutination), Brucella (agglutination), Candida (agglutination), tetanus (hemagglutination), diphtheria (hemagglutination, PAS reaction), influenza, as well as to streptolysin histoplasmin and blastomycin (RSK) ).
Detection of autoantibodies (antibodies to DNA, rheumatoid factor, incomplete antibodies to the Coombs reaction, antibodies to tissue antigens thyroid gland and gastric mucosa).
Evidence of impaired immunoregulation. Determining the direct effect of helper cells. Identification of immunoregulatory cells using CD4 and CD8 markers. An indicator of a violation of the immune system is an imbalance of immunoregulatory cells.
Manifestation of cellular cytotoxicity. If immunodeficiency is suspected, it is advisable to evaluate ADCC and natural killer activity.
Diagnostic sensitization. Test with DNCB. 2,4-dinitro-1-chlorobenzene is used to assess cellular immunity, since almost 95% healthy individuals become sensitized after a single contact. Antigenic properties appear after covalent binding of the drug (hapten) with the protein of the epidermis. For sensitization, 1-2 mg of DNCB (1-2% solution in acetone) is applied to the surface of the skin with an area of 3 cm2. As a result of the irritation caused, in most cases, erythema and edema occur after 3-12 hours, after 3-4 days these phenomena gradually disappear. Sensitization develops within 7-21 days. DNCB at a dose of 50-100 mcg (0.05-1% solution) after 14 days is applied as an application to another place. The results are taken into account after 48 hours. At the site of repeated contact, redness, infiltration are noted, sometimes a bubble forms. In some cases, a positive reaction is detected only by histological examination. For quantitative assessment, DNCB is applied in different doses (0.1 - 100 μg) and carried out comparative analysis. A false-positive reaction as a result of the toxic effect of the drug should be excluded (the histological picture is typical for an allergic reaction). lymphoid infiltration). Sometimes false-negative reactions are noted. For a semi-quantitative assessment of the results of the test with DNCB, the following scale is proposed: N-erythema, ++ erythema-4-induration, + ++ blistering, + + + + ulceration.
Instead of DNCB, 2,4-dinitro-1-fluorobenzene or SCHN (snail hemocyanin) can be used.
Introduction of bacterial and viral antigens. The use of live vaccines is contraindicated. For sufficiently effective stimulation, 3-4 applications of the corresponding antigens should be carried out. The examination program includes the following antigens:
- diphtheria and tetanus, whooping cough: application in generally accepted doses; antibody levels are determined after 2 weeks (Pchic reaction, passive hemagglutination);
- (killed!) polio vaccine (1 ml IM); triple administration within 2 weeks; antibody levels are determined 2 weeks after the last injection (virus neutralization test);
Pneumococcal polysaccharide (0.1 mg IM); twice within 1 week; antibody levels are determined 2 weeks after the last injection (precipitation);
Polyribose phosphate (0.05 mg subcutaneously); antibody levels are determined after 2 weeks (hemagglutination);
Bacteriophages X174: This is a group of rather strong antigens. Determine the clearance of the antigen by comparing the primary and secondary immune response;
Vi antigen or E. coli (0.1 mg subcutaneously); antibody levels are determined after 2 weeks (passive hemagglutination). Similarly, use flagillin (5 μg) or snail hemocyanin.
In unvaccinated children, diphtheria, tetanus and polyoantigens are primarily used. In vaccinated children, an effect is possible with small doses of these antigens. Children under 1 year old should not be injected with antigens containing polysaccharides.
1st day - blood test: determination of Ig concentration, level of antibodies to streptococcal antigens, influenza virus, isohemagglutinins; skin tests (streptokinase, candidin, PAS-reaction);
3rd day - accounting skin tests(late reaction), immunization with antigens of causative agents of typhoid or tetanus, sensitization of DNCB (with negative intradermal tests);
17th day - determination of the level of antibodies, a test with DNCB.
Histological studies. The above immunological methods, as a rule, allow you to determine the level of disorders of the immune system in accordance with the generally accepted classification. However, in some cases there is a need for histological analysis. Material for histological studies are lymph nodes, Bone marrow and mucous membrane.
Lymph nodes: structural analysis of thymus-dependent and thymus-independent zones is carried out 5-7 days after local antigen stimulation (application with diphtheria and tetanus toxoids on the inner side of the thigh and examination of inguinal lymph nodes). Lymphoid devastation in the paracortical zone is evidence of a T-cell deficiency, the absence of plasma cells and germinal centers indicates a violation of the B-link of the immune system.
Bone marrow: quantitative and functional assessment of plasma and lymphoid cells.
Mucosa: determine the number of Ig-secreting plasma cells (especially IgA), mainly in conditions associated with insufficient local antibody production.
Metabolism study. If combined immunodeficiency or a defect in the T-link of the immune system is suspected, the activity of ADA and PNP enzymes should be determined. It is advisable to detect fetoprotein in the diagnosis of ataxia - telangiectasia (46-2200 mg / l in 95% of patients). Transcobalamin deficiency is indicated by symptoms of megaloblastic anemia with normal B12 concentrations and a normal ability to absorb B12.
Early diagnosis is of particular importance for the timely recognition and acceptance urgent action to prevent infectious complications. When immunological examination of newborns, cases of morbidity in families are taken into account. The Ig level indicator is not informative, as it refers to the Ig of the mother. The number of lymphocytes may be normal. Diagnostic value has an indicator of proliferative activity of lymphocytes. The immune system is assessed in accordance with the well-known WHO program. To detect hypogammaglobulinemia, the level of IgM is determined. One of the methods for prenatal diagnosis of ADA and transcobalamin-2 deficiency is the cultivation of amnion fibroblasts. Chronic granulomatosis can be detected by a fetal blood test as early as the 20th week of pregnancy.
are diseases of the immune system that occur in children and adults, are not associated with genetic defects and are characterized by the development of repeated, protracted infectious and inflammatory pathological processes, poorly amenable to etiotropic treatment. 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. The treatment uses vaccination, substitution 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 medicines, chronic psycho-emotional overload, malnutrition, trauma, surgical interventions and severe somatic diseases leading 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 may be latent (complaints and clinical symptoms 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. Unlike transient changes in immunity, with secondary immunodeficiency pathological changes persist even after the elimination of the causative agent of the disease and the relief of inflammation.
Causes
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.
Heavy traumatic injuries 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.
Express violation metabolic processes in the body with 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 different localization(more often it is pyoderma, abscesses and phlegmon).
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 immunomodulatory 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 generalization tumor process and metastasis to the bone marrow. Secondary immunodeficiencies often develop in autoimmune diseases, acute and chronic poisoning, in people old 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 arising from specific causative factors ( x-rays, long-term use cytostatics, corticosteroid hormones, severe trauma and extensive surgical operations with intoxication, blood loss), as well as in severe somatic pathology (diabetes mellitus, hepatitis, cirrhosis, chronic renal failure) and malignant tumors.
In the spontaneous form, the visible etiological factor that caused the violation of the immune defense is not determined. Clinically, with 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), digestive tract And urinary tract, skin and subcutaneous tissue(boils, carbuncles, abscesses and phlegmon), which are 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 , as well as identifying opportunistic infections caused by opportunistic pathogens.
Study needed immune status body using all available techniques 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), the level of protein and serum immunoglobulins G, A, M and E, hemolytic activity of complement. 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 data obtained should be carried out only taking into account the specific condition of the patient, concomitant diseases, age, availability 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 detection 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 arisen 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, carrying out adequate antiviral therapy, the use of interferons, etc. If causal factor – malnutrition and avitaminosis, measures are being 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 underlying disease (endocrine, somatic pathology, neoplasms).
An important component of the treatment of patients with secondary immunodeficiency is immunotropic therapy using active immunization (vaccination), substitution treatment blood products ( intravenous administration 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 specific situation. With a transitory nature immune disorders, timely detection of secondary immunodeficiency and selection proper treatment, the prognosis of the disease may be favorable.
Immunodeficiency - a decrease in the quantitative indicators and / or functional activity of the main components of the immune system, leading to a violation of the body's defense against pathogenic microorganisms and manifested by increased infectious morbidity.
As you know, the main function of the immune system is the recognition and elimination of foreign substances antigenic nature, penetrating into the body from environment(microorganisms) or occurring endogenously ( tumor cells). This function is implemented using factors innate immunity(phagocytosis, antimicrobial peptides, complement system proteins, NK cell systems, etc.) and acquired or adaptive immunity, carried out using cellular and humoral immune responses. The regulation of the activity of the components of the body's immune defense and their interaction occurs with the help of cytokines and intercellular contacts.
In each of the listed components of the immune system, as well as in the mechanisms of their regulation, disturbances can occur, leading to the development of immunodeficiency, the main clinical manifestation of which is hypersensitivity to pathogens of infectious diseases. There are 2 types of immunodeficiencies: primary and secondary.
Primary immunodeficiencies(PID) - hereditary diseases caused by defects in genes that control the immune response. PID is a disease that is diverse in the nature and severity of immune defects, clinical manifestations and molecular disorders. The clinical picture of PID is characterized by repeated and chronic, severe infectious processes, to a greater extent bronchopulmonary system
and ENT organs, skin and mucous membranes; purulent lymphadenitis, abscesses, osteomyelitis, meningitis and sepsis may develop. In some forms, there are manifestations of allergies, autoimmune diseases and the development of some malignant tumors. Attention should be paid to the lag in age indicators physical development. Currently, about 80 PIDs have been described, and the genes responsible for the development of most of these diseases have been identified. Adequate laboratory analyzes make it possible to differentiate pathology at the level of lymphocytes and pathology at the level of non-lymphocyte mechanisms of destruction and excretion of antigens.
Prevalence of PID depends on the form of the disease and averages from 1:10,000 to 1:100,000 newborns. Selective IgA deficiency, for example, occurs much more frequently between 1:500 and 1:1500 people in the general population. Prevalence various forms PID varies in different countries. The most common defects in antibody production - 50-60% of cases, combined PID - 10-30%, phagocytosis defects - 10-20%, complement defects - 1-6%. Most PIDs manifest in early childhood, although some forms of PIDs, such as common variable immunodeficiency (CVID), may have a later onset.
According to the mechanisms of development, 4 main groups of PID are distinguished:
Group 1 - predominantly humoral, or B-cell
PID;
group 2 - combined PID (with all T-cell immunodeficiencies there is a violation of the function of B-cells);
group 3 - PID caused by defects in phagocytosis;
4th group - PID caused by defects in the complement system.
Principles of diagnosis of primary immunodeficiencies
Early diagnosis and timely initiation of treatment determine the prognosis of the disease. Making a diagnosis at the level of district pediatricians presents certain difficulties, which is often due to the lack of timely consultation of the patient by an immunologist and the conduct of a special laboratory immunological examination (Table 11-1). Although knowledge of the features of the clinical picture of PID and changes
research in general clinical laboratory tests allow suspecting PID and refer the patient to specialists. The European Society for Immunodeficiencies has developed protocols early diagnosis PID, and also created an electronic database of the European PID Register. The PID diagnostic algorithm is shown in fig. 11-1.
Table 11-1. Stages of immunological examination for suspected immunodeficiency
Rice. 11-1. Algorithm for the diagnosis of primary immunodeficiencies
General features of the clinical picture of primary immunodeficiencies
Leading in clinical picture PID is the so-called infectious syndrome - increased susceptibility to pathogens of infectious diseases in general, their unusually severe recurrent (recurrent) clinical course, the presence of atypical pathogens (often opportunistic) in the etiology of the disease. The type of pathogen is determined by the nature of the immune defect. With defects in antibody formation, it is possible to identify resistant to antibacterial drugs flora - staphylococci, streptococci, Haemophilus influenzae. In T-cell immune deficiency, in addition to bacteria, viruses (for example, the herpesvirus family), fungi are detected (Candida spp., Aspergillus etc.), and with phagocytic defects - staphylococci, gram-negative bacteria, fungi, etc.
Laboratory research
If clinical findings suggest PID, then the following investigations should be performed:
Determination of a detailed blood formula (quantitative and percentage indicators of lymphocytes are especially important);
Definition IgG levels, IgA and IgM in blood serum;
Counting subpopulations of T- and B-lymphocytes;
◊ analysis functional state phagocytes (the most simple and informative analysis- tetrazolium blue reduction test);
◊ analysis for the content of the main components of the complement (begin with C3 and C4);
◊ HIV test (if available) possible factors risk);
◊ molecular genetic studies when indicated.
Principles of treatment of primary immunodeficiencies
The main goal of PID therapy is the treatment of complications of the disease and their prevention. This approach is due to the fact that defects in the immune system in PID are laid down at the genetic level. At present, intensive research is being carried out on
therapy of immunodeficiencies, which may lead to the emergence of more radical methods of their treatment.
Depending on the form of PID, treatment consists of replacement therapy, treatment and prevention of infectious, autoimmune manifestations of the disease, treatment malignant neoplasms and the use of special methods, including transplantation of hematopoietic stem cells (depending on the type of PID).
DEFECTS IN IMMUNOGLOBULINS
Transient hypogammaglobulinemia in children
Transient hypogammaglobulinemia in children is associated with physiological feature step-by-step formation of the immunoglobulin system. IN most"late" maturation of IgM and IgA antibody formation. In healthy children, the content of maternal IgG gradually decreases and after six months the production of their own IgG antibodies increases. In some children, however, the rise in immunoglobulin levels is delayed. Such children may suffer from recurrent bacterial infectious diseases. In these cases, infusions of donor immunoglobulin preparations (administration of intravenous immunoglobulin) should not be resorted to.
Selective immunoglobulin A deficiency
Selective deficiency of immunoglobulin A (SD IgA - Selective Deficiency of IgA) develops as a result of a gene defect tnfrsf13b
or r). IgA deficiency in the presence of immunoglobulins of other classes is the most common immunodeficiency, detected in the general population with a frequency of 1:500-1500 people (in patients with allergies, even more often). There are selective IgA deficiency, i.e. consisting in the deficiency of one of the subclasses (30% of cases), and complete (70% of cases). Deficiency of the IgA2 subclass leads to a more pronounced clinical picture than a deficiency of the IgA1 subclass. Combinations of IgA deficiency with other disorders are also possible: with a defect in IgG biosynthesis and with abnormalities of T-lymphocytes. The vast majority of individuals with selective
IgA deficiency is practically healthy. For children under 2 years of age, IgA deficiency is a physiological condition.
Detect a decrease in serum IgA concentration to<5 мг/дл у детей старше 4 лет; IgG и IgM в норме, количество и соотношение субпопуляций лимфоцитов и их функциональная активность могут быть в норме.
clinical picture. With IgA deficiency, 3 groups of pathological syndromes can develop: infectious, autoimmune and allergic. Patients with IgA deficiency are predisposed to recurrent infectious diseases of the upper respiratory tract and digestive organs. The most frequent and severe are a variety of autoimmune diseases (rheumatoid arthritis, ankylosing spondylitis, Sjögren's syndrome, vasculitis with damage to cerebral vessels, autoimmune thyroiditis, SLE, glomerulonephritis, hemolytic anemia, diabetes type I, vitiligo, etc.). The incidence of celiac disease exceeds that in children with normal IgA by 10 times. The most frequently detected allergic manifestations are cow's milk protein intolerance, atopic dermatitis (AtD), bronchial asthma.
Treatment. Asymptomatic cases do not require any special treatment; in the presence of clinical manifestations of infectious, autoimmune and allergic diseases, treatment is carried out in accordance with the standards.
Replacement therapy with donor immunoglobulins is not indicated for either selective or complete IgA deficiency, since there is a high probability of formation of antiisotypic antibodies to IgA in the recipient and the development of transfusion complications caused by them.
Agammaglobulinemia with B-cell deficiency
X-linked agammaglobulinemia (Bruton's disease) accounts for 90% of all cases of agammaglobulinemia. Boys, sons (אּ, ρ) of carriers of the defective gene get sick btk (Xq21.3-q22), encoding B-lymphocyte-specific protein tyrosine kinase Btk (Bruton's tyrosine kinase- Bruton's tyrosine kinase). As a result of the defect, there is a violation of intracellular signaling pathways, recombination of heavy chains of immunoglobulins, differentiation
replication of pre-B cells into B-lymphocytes. In 10% of patients with B-cell deficiency, agammaglobulinemia is inherited autosomal recessively. Six genetic defects have been described so far, including the pre-B cell receptor, cytoplasmic B cell adapter protein (BLNK) and gene Leucine-Rich Repeat-Containing 8 (LRRC8).
Data from laboratory studies. There are no peripheral B-lymphocytes. The bone marrow contains pre-B cells with a μ-chain in the cytoplasm. The number of T-lymphocytes and functional tests for T-lymphocytes may be normal. IgM and IgA in the blood can not be detected; IgG may be present, but in small amounts (0.4-1.0 g/l). There are no antibodies to antigens of blood groups and to vaccine antigens (tetanus, diphtheria toxins, etc.). Neutropenia may develop. Histological examination of the lymphoid tissue: there are no germinal (germ) centers and plasma cells in the lymphoid follicles.
clinical picture. If the family history is unknown, the diagnosis becomes apparent by an average of 3.5 years of age. The disease is characterized by lymphoid tissue hypoplasia, severe purulent infections, infectious diseases of the upper (sinusitis, otitis media) and lower (bronchitis, pneumonia) respiratory tract; possible gastroenteritis, pyoderma, septic arthritis (bacterial or chlamydial), septicemia, meningitis, encephalitis, osteomyelitis. The most common causative agents of respiratory diseases are Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, diarrhea intestinal bacteria or giardia Giardia lamblia. Also, patients with agammaglobulinemia are susceptible to infectious diseases caused by mycoplasmas and ureaplasmas, which are the cause of chronic pneumonia, purulent arthritis, cystitis, and subcutaneous tissue abscesses. Of the viruses, neurotropic viruses ECHO-19 and coxsackie are typical, causing both severe acute and chronic encephalitis and encephalomyelitis. Manifestations of enterovirus infections can be dermatomyositis-like syndrome, ataxia, headaches, and behavioral disorders. In sick children, during immunization with live polio vaccine, as a rule, prolonged excretion of the poliomyelitis virus through the mucous membranes is detected, moreover, with restored and increasing virulence (i.e., in the children's collection -
there is no real risk of polio infection in healthy children as a result of contact with a vaccinated immunodeficient child). Autoimmune disorders in agammaglobulinemia can be represented by rheumatoid arthritis, scleroderma-like syndrome, scleredema, ulcerative colitis, type I diabetes mellitus (due to the predominance of the Th1 immune response).
Physical examination. Pay attention to the lag in physical development, the shape of the fingers (fingers in the form of drumsticks), changes in the shape of the chest, characteristic of diseases of the lower respiratory tract, hypoplasia of the lymph nodes and tonsils.
Treatment.
Replacement therapy: intravenous immunoglobulin preparations are administered every 3-4 weeks for life. Doses of immunoglobulins are selected so as to create their concentration in the patient's serum, which overlaps the lower limit of the age norm.
Discussing the Possibility of Gene Therapy - Gene btk cloned, but its overexpression is associated with malignant transformation of hematopoietic tissue.
In the case of persistent neutropenia, growth factors are used. When signs of autoimmune pathology appear, it is possible to prescribe monoclonal antibodies (infliximab, etc.).
Common Variable Immunodeficiency
Common variable immune deficiency (CVID) is a group of syndromes characterized by a defect in antibody synthesis and cellular immunity. A reliable diagnostic criterion for CVID is a significant decrease in the content of immunoglobulins of two or three main isotypes in both sexes in combination with one of the following signs:
The debut of the disease over the age of 2 years;
Absence of isohemagglutinins and/or low response to vaccination;
Exclusion of other causes of agammaglobulinemia.
In some patients, the cause of the development of CVID is mutations in genes encoding molecules involved in the processes of maturation and survival of B cells: BAFF-R (B-cell Activating Factor Receptor), Blimp-1 (B-lymphocyte induced maturation protein-1) and ICOS (Inducible costimulator). There is a violation of the ability of B-lymphocytes to differentiate into plasma cells, defects in antibody formation develop, dysfunction of T-lymphocytes is possible, and an increased susceptibility to infectious diseases is observed. The syndrome may present in early childhood, adolescence, or in young adults.
Data from laboratory studies. Significantly reduced levels of IgG and IgA (in about 50% of patients) and IgM (down to undetectable amounts). The number of B-lymphocytes in the blood is normal or reduced. The number of T-lymphocytes in most patients is normal. Severe patients may develop lymphopenia (less than 1500x10 3 cells per 1 liter of blood). The number of NK cells is reduced. The production of specific antibodies in response to immunization is reduced or absent. The proliferation of lymphocytes and the formation of IL-2 under the influence of mitogens and antigens are significantly impaired.
clinical picture. Recurrent bacterial infectious diseases are detected with localization mainly in the respiratory tract and paranasal sinuses. By the time of diagnosis, respiratory tract infections may progress to bronchiectasis and diffuse lung tissue lesions. Perhaps an infectious lesion of the digestive system, manifested by diarrhea, steatorrhea and malabsorption (and, accordingly, weight loss). Often infections are caused by Giardia lamblia, Pneumocystis carinii or viruses of the family Herpetoviridae. Patients with CVID are prone to the development of purulent arthritis caused by mycoplasmas and ureaplasmas. Encephalomyelitis, poliomyelitis and dermatomyositis-like syndromes, lesions of the skin and mucous membranes can be manifestations of enterovirus infections. Autoimmune diseases are severe and can determine the prognosis of CVID. Sometimes the first clinical manifestations of CVID are arthritis, ulcerative colitis and Crohn's disease, sclerosing cholangitis, malabsorption, SLE, nephritis, myositis, autoimmune lung damage in the form of lymphoid interstitial pneumonitis, neutropenia,
thrombocytopenic purpura, hemolytic anemia, pernicious anemia, total alopecia, retinal vasculitis, photosensitivity. In patients with CVID, the frequency (in 15% of cases) of sarcoidosis-like granulomas and non-malignant lymphoproliferation is significantly increased. Treatment.
Antibacterial chemotherapy.
Replacement therapy: intravenous immunoglobulin preparations are administered every 3-4 weeks for life.
With autoimmune complications - immunosuppressive therapy (glucocorticoids, azathioprine, cyclosporine A) and the appointment of monoclonal antibodies (infliximab, etc.) is possible.
Hyper-IgM syndromes
Hyper-IgM syndromes are rather rare diseases characterized by a pronounced decrease or complete absence of IgG, IgA and normal or elevated serum IgM concentrations. This is due to the inability of B-lymphocytes to carry out immunoglobulin class switching and variable domain hypermutagenesis. To date, 6 genetic defects have been identified that lead to the development of hyper-IgM syndrome.
. Type 1 (HIGM 1). X-linked deficiency of CD40 ligand (70% of cases of hyper-IgM syndromes), resulting in the inability of T cells to effectively interact with B lymphocytes.
. Type 2 (HIGM 2). Autosomal recessive, associated with the defect AID - induced activation of cytidine deaminase (gene Aicda, 12p13)- an enzyme involved in switching classes of immunoglobulins and hypermutagenesis.
. Type 3 (HIGM 3). Autosomal recessive, associated with a mutation in the CD40 molecule gene. At the same time, B-cells themselves are not able to effectively interact with T-lymphocytes. Phenotypic manifestations are similar to those for type 1.
. Type 4 (HIGM 4). Autosomal recessive; in some cases, mutations occur de novo. Associated with a defect in UNG - uracil-DNA glycosylase - an enzyme also involved
in switching classes of immunoglobulins, but after the action of AID. In this case, hypermutagenesis is not affected and the syndrome is less severe.
. Type 5 (HIGM 5). The defect is only in class switching, hypermutagenesis is not affected. The causal mutation has not yet been identified, but there is obviously a defect in the enzyme acting after
AID.
. Type 6 (HIGM-ED). X-linked, associated with dyshidrotic ectodermal dysplasia, is caused by a deficiency of NEMO (NF-kB modulator) leading to impaired signaling from CD40.
X-linked hyper-IgM syndrome are detected more often than others. Develops with a defect in the gene encoding CD40L (CD154, the gene is located on Xq26-q27.2)- ligand for CD40. Insufficiency of CD40L expression by T-lymphocytes leads to the impossibility of switching classes of immunoglobulins in B-lymphocytes from IgM to other isotypes, as well as to impaired formation of memory B-cells, T-cell repertoire, and Th1-cell response directed against intracellular microorganisms. Boys get sick
Data from laboratory studies. IgG, IgA, IgE cannot be determined or are detected in very small quantities. The level of IgM is normal (in 50% of cases) or elevated, often significantly. The number of T- and B-cells is normal; reduced proliferative response of T cells induced by antigens. IgM are polyclonal, sometimes monoclonal. Autoantibodies of the IgM isotype are detected (antierythrocyte, antiplatelet, antithyroid, antibodies to antigens of smooth muscle tissue). There are no germinal centers in the lymphoid tissue, but there are plasma cells.
clinical picture. The first manifestations occur in infancy and early childhood. Characterized by repeated infections different localization (primarily the respiratory tract), including opportunistic (caused by Pneumocystis carini). Virus infections (cytomegalovirus and adenoviruses) are also characteristic, Criptococcus neoformans, mycoplasmas and mycobacteria. Cryptosporidial infection can cause acute and chronic diarrhea (developing in 50% of patients) and sclerosing cholangitis. Often develop anemia, neutropenia, ulceration of the oral mucosa, gingivitis, ulcerative
lesions of the esophagus, various parts of the intestine, ulcerative colitis. Shows a predisposition to autoimmune disorders(seronegative arthritis, glomerulonephritis, etc.) and malignant neoplasms (mainly lymphoid tissue, liver and biliary tract). Lymphadenopathy, hepato- and splenomegaly may develop. Treatment
Regular replacement therapy with intravenous immunoglobulin.
Antibacterial chemotherapy. For the prevention and treatment of pneumocystis pneumonia, co-trimoxazole [sulfamethoxazole + trimethoprim] and pentamidine are used.
To prevent damage to the liver and biliary tract, you should only use boiled or filtered water, conduct regular examinations (ultrasound, liver biopsy if indicated).
In the treatment of neutropenia and ulceration of the oral cavity, glucocorticoids and preparations of granulocyte colony-stimulating factor are used.
With the development of autoimmune complications, immunosuppressive therapy (glucocorticoids, azathioprine, cyclosporine A), as well as drugs based on monoclonal antibodies, are prescribed.
The optimal treatment is bone marrow transplantation from HLA-matched donors (survival rate 68%, best performed before the age of 8 years).
COMBINED IMMUNODEFICIENCY WITH PRIMARY T-LYMPHOCYTE DEFECT
Severe combined immunodeficiency
TKIN (SCID - Severe Combined Immune Deficiency)- a group of syndromes characterized by a decrease in the level of T-lymphocytes or their complete absence and a violation of adaptive immunity. . Reticular dysgenesis, characterized by impaired maturation of lymphoid and myeloid progenitors in the early stages: neutropenia and T - B - NK - .
. X-linked SCID due to gene mutation IL-2RG[(CD132, total at- receptor chain for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21), Xq13.1-q21.1,אּ ], which leads to blockade of receptors and the inability of target cells to respond to the action of the corresponding interleukins (more than 50% of all cases of SCID); T - B + NK - .
. Janus3 tyrosine kinase deficiency [gene JAK3 (19p13.1),ρ ]; with gene defects, the transmission of the activation signal from the general at- chains of IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 to the cell nucleus, which leads to impaired differentiation of T and NK cells; T - B+NK - .
. Protein tyrosine phosphatase deficiency (CD45, gene PTPRC, 1q31-q32); when the gene is defective, the inhibitory activity of Csk kinase on protein tyrosine kinase Src is enhanced with impaired phosphorylation of the ITAM domains of TCR and BCR; T - B+NK+.
. Complete deficiency of RAG1 and RAG2 enzymes that activate recombination of V(D)J-segments of immunoglobulins and TCR [genes RAG1 And RAG2 (11r13),ρ ]; T-B-NK+.
. Omenn's syndrome (incomplete deficiency of RAG1 enzymes and
RAG2) [genes RAG1 and/or RAG2 (11p13-p12),R]. Thanks to
However, due to the low residual activity of these enzymes, a certain number of clones of T-lymphocytes develop that are specific for antigens of the epithelial tissues of the skin and digestive tract, where they multiply and produce large amounts of IL-4 and IL-5, causing hypereosinophilia and the formation of IgE by residual B-lymphocytes. (in the absence of immunoglobulins of other classes). Characterized by erythroderma and pachydermia with alopecia in the scalp and eyebrows, debilitating diarrhea, life-threatening infectious syndrome; hepatosplenomegaly and lymph node hyperplasia.
. SCID with hypersensitivity to ionizing radiation. Artemis nuclear protein defect [gene DCLRE1C, (10p),R], included in the complex of enzymes necessary for DNA repair (participates in the connection of double-strand breaks), when the gene is mutated, a violation of V (D) J-recombination occurs; T-B-NK+.
. IL-2 deficiency [gene IL-2, 4q26-q27].
Mutations in the α-chain IL-2 receptor gene (CD25) (10r15-r14);T - B + NK + .
Mutations in the α-chain gene of the IL-7 receptor (CD127) (5r13);T - B + NK + .
TAP deficit (Transporter for Antigen Presentation), necessary for the transport of antigenic peptides into the endoplasmic reticulum of the α-chain gene of the IL-7 receptor (CD127) (5r13);T - B + NK + .
Mutations in the genes of CD3 chains (CD3γ, CDδ and CDε), leading to a decrease in the number of mature T-lymphocytes, a violation of their differentiation; T - B + NK + .
Deficiency of protein tyrosine kinase ZAP-70 [gene ZAP-70 (2q12), R]. When the gene is mutated, phosphorylation of the ITAM domains of the TCR ζ chain and ITAM-containing NK cell receptors suffers, a selective deficiency of CD8 + T cells develops (the content of CD4 + T-lymphocytes is normal, but functional disorders are expressed in the form of the absence of formation of IL- by these cells). 2 and proliferation).
Adenosine deaminase deficiency [gene ada (20q12-q13.11 , p)], leading to the accumulation of metabolites in cells (deoxyadenosine triphosphate and S-adenosylhomocysteine), which inhibit the proliferation of T- and B-lymphocytes (variants with a late onset of the disease are described); T-B-NK-.
Purine nucleoside phosphorylase deficiency [gene pnp (14q11.2), p], leading to the accumulation of deoxyguanosine triphosphate in cells, which inhibits the proliferation of T-lymphocytes (associated syndromes are uricemia and uricuria); T - B + NK - .
Data from laboratory studies. Reveal variable, sometimes deep lymphopenia; lymphocytes are unable to proliferate in response to a specific antigen; a decrease in the level of immunoglobulins in the blood serum is often expressed. There is no shadow of the thymus on the chest x-ray.
clinical picture. Usually, the clinical diagnosis becomes clear in the first 6 months of life, when maternal IgG antibodies disappear. In the clinical picture, come to the fore severe infectious syndrome hypoplasia of lymphoid tissue and developmental delay. The infectious syndrome is characterized by oral candidiasis, chronic diarrhea, pneumonia, fever,
sepsis of bacterial etiology, viral infections. Infectious agents belong to different taxonomic groups: bacteria, viruses, fungi, opportunistic microorganisms (Pneumocystis carini). Pneumonia is often caused P. carini, diarrhea - rotaviruses, Campylobacter, Giardia lamblia. Often manifests viral hepatitis. The development of regional or generalized BCG is characteristic after vaccination.
Treatment provides for the appointment of maintenance therapy, including parenteral nutrition, the introduction of intravenous immunoglobulin, the appointment of antibiotics, antifungal and antiviral drugs. One of the main methods of treatment to achieve recovery is bone marrow transplantation, without which children with SCID usually die in the 1st year of life. Isolated cases are described when a child in especially sanitized conditions lived up to 2-3 years. It is important to recognize SCID as early as possible in newborns, since for them, for example, immunization with live vaccines is fatal. Immediately after the diagnosis is made, such children should be placed in gnotobiological conditions (sterile box). In case of joining infectious diseases, intensive antibacterial, antiviral and antifungal therapy, intravenous immunoglobulin replacement therapy are carried out. For the prevention of pneumocystic pneumonia, co-trimoxazole is prescribed. In the case of the development of BCGit, it is necessary to conduct long-term intensive anti-tuberculosis therapy. For transfusion of blood components, only irradiated and filtered preparations should be used. There is a risk of post-transfusion graft-versus-host disease due to transplacental transfer of maternal lymphocytes.
Naked lymphocyte syndrome
This is the name of the pathology when MHC-I or MHC-II molecules are not expressed in the body. In the absence of expression of MHC-I molecules, the content of CD8 + T-lymphocytes is reduced and there is no activity of NK cells; in the absence of MHC-II, the level of CD4 + T-lymphocytes is reduced. Several genetic defects have been characterized. However, these defects are not localized in the MHC genes, but in several different factors responsible for their regulation.
expression. Clinical picture Naked lymphocyte syndrome and treatment similar to those for other SCIDs.
DiGeorge Syndrome
In DiGeorge syndrome, or defect syndrome of the third and fourth pharyngeal pockets [deletions in 22q11, including the gene TBX1 (22q11.2), reveal hypoplasia or aplasia of the thymus, hypoplasia of the parathyroid gland, heart defects, deficiency of T-lymphocytes, variable numbers of B-lymphocytes.
Data from laboratory studies. A significant decrease in the number of CD3+, CD4+ and CD8+ T cells and a sharp decrease in their proliferative activity induced by mitogens and antigens. The number of B- and NK-cells is normal. The concentration of serum immunoglobulins in most cases is within the normal range, various variants of dysgammaglobulinemia are possible.
clinical picture. The immunodeficiency component is represented by hypoplasia or aplasia of the thymus and recurrent, severe infectious diseases. Hypoparathyroidism is also detected (hypocalcemia and, as a result, tetany, noticeable on the 1-2nd day after birth); malformations of the circulatory system (right reversal of the aortic arch, right ventricular stenosis, defects in the interventricular and interatrial septa, tetralogy of Fallot, atresia or hypoplasia of the pulmonary artery); the cavity of the palate; anomalies of the facial skeleton (increased distance between paired organs, reduced jaws, especially the lower one, low-set auricles, short nasal groove). Expressed anomalies in the structure of the larynx, pharynx, trachea, inner ear, esophagus; impaired development of the kidneys, central nervous system and other malformations (polydactyly, absence of nails, anus atresia, anal fistulas). A delay in speech and psychomotor development is characteristic. indicate a predisposition to autoimmune disorders(cytopenia, autoimmune thyroiditis) and malignant neoplasms.
Treatment.. Antibacterial and antiviral therapy. . Replacement therapy with intravenous immunoglobulin preparations. . Surgical treatment to correct malformations. . With autoimmune complications - immunosuppressive therapy. . In the presence of endocrinopathies - correction of the corresponding violations. . Bone marrow transplantation is ineffective
tive. . Thymus epithelial tissue transplantation is justified. Correction of the function of the parathyroid glands.
X-linked lymphoproliferative syndrome
X- linked lymphoproliferative syndrome is characterized by impaired immune response to the Epstein-Barr virus [due to defects in the gene SH2D1A(SAP) in xq25,אּ], leading to uncontrolled proliferation of B-lymphocytes transformed by the Epstein-Barr virus and infection of new target cells by the virus.
clinical picture. The 4 most common phenotypes are described: severe infectious mononucleosis, malignant lymphoproliferative conditions (lymphomas, leukemias, predominantly B-cell), anemia or pancytopenia (including due to virus-induced hemophagocytic syndrome), dysgammaglobulinemia. Epstein-Barr virus infection is a trigger (starting) mechanism for the formation of the most severe, rapidly progressive and fatal diseases: fulminant infectious mononucleosis (in 58% of cases it leads to death), hemophagocytic syndrome (without treatment in 100% of cases it leads to death). In 10% of cases, the phenotype appears before infection with the Epstein-Barr virus (in this case, as a rule, dysgammaglobulinemia and lymphomas develop). The most common are various types of hypogammaglobulinemia. Immunodeficiency leads to the development of bacterial, fungal and viral infectious diseases. The disease can be suspected in boys with a characteristic family history and a sero- or PCR-positive Epstein-Barr virus test. A combination of genetic analysis is recommended for diagnosis. SH2D1A and evaluation of SAP expression level.
Treatment
For the purpose of prevention, it is recommended to use antiviral drugs - acyclovir, valaciclovir (their early administration suppresses the replication of the Epstein-Barr virus in the oropharynx) and intravenous immunoglobulin (with a high titer of antibodies to the Epstein-Barr virus).
With hypogammaglobulinemia, intravenous immunoglobulin is used monthly in combination with antibiotic therapy.
For the treatment of fulminant infectious mononucleosis, high doses of acyclovir and methylprednisolone are prescribed, high-dose therapy with intravenous immunoglobulin with a high titer of antibodies to the Epstein-Barr virus and IFN.
With the development of hemophagocytic syndrome, high doses of dexamethasone are combined with vepezid ♠ (etoposide).
In the treatment of malignant diseases, standard therapy protocols are used.
A radical method of treatment is bone marrow transplantation from HLA-compatible donors.
Autoimmune lymphoproliferative syndrome
Autoimmune lymphoproliferative syndrome - a group of diseases characterized by benign lymphoproliferation, hyperimmunoglobulinemia, autoimmune disorders, increased levels of CD3 + CD4 - CD8 - T-lymphocytes (double negative) in the peripheral blood and a defect in apoptosis [gene defect Fas(CD95)- TNFRSF6 (10q24.1), gene caspase-10, Fas-ligand - FasL(1q23)].
Data from laboratory studies. The content of CD3 + CD4 - CD8 - T-lymphocytes in peripheral blood or lymphoid tissues is more than 1%. IgG, IgA, and IgM levels may be normal, elevated, or even reduced. With age, hypergammaglobulinemia is replaced by a low concentration of serum immunoglobulins, up to agammaglobulinemia. Autoantibodies to erythrocytes, platelets, neutrophils, smooth muscles, to factor VIII are detected; antinuclear and antiphospholipid autoantibodies, as well as rheumatoid factor, etc. Lymphocytosis is characteristic.
clinical picture. All patients have enlarged liver, lymph nodes (in the first 5 years of life) and spleen. Lymphoproliferation is not accompanied by fever and night sweats. Debut autoimmune reactions may not coincide with lymphoproliferation and occurs later. With age, the severity of autoimmune reactions increases. More often develop autoimmune reactions against blood cells (hemolytic anemia, thrombocytopenia, neutropenia), less often other organs are affected. The risk of developing malignant neoplasms (T- and B-lymphomas, Burkitt's lymphoma, atypical lymphoma, lymphogranulomatosis, etc.) is increased.
Treatment.. Chemotherapeutic agents (cyclophosphamide, azathioprine, methotrexate, chlorambucil). . Glucocorticoids. . Splenectomy with severe hypersplenism and hemocytopenia. . In severe cases, bone marrow transplantation is possible.
Hyperimmunoglobulinemia syndrome E
Hyper-IgE syndrome is characterized by a significant increase in the level of serum IgE, repeated abscesses of the skin and subcutaneous tissue of staphylococcal etiology, pneumonia with the formation of a pneumocele, anomalies in the structure of the facial skeleton, AD. The molecular genetic nature of hyper-IgE syndrome has not yet been established. In some cases, autosomal dominant inheritance has been identified, in others, autosomal recessive inheritance. It is assumed that the defects affect the signaling molecules of cytokine receptors (in the autosomal dominant form of this syndrome, mutations in stat3) and possibly associated with impaired functioning of the Th17 cell subpopulation. Another gene responsible for the formation of hyper-IgE syndrome is localized on chromosome 4 (4q).
Data from laboratory studies. A variety of immunological disorders are detected: an increase in the level of IgE in serum, a violation of neutrophil chemotaxis, a defect in the formation of antibodies; decrease in the response of HRT to candidin, diphtheria and tetanus toxoids; weakening of the proliferative activity of T cells in response to Candida and tetanus toxoid while maintaining a response to mitogens. Eosinophilia in the peripheral blood and fluid of skin abscesses. The number of T and B cells is normal.
clinical picture. Eczema of moderate course at an early age. Characteristic features of the face (broad bridge of the nose, wide snub nose, asymmetry of the facial skeleton, protruding forehead, deep-set eyes, high palate). Anomalies in the development of the skeleton, scoliosis, increased mobility of the joints, a tendency to fractures of bones after minor injuries, and a violation of the change of teeth are revealed. There are abscesses of the skin, subcutaneous tissue and lymph nodes. Pneumonia develops at an older age (the most common pathogens S. aureus And H. in-
fluenzae), in 77% of cases, a pneumocele is formed, an infection due to P. aeruginosa And A. fumigatus. Pneumonia can occur without fever. Chronic candidiasis of the mucous membranes and nails develops in 83% of cases.
Treatment.. Long-term (for the purpose of prevention - lifelong) antibacterial and antifungal therapy. . For the treatment of dermatitis, topical agents are used, in severe cases, low doses of cyclosporine A. . Bone marrow transplantation is ineffective.
CHROMOSOME BREAKDOWN SYNDROMES
For syndromes with chromosomal instability: ataxiatelangiectasia[defect in DNA topoisomerase gene ATM (11q22), p] and Nijmegen syndrome[nibrin gene defect NBS1(8q21)] - an increased frequency of malignant tumors, spontaneous chromosomal instability and chromosomal breakdowns are characteristic. Both proteins are involved in the repair of DNA double-strand breaks and the regulation of the cell cycle. Normally, DNA double-strand breaks occur during V(D)J recombination of the immunoglobulin and TCR genes, switching classes of immunoglobulins, during crossing over, and during meiosis. Similar processes occur during the maturation of brain neurons. Defects in DNA repair in ataxia-telangiectasia and Nijmegen syndrome cause such clinical manifestations as impaired immunoglobulin synthesis, the functions of the genital organs and the nervous system.
Ataxia-telangiectasia
This syndrome (frequency 1:300 thousand newborns) with a very heterogeneous phenotype was described by the French doctor D. Louis-Bar. Symptoms of ataxia can be detected in a child already at the age of 2-4 months. Ataxia is caused by progressive degeneration of Purkinje cells in the cerebellum. Telangiectasias on the skin of the nose, auricles, and on the conjunctiva appear somewhat later, by 3-6 years. Café au lait spots often appear on the skin. Characterized by hypoplasia of the thymus, lymph nodes, spleen, tonsils. Immunodeficiency is manifested by a decrease (often an imbalance) in the production of IgA, IgE, IgG2, IgG4. 80% of patients develop
corresponding infectious clinical symptoms. Reduced number and functional activity of T cells (mainly CD4 + T cells). The total number of T-lymphocytes in most patients is normal. The frequency of neoplasms (mainly lymphomas and carcinomas) is unusually high (200 times higher than in the general population), often leading to death by 10-12 years. Treatment symptomatic.
Nijmegen syndrome
Nijmegen syndrome (named after the city in Holland where the disease was first described) is manifested by microcephaly, specific disorders of the facial skeleton (sloping forehead, protruding middle part of the face, long nose, lower jaw hypoplasia, Mongoloid eye slit, epicanthus, large ears), physical development lag , the presence of "coffee with milk" spots on the skin; clinodactyly and syndactyly, ovarian dysgenesis, etc. Most children suffer from recurrent and chronic bacterial infectious diseases respiratory tract, ENT organs and urinary system. In 50% of cases, malignant neoplasms develop, predominantly B-cell lymphomas. Reveal various forms of dysgammaglobulinemia, a decrease in CD4 + T-cells.
Treatment.. Symptomatic therapy of neurological disorders. . Replacement therapy with intravenous immunoglobulin. . According to indications, antibacterial, antiviral, antifungal therapy is used. . In the treatment of malignant neoplasms, increased sensitivity to radiation and chemotherapy is taken into account.
Wiskott-Aldrich Syndrome
Wiskott-Aldrich syndrome [defective gene WASP (Xp11.23p11.22),אּ; also ρ and Ʀ] Gene WASP(from Wiskott-Aldrich syndrome expressed in lymphocytes, spleen tissue and thymocytes. Mutations of this gene are associated with abnormal expression in neutrophils and T-lymphocytes (CD4 and CD8) of the CD43 molecule (ligand for ICAM-1, performs an antiadhesive function).
Data from laboratory studies. Thrombocytopenia (less than 10% of normal) is due to increased cell destruction.
Platelets are smaller than in healthy people. The level of IgM in the blood serum is reduced with a normal level of IgG and an increase in the content of IgA and IgE. The titers of isohemagglutinins are reduced, the formation of antibodies to polysaccharide antigens of pneumococcus, streptococcus, Escherichia coli, salmonella, as well as antiviral antibodies is impaired. At an early age, as a rule, the number of lymphocytes is normal; after 6 years, lymphopenia (less than 1x10 9 /l), a decrease in CD3 + and CD4 + T cells with a normal level of B and NK cells are detected. Eosinophilia and the development of posthemorrhagic anemia are possible. The proliferative response of T cells to mitogens and antigens is reduced, HRT is weakened. In the spleen, normal structures of germinal centers and T-cell zones are not detected.
clinical picture. The disease is characterized by a triad of signs: thrombocytopenia, eczema and recurrent infectious diseases. Hemorrhagic syndrome manifests itself early, already in the neonatal period (petechial rash, cephalohematomas, bleeding from the umbilical wound, intestinal bleeding). Eczema manifests itself from an early age in 80% of patients. With age, signs of immunodeficiency increase: bacterial infectious diseases of the upper respiratory tract, respiratory system, digestive organs, skin; common or generalized herpes infection (Herpes simplex And Varicella zoster) cytomegalovirus, as well as fungal (candidiasis of the mucous membranes), less often opportunistic infectious diseases. Autoimmune diseases (hemolytic anemia, neutropenia, arthritis, cutaneous vasculitis, ulcerative colitis, cerebral vasculitis, glomerulonephritis, autoimmune thrombocytopenia) are detected in 70% of patients. Patients older than 5 years have an increased frequency malignant neoplasms(mainly tumors of lymphoid tissue).
Treatment.. Transplantation of allogeneic bone marrow or stem cells (the success rate of the operation reaches 90% with a transplant from a histocompatible donor and 50% with a haploidentical transplant). . Replacement therapy with intravenous immunoglobulin. . Prophylactic administration of antibacterial, antifungal and antiviral drugs. . To reduce the hemorrhagic syndrome, a splenectomy is performed. . With autoimmune complications, immunosuppressive therapy is prescribed.
DEFECTS OF PHAGOCYTOSIS
chronic granulomatous disease
Chronic granulomatous disease is characterized by a violation of the functional activity of phagocytes (the formation of active forms of oxygen radicals, intracellular killing and fragmentation of phagocytosed pathogens), persistent bacterial and fungal infections and the development of granulomatous inflammation. Chronic granulomatous disease develops in individuals with various genetic defects [in 65% of cases - X-linked variant of the disease: gene gp91-phox (Xp21.1),אּ; in 35% of cases - autosomal recessive: gene f47-phox (7q11.23),ρ; gene p67-phox (1q25),ρ; gene p22-phox (16q24), p], leading to disturbances in the NADP-oxidase system. With the death of short-lived (several hours) neutrophils, unkilled bacteria “leak” into the focus of inflammation. Macrophages are long-lived cells, and their precursors (monocytes) migrate to the focus in increased numbers (which leads to the formation granulomas), phagocytose microorganisms, but are not able to kill them.
Data from laboratory studies. Characterized by normal values of serum immunoglobulins and subpopulations of lymphocytes. The formation of peroxide radicals by neutrophils, assessed in tests (luminol-dependent chemiluminescence or tetrazolium blue reduction), is sharply reduced or absent. Against the background of infectious diseases, leukocytosis, neutrophilia, increased ESR, anemia, hypergammaglobulinemia are characteristic.
clinical picture. The disease in most cases manifests itself in the first year of life. infectious syndrome(infections with intra- and extracellular pathogens) and the formation of granulomas. The most typical are: damage to the lungs (recurrent pneumonia, damage to the hilar lymph nodes, lung abscesses, purulent pleurisy), digestive tract, skin abscesses and lymphadenitis. The most common pathogens are catalase-positive microorganisms: S. aureus, Aspergillus spp., intestinal gram-negative bacteria (E. coli, Salmonella spp., Serratia marcescens), less often - Burkholderia cepacia And Nocardia farcinica. The development of hepatic and subdiaphragmatic abscesses, osteomyelitis, pararectal abscesses, and sepsis is characteristic.
The most severe, life-threatening infectious complication is aspergillosis, which can occur as a diffuse lesion of the lungs and other organs (adipose tissue, brain, bones, joints, endocardium). Patients with chronic granulomatous disease after BCG vaccination often develop a vaccine-associated infection involving regional lymph nodes. Mycobacterial lesion in patients with chronic granulomatous disease can have both pulmonary and extrapulmonary localization and has a protracted course. For patients with chronic granulomatous disease, a lag in physical development is characteristic.
Treatment.. Antimicrobial therapy: prophylactic continuous use of co-trimoxazole and antifungal drugs (itraconazole, etc.); in the event of infectious complications, combined antibacterial therapy is carried out parenterally (2-3 bactericidal antibiotics penetrating intracellularly) in combination with antifungal therapy. With the development of aspergillosis, long-term use of amphotericin B or caspofungin is indicated. In mycobacterial infection, a combination of long-term specific therapy with anti-tuberculosis drugs with broad-spectrum antibiotics is used. . Surgical treatment is often accompanied by suppuration of the postoperative wound and the formation of new foci. Perhaps puncture drainage of the abscess under ultrasound control. . For the treatment of severe infectious complications with the ineffectiveness of antibiotic therapy, it is possible to use granulocytic mass, high doses of IFNy and G-CSF. . Bone marrow transplantation or cord blood transplantation from a compatible sibling may be successful at an early age when the risk of death from infectious complications and graft-versus-host disease is minimal.
Defects in leukocyte adhesion
To date, 3 leukocyte adhesion defects have been described. All of them have
autosomal recessive inheritance, characterized by repeated and chronic bacterial and fungal infections. Type I is characterized by the absence or decrease in the expression of CD11/CD18 on leukocytes, impaired neutrophil chemotaxis, leukocytosis (more than 25x10 9), late fall-off of the umbilical cord and the development of omphalitis, poor wound healing, and the absence of pus formation at the site of penetration of the pathogen into the body.
Treatment.. Antibacterial therapy: infectious episodes and prophylactic. . In severe cases, bone marrow transplantation from an HLA-compatible donor is prescribed.
DEFECTS OF THE COMPLEMENT SYSTEM
Complement Deficiency Diseases
Manifestations of gene defects in individual components of the complement system are given in Table. 11-2.
hereditary AO. Diseases caused by deficiency of complement components are rarely detected, since their manifestation requires a homozygous state for autosomal alleles. There is one exception related to C1inh (C1-esterase inhibitor): a gene mutation c1inh, leading to inhibitor deficiency, in the heterozygous state, manifests a phenotype known as hereditary AO (see Chapter 13, Angioedema for more details).
Diseases of immune complexes. C1-C4 deficiency is manifested by the development of immune complex diseases - systemic vasculitis and kidney damage, which is collectively called the syndrome of systemic lupus erythematosus (SLE).
pyogenic infections. Deficiency of C3 (also factors H and I) is associated with increased susceptibility to pyogenic infections. Deficiency of components involved in the alternative pathway of complement activation, as well as deficiency of components C5-C8, are associated with increased susceptibility to infection caused by Neisseria spp. C9 deficiency is usually clinically asymptomatic.
Table 11-2. Clinical manifestations of defects in individual components of the complement system
Mannose-binding lectin deficiency
Deficiency of mannose-binding lectin (also called mannose-binding lectin - MBL) is due to a gene defect MBL(various point mutations and deletions in the gene MBL found in 17% of Caucasians). With gene defects, the activation of proteases that cleave complement components C2 and C4 and the activation of the complement system along the lectin pathway are disrupted. Clinically this pathology is manifested by an infectious syndrome.
Data from laboratory studies. Analysis of subpopulations of lymphocytes, leukocytes, as well as immunoglobulin isotypes does not show significant deviations adequate to clinical symptoms. There is no MSL in the blood serum.
Treatment. This disease is not a classic immunodeficiency. Therefore, immunocorrection with immunotropic agents is contraindicated. Recombinant MSL can be used as a pharmacological agent for etiopathogenetic replacement therapy in patients with this hereditary defect. This drug is currently undergoing clinical trials.
The problem of diagnosis and treatment of immunodeficiency states is currently extremely relevant for clinical medicine.
This is due to the fact that in recent years a large amount of new information about the structure and functioning of the human immune system has accumulated.
Immunomodulatory therapy began to be actively introduced into the practice of not only immunologists, but also doctors of other specialties, many new immunomodulatory drugs have appeared, and the number of nosological forms in the treatment of which immunotropic agents are used has increased.
All immunodeficiency states are usually divided into primary and secondary.
Primary immunodeficiencies (PIDs) are congenital diseases caused by defects in genes that control the immune response; in this case, the defect may affect one or more components of the immune system: cellular and humoral immunity, phagocytosis, and the complement system.
PID is characterized by persistent impairment of immune parameters. Clinically, PID is manifested by recurrent infectious diseases, a tendency to autoimmune pathology, and tumor diseases. These immunodeficiencies usually make their debut in early childhood.
Secondary immunodeficiency states (SIDs) are characteristic changes in the functioning of the immune system that develop in the late postnatal period or in adults and are not associated with genetic defects.
With secondary immunodeficiency, the immune system, which is completely normal at birth, for some reason, begins to malfunction.
There are three forms of VIS: acquired, induced and spontaneous.
The most typical acquired form of secondary immunodeficiency is AIDS, which develops as a result of damage to human lymphoid tissue by a virus.
The reasons for the development of the induced form can be varied: often recurrent bacterial, fungal, viral infections of various localization; allergopathology (atopic dermatitis, bronchial asthma, hay fever, eczema with an infectious syndrome); autoimmune pathology; neoplasms of different localization; blood diseases; pathology of the gastrointestinal tract; pathology of the endocrine system; aging; surgical interventions; trauma; eating disorders; x-ray radiation; cytostatic therapy.
In the spontaneous form of secondary immunodeficiency, the obvious cause of impaired immune reactivity cannot be identified (in some cases this is due to insufficient diagnostic capabilities of modern clinical medicine). 
Clinical signs of secondary immunodeficiency states (VIS) are chronic, often recurrent, sluggish, difficult to treat with traditional means of infectious and inflammatory diseases of any localization caused by opportunistic or conditionally pathogenic microorganisms, as well as pathogenic flora with atypical biological properties and / or multiple resistance to antibiotics .
The state of the immune system is of great importance for the formation of infectious resistance. The main task of the anti-infective defense system is to eliminate infectious agents, preserving the memory of them (memory lymphocytes) for a faster and more efficient response in case of re-infection.
The development of a chronic disease indicates that there are malfunctions in the complex defense system of the body. When infected, natural resistance factors turn on instantly and in the early stages are practically the only defenders of the body. Only after 2-3 weeks, the elements of specific protection begin to function.
In the dynamics of the development of the disease, these two components of the body's defense reaction (innate and acquired immunity) function in parallel, complementing and reinforcing each other.
The specific immune response includes the production of antibodies (classes IgG, IgA, IgM, IgE), the formation of a clone of antigen-specific T-lymphocytes (Th1, Th2, cytotoxic T-lymphocytes, T-effector cells in delayed-type hypersensitivity reactions) and memory cells .
The detected changes in the immune status depend on the nature of the infectious agent that causes inflammation, on the severity of inflammation and its duration.
At the same time, it should be emphasized that the immune response to the same infections in different patients may vary, the features of the functioning of the immune system are strictly individual.
The works of numerous researchers describe the most frequent changes in the immune status, characteristic of viral, bacterial infections, extra- and intracellular pathogens.
The processes caused by bacterial pathogens are characterized by changes in the phagocytic and humoral parts of the immune system.
An adequate response of the immune system to acute bacterial inflammation consists in an increase in the indicators characterizing the absorptive and digesting ability of phagocytes, and an increase in the levels of immunoglobulins of classes A, M, and G. On the contrary, with VIS, in this case, a decrease in phagocytosis and hypogammaglobulinemia are noted in the immune status.
Quantitative ratios of immunocompetent cells are variable; only a pronounced decrease in the number of mature T cells is of clinical importance for the appointment of immunomodulators. 
In the chronic course of the infectious-inflammatory process, changes in the immune status may be absent or depletion of the functions of the macrophage-monocyte link and antibody formation is determined, which, as in acute bacterial inflammation, is accompanied by a decrease in phagocytosis and hypogammaglobulinemia.
Identification of a viral pathogen in chronic infectious and inflammatory processes is quite difficult. As a rule, we are talking about viral-bacterial associations. Therefore, the problem of the influence of viral pathogens on the state of immunity in chronic infectious and inflammatory processes is much less studied, the same applies to intracellular pathogens.
The atypical clinical course of the infectious-inflammatory process is typical for infectious agents, the recognition of which by immunocompetent cells is difficult. In viral and intracellular infections, patients with the highest frequency usually present with signs of VIS.
Chronic viral infection, unlike acute, is often accompanied by lymphopenia and a decrease in the number of immunocompetent cells, depletion of the IFN system.
With an adequate response of the immune system to a viral pathogen, an increase in the level of IgM and other classes of immunoglobulins is noted, hypogammaglobulinemia is characteristic of an immunodeficiency state.
Changes in immunological parameters can be transient in nature and form at the later stages of the existence of VIS in the absence of adequate therapy for the underlying disease.
The cause-and-effect relationships of the immune status and the clinical picture of the disease are very complex, and most often it is not possible to decide what is primary and what is secondary.
The most common clinical conditions associated with infection that require observation and examination by an immunologist:
- chronic bronchitis, often recurring, with a history of pneumonia, in combination with diseases of the ENT organs (purulent sinusitis, otitis media, lymphadenitis);
- recurring pneumonia, bronchopleuropneumonia;
- bronchiectasis;
- bacterial infections of the skin and subcutaneous tissue (pyoderma, furunculosis, abscesses, cellulitis, septic granulomas, recurrent paraproctitis in adults);
- aphthous stomatitis in combination with an increased incidence of acute respiratory viral infections;
- recurrent herpesvirus infection of various localization;
- gastroenteropathy with chronic diarrhea of unclear etiology, dysbacteriosis;
- lymphadenopathy, recurrent lymphadenitis;
- prolonged subfebrile condition, fever of unknown etiology;
- generalized infections (sepsis, purulent meningitis, etc.).
The number of clinical situations in which the inclusion of immunomodulators in the complex therapy of patients is justified is quite large.
In clinical practice, before prescribing immunomodulatory therapy, patients are examined to clarify the nosological form of the disease associated with VIS syndrome.
Not all conditions, often accompanied by the formation of the VIS syndrome, require the inclusion of immunomodulatory drugs in therapy. In many cases, correctly selected basic therapy for the underlying disease allows you to eliminate signs of immune deficiency without the use of immunomodulators.
Thus, secondary immune deficiency syndrome is a disorder of the immune system that develops in the late postnatal period or in adults and is characterized by chronic infectious and inflammatory diseases that are torpid to traditional (standard) therapy.
For effective therapy, the attending physician must determine the causal relationship in the formation of immunodeficiency, adequately select the basic therapy for the underlying disease, evaluate immunological disorders, and choose the right immunotropic therapy.
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