Bruton's disease: etiology, causes, symptoms and treatment features. Agammaglobulinemia - treatment, prognosis, signs and symptoms
CHAPTER 3. IMMUNODEFICIENCY CONDITIONS
Definition, clinical manifestations and classification of immunodeficiency states. Classifications of primary IDS. Primary IDS of adaptive immunity with a predominant lesion of the B-cell link. Primary IDS of adaptive immunity with a predominant lesion of the T-cell link. Combined T- and B-immunodeficiencies. Primary deficiencies of the phagocytic link of innate immunity. Primary deficiencies of the complement system. Preliminary diagnosis of primary IDS. Definition, the main causes of the formation of secondary immunodeficiencies. Physiological (age-related) immunodeficiencies. The role of preexisting diseases, iatrogenic factors, adverse environmental factors and lifestyle risk factors in the occurrence of secondary IDS.
In the functioning of the immune system, like any other system of the body, disturbances can occur that lead to the development of diseases that are primarily characteristic of this system. One of the most common variants of such disorders are immunodeficiency states (IDS), characterized by the inability of the immune system to develop a normal immune response.
Immunodeficiency states (IDS) are a decrease in the functional activity of the main components of the immune system, leading to a violation of the immunological response, to a decrease or to the formation of an inadequate innate or adaptive immune response to a wide variety of pathogens and antigens, primarily to infectious ones.
It is necessary to distinguish the concept of immunodeficiency from the concept of immunological tolerance, in which the immune response is also reduced or absent. Unlike immunodeficiency, immunological tolerance is always specific, that is, it is formed only against one particular antigen or group of antigens. In immunodeficiency states, as a rule, immunological reactivity in general decreases.
The presence of IDS primarily leads to a decrease in the anti-infective defense of the body, which is clinically manifested in an increase in infectious morbidity.
For IDS with a predominant lesion of the B-cell link of adaptive immunity characterized by the occurrence of recurrent infections, including those caused by staphylococci, streptococci, pneumococci, pathogens of intestinal infections, etc.
In IDS with a predominant lesion of the T-cell link of adaptive immunity in addition to many bacterial infections, there are infectious diseases caused by such opportunistic flora as Candida fungi, viruses (herpes, cytomegalovirus, adenoviruses), pneumocystis, intracellular bacteria (mycobacteria, ureaplasmas, etc.). A tendency to generalization of tuberculosis infection is also characteristic, and the frequency of helminthiases is increased.
Primary IDS may also be due to defects in components of innate immunity. These defects can affect various parts of the innate immunity system: components and inhibitors of the complement system, defects in phagocytic cells, NK cells, receptors and transport molecules (TARs) involved in antigen processing. In connection with intensive research in this area, which is carried out using modern genetic and molecular biological methods, more and more new variants of primary IDS of innate immunity, as well as combined IDS of innate and adaptive immunity, are being identified. As a rule, primary IDS of innate immunity manifests itself in the form of a wide variety of infectious diseases, for example:
· Deficiency of complement components(C1, C4, C2; C3, C5-9, etc.) leads to recurrent generalized infections caused by encapsulated microorganisms (Neisseria meningitidis, pneumococcus, Haemophilus influenzae). Systemic lupus erythematosus is common.
· Defects in the phagocytic system clinically more often manifested in the form of infectious lesions of the skin and parenchymal organs, for example, caused by staphylococci and Klebsiella in chronic granulomatous disease.
The clinical manifestations of IDS also include hematological disorders (lymphadenopathy, leukemia), the occurrence of lesions of the gastrointestinal tract, which is largely due to a violation of the local immunity of the gastrointestinal tract, is characteristic. Often, IDS is accompanied by the occurrence of autoimmune and allergic diseases. A special place belongs to oncological diseases. Most often in patients with IDS there are hemoblastoses, lymphoproliferative diseases, Kaposi's sarcoma.
All immunodeficiencies are usually divided into primary, or congenital, and secondary, or acquired. Secondary IDS are not genetically determined, such defects in the immune system are acquired during life and are the result of any damaging effects on the immune system or the presence of other diseases.
Primary immunodeficiency states
Primary IDS are hereditary disorders of the innate and/or adaptive immune system associated with genetic defects in one or more components. Primary IDS of the adaptive immune system due to predominant defects in its B-cell and T-cell link, in many cases there are combined lesions of both links. most studied primary IDS of innate immunity are IDS caused by genetic defects in the complement system and the phagocytic system.
In the normal course of pregnancy in the intrauterine period of development, the child is in sterile conditions. Immediately after birth, his body begins to be populated by microorganisms. Since the microflora surrounding the person is not pathogenic, this colonization does not cause disease. Subsequently, a meeting with pathogenic microorganisms that the child has not yet met causes the development of the corresponding infectious disease. Each contact with a pathogen leads to the expansion of immunological memory and forms long-term immunity.
Two main components of innate immune defense, phagocytosis and complement, as well as two components of adaptive defense, B-cell (antibodies) and T-cell, are involved in protecting the body from the constant attacks of pathogenic viruses, bacteria, fungi, and protozoa. Each of these components can function independently, but most often they work in close complex interaction. Congenital defects of one of these links lead to a violation of the body's defenses as a whole and are clinically manifested in the form of various variants of primary immunodeficiencies.
At present, thanks to the identification of molecular disorders underlying the pathogenesis of many primary immunodeficiencies, and due to the great variability of the clinical picture, it has become clear that this type of pathology is much more common than previously thought.
Early diagnosis and adequate treatment are essential for patients with many forms of primary immunodeficiency. Without timely correct diagnosis and adequate treatment, the child dies, as a rule, during the first year of life. Each type of immunodeficiency has its own, already developed treatment tactics, and most of the primary defects of the immune system are currently subject to correction. Timely diagnosis and treatment of primary immunodeficiencies is one of the untapped reserves for reducing morbidity, mortality and disability in the population as a whole.
Primary CIDs usually have hereditary nature, therefore they are also called genetically determined IDS. Most often, primary CIDs are inherited by recessive type. In cases where genetic defects affect specific immunity factors (antibody formation, cellular forms of the adaptive immune response), they are also called specific IDS, in contrast to defects in nonspecific (innate) defense components (phagocytosis, complement system, etc.).
Sometimes the term “congenital” is used in relation to primary IDS, which implies the possibility of a disease based on hereditary defects that arose in the embryonic period, for example, a selective IgA deficiency as a result of intrauterine rubella.
Primary immunodeficiencies are diverse, and their description and classification in the literature is constantly changing. One of the first classifications of immunodeficiencies of the adaptive immune system is proposed in 1974 by Yu.M. Lopukhin and R.V. Petrov classification, which is based on the levels of genetic blocks at different stages of differentiation of T- and B-lymphocytes.
According to this classification, the whole variety of forms of IDS of the adaptive immune system is divided into three groups:
1. Primary IDS with a predominant lesion of the T-system (block II, VI).
2. Primary IDS with a predominant lesion of the B-system (block III, IV, V).
3. Combined primary IDS with simultaneous damage to the T-and B-systems (block I, blocks V + VI, etc.).
I
Stem III
hematopoietic
|
|
|
Figure 42. Pathogenetic scheme for the classification of primary IDS of the T- and B-systems of immunity
(R.V. Petrov, Yu.M. Lopukhin)
Block I. There are practically no hematopoietic stem cells. Generalized aplasia of hematopoietic and lymphoid tissue is characteristic. Neither T- nor B-lymphocytes are formed.
This block included severe combined immunological deficiency (SCID), which occurs in various forms.
Block II. Block in the early stages of development of intrathymic T-lymphocytes. Complete shutdown of cellular adaptive immunity. Such patients are characterized by the occurrence of severe recurrent viral infections, leading to death at an early (up to 1 year) age; high frequency of congenital anomalies of development; 100-1000 times higher risk of malignant tumors; the patient's body does not reject the foreign transplant.
This block is represented, in particular, by aplasia or hypoplasia of the thymus (DiGeorge syndrome).
Block III. This block is characterized by agammaglobulinemia linked to the X chromosome (boys get sick). In such children, antibodies are practically not produced, which leads primarily to frequent, severe bacterial infections. This variant of immunodeficiency is called Bruton's disease, it is usually diagnosed in the second half of life, since during the first months the child's body is protected by maternal antibodies that have passed through the placenta and are contained in mother's milk.
Block IV. The number of B-lymphocytes is somewhat reduced. Hypogammaglobulinemia with macroglobulinemia, since IgM synthesis is preserved or even increased, while the level of IgG and IgA is sharply reduced.
Block V. Selective deficiency of IgA. Due to the lack of the main secretory immunoglobulin, such children develop primarily infectious diseases associated with the mucous membranes of the nasopharynx, respiratory tract, gastrointestinal tract, and urogenital tract.
Block VI. It affects the processes of maturation and release of T-lymphocytes into peripheral lymphoid organs and the bloodstream. Combined pathology with a predominant lesion of the functions of T-cell immunity is characteristic.
Currently, more than 70 birth defects of both the innate and adaptive immune systems have been identified. Probably, as the methods of molecular immunodiagnostics improve, their number will grow. Endogenous, as a rule, genetically determined defects in one of the components of the immune system lead to a violation of the entire defense system of the body and are clinically detected as one of the forms of the primary immunodeficiency state. Since many types of cells and hundreds of molecules are involved in the complex immune response during the normal functioning of the immune system, the pathogenesis of clinical forms of primary IDS is based on numerous types of defects.
In recent years, the realization of the fact that the clinical manifestations of primary IDS can be observed not only in newborns, but also at a later age has come. This is due to the fact that a defect in one of the links of immunity may not manifest itself clinically in the form of increased infectious morbidity for some time, since all other components of immunity are preserved and compensate for this defect until their reserve capabilities are depleted.
Primary CIDs are relatively rare diseases, with an average incidence of 1/25,000 - 1/100,000, although selective IgA deficiency is much more common: 1/500 - 1/700 people. According to the European Register of Primary CIDs for 1997, the frequency of registered primary CDIs in Europe averaged 1/96,000 of the population, while in some countries it was significantly higher: 1/38,000 (UK); 1/12500 (Switzerland); 1/10000 (Sweden). Most likely, such differences are due to the level of development of medicine in different countries, and the real frequency of primary IDS is significantly higher than the published average figures.
Currently, the following simplified classification of primary CIDs is generally accepted:
I. Primary IDS with a predominant lesion of humoral adaptive immunity
1. X-linked agamma (hypogamma) globulinemia - Bruton's disease.
2. Common variable immunological deficiency (CVID) - common variable hypogammaglobulinemia.
3. Transient hypogammaglobulinemia in children (slow immunological start).
4. Selective deficiency of immunoglobulins (selective deficiency of IgA).
II. Primary IDS with a predominant lesion of T-cell adaptive immunity
1. DiGeorge's syndrome (hypo-, aplasia of the thymus).
2. Chronic mucocutaneous candidiasis.
III. Combined T- and B-immunodeficiencies of adaptive immunity
1. Severe combined immunological deficiency (SCID):
a) X-linked;
b) autosomal recessive.
2. Ataxia - telangiectasia (Louis-Barr syndrome).
3. Wiskott-Aldrich syndrome.
4. Immunodeficiency with elevated levels of IgM (linked to the X chromosome).
5. Immunodeficiency with dwarfism.
IV. Deficiencies of the phagocytic system
1. Chronic lymphogranulomatosis.
2. Chediak-Higassi syndrome.
3. Hyper-IgE syndrome (Job's syndrome).
V. Deficiencies of the complement system
1. Primary IDS due to deficiency of complement components.
2. Primary IDS caused by deficiency of complement system inactivators.
Primary IDS with a predominant lesion
humoral adaptive immunity
Bruton's disease
For the first time in 1952, the American pediatrician Bruton (Bruton) described an 8-year-old boy who suffered from various infectious diseases, who by the age of 4 had pneumonia 14 times, repeatedly otitis, sinusitis, suffered sepsis and meningitis. During the study, no antibodies were found in his blood serum. This was the first description of primary immunodeficiency in the scientific medical literature, singled out as an independent nosological form.
Bruton's disease is X-linked recessive and affects only boys. The disease is also referred to as X-linked agammaglobulinemia. Occurs with a frequency of 1/1000000 of the population. In the UK, the incidence of this immunodeficiency is 1/100,000.
Bruton's disease is based on a defect in the cytoplasmic tyrosine kinase enzyme, which transmits a signal to the nucleus of B-lymphocytes for its activation with subsequent transformation into a plasma cell. Thus, the synthesis of immunoglobulins becomes impossible.
The first signs of the disease appear from 7-8 months to 2-3 years. Transplacental transfer of immunoglobulins usually provides children with this disease with enough antibodies to avoid infections during the first few months of life. In the future, the lack of antibody synthesis leads, as a rule, to the occurrence of recurrent bacterial infections, mainly of the respiratory tract and skin. Usually pathogens are streptococci, staphylococci and gram-negative bacteria. Infections tend to spread, leading to septicemia and meningitis. However, these children remain resistant to viral infections, since cellular immunity is not impaired.
On objective examination find unusually small, smooth tonsils, small lymph nodes, the spleen is not enlarged. Pays special attention to the fact that the lymph nodes, liver and spleen do not respond with an increase in the infectious and inflammatory process in the body, which is an important diagnostic sign.
In the intestinal mucosa, plasma cells completely disappear, although normally they are contained there in a fairly large amount. In this regard, absorption disorders are observed, chronic enteritis often develops. In the intestine, abscesses are often detected with an accumulation of decaying leukocytes in the crypts of the intestine.
During laboratory examination in the peripheral blood there is a sharp decrease or absence of B-lymphocytes, low levels or the absence of all classes of immunoglobulins.
Treatment: permanent replacement therapy with immunoglobulins. Immunoglobulin preparations are administered intravenously at a dose of 200-600 mg/kg per month. In the event of an infectious disease, specific immunoglobulins (anti-staphylococcal, anti-streptococcal, anti-measles, etc.) are additionally administered.
Forecast: with a correct diagnosis and timely treatment, it is relatively favorable.
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Abstract on the topic:
"Bruton's Disease and Syndrome"
INTRODUCTION
1. IMMUNODEFICIENCY CONDITIONS
2. PRIMARY IMMUNODEFICIENCY
4. BRUTON'S DISEASE
4.1 Reasons
4.2 Pathophysiology
4.3 Symptoms and manifestations
4.4 Diagnostics
4.5 Treatment
4.6 Complications
4.7 Prevention
CONCLUSION
BIBLIOGRAPHY
INTRODUCTION
Immunodeficiency states (IDS) are persistent or temporary changes in the immune status caused by a defect in one or more mechanisms of the immune response to antigenic exposure.
1. IMMUNODEFICIENCY CONDITIONS
Classification of immunodeficiency states (IDS)
I. By origin, IDS are classified as follows:
1) primary (hereditary)
2) secondary (acquired)
A) physiological
B) pathological
II. According to the mechanisms of development, the following groups of IDS are distinguished:
The first mechanism is due
1) the absence or decrease in the number of auxiliary cells (ASCs), i.e. mononuclear cells - macrophages;
2) absence or decrease in the number of B-system lymphocytes;
3) the absence or decrease in the number of T-lymphocytes and their subpopulations of the T-system;
4) the absence or decrease in the number of cells of all the listed categories of ICS, i.e. combined forms of IDS;
5) the absence or reduction of ICS precursor cells due to the blockade of their maturation or destruction.
The second mechanism is associated with disturbances in the processes of regulation of cell differentiation of the B- and T-systems, as well as their cooperation and other cells in the implementation of the immune response.
III. According to the predominant damage to cells of various ICS systems, the following are distinguished:
1) B-dependent, or humoral IDS;
2) T-dependent, or cellular IDS;
3) phagocytic IDS (“A-dependent”);
4) combined IDS - damage to the cellular and humoral mechanisms of immunity (for example, B- and T-lymphocytes).
IV. Symptoms of impaired immunity may be associated with:
with the absence, insufficient number and / or limited function of ICS cells, as well as impaired phagocytosis and complement components. Various forms of IDS are encountered differently - most often the mechanisms of humoral immunity are damaged, less often violations of cellular and combined forms of immunity are found; other disorders, called non-specific immunodeficiency states (defects in the complement system and phagocytosis), are extremely rare:
Humoral disorders 75%
Combined forms of IDS 10-25%
Defects in cellular immunity 5-10%
Dysfunction of phagocytosis 1-2%
Complement protein defect
2. PRIMARY IMMUNODEFICIENCY
Primary immunodeficiencies (inherited and congenital defects of the immune system) are manifested by the development of infectious lesions of the body soon after birth, but may not have clinical manifestations until later in life.
Gene and chromosomal defects (numerous immunodeficiencies of different classes).
Secondary immunodeficiencies, or immunodeficiency states - immune deficiency develops due to endo- and exogenous effects on the normal immune system (for example, about 90% of all viral infections are accompanied by transient immunosuppression).
The causes of immunodeficiency states are diverse, they include:
Immunosuppressive drugs (including phenytoin, penicillamine, glucocorticoids).
Malnutrition, cavitary and membrane digestion, as well as intestinal absorption.
Drugs and toxic substances.
Radiation exposure, chemotherapy drugs.
The growth of malignant tumors.
Viruses (for example, HIV).
Conditions leading to protein loss (eg, nephrotic syndrome).
Hypoxia.
Hypothyroidism.
Asplenia.
Primary immunodeficiencies
In accordance with the WHO nomenclature, immunological deficiency of primary origin is commonly understood as a genetically determined inability of the body to realize one or another link of the immune response.
According to the classification proposed by WHO, depending on the predominant lesion of the B- and T-links of the immune system, the following primary specific immunodeficiency states are distinguished:
Combined, with simultaneous, to the same or different degree of severity, damage to the cellular (T) and humoral (B) parts of the immune system;
With predominant damage to the cellular (T) link of the immune system;
With predominant damage to the humoral (B) link of the immune system (pathology of antibody production).
Primary immunodeficiency states are, as a rule, rare. According to the international classification of diseases, several varieties are distinguished.
Severe combined T- and B-immunodeficiency is characterized by the development of a defect in immunocompetent structures at the earliest stages of development of the organism. Clinically it is the most difficult. The death of the organism can occur in utero, in the first days after birth due to the absence or sharp inhibition of stem and committed hematopoietic cells, as well as due to the absence or sharp inhibition of the thymus and other organs of the immune system, with a simultaneous and pronounced decrease in the number of both T-, as well as B-lymphocytes and plasma cells. It is clinically manifested by a sharp decrease in the reactivity and resistance of the body to the action of various pathogenic factors, including viruses, bacteria, fungi.
Variants of combined immunodeficiency states are caused by genetic defects affecting various lines of lymphocyte differentiation, as well as the early stages of their development, common to T- and B-populations.
Principles of treatment of primary IDS
Treatment depends on the type of primary immunological deficiency and includes targeted replacement therapy (transplantation of immunocompetent tissues, transplantation of embryonic thymus, bone marrow, administration of ready-made immunoglobulins - gglobulins, concentrated antibodies, direct blood transfusion from immunized donors, administration of thymus hormones).
Active immunization is used against frequent infections with the help of killed vaccines, sulfonamides are administered.
3. SECONDARY (ACQUIRED) IMMUNODEFICIENCY
Secondary, or acquired, immunodeficiencies are a violation of the body's immune defense, occurring in the postnatal period as a result of the action of external or internal factors, not associated with a primary lesion of the genetic apparatus.
Secondary immunodeficiencies are quite common.
List of major diseases accompanied by secondary immunodeficiency proposed by WHO experts.
1. Infectious diseases:
a) protozoal and helminthic diseases - malaria, toxoplasmosis, leishmaniasis, schistosomiasis, etc.;
b) bacterial infections - leprosy, tuberculosis, syphilis, pneumococcal, meningococcal infections;
c) viral infections - measles, rubella, influenza, mumps, chicken pox, acute and chronic hepatitis, etc.;
d) fungal infections - candidiasis, coccidioidomycosis, etc.
2. Nutritional disorders - malnutrition, cachexia, intestinal absorption disorders, etc.
3. Exogenous and endogenous intoxications - with renal and hepatic insufficiency, with herbicide poisoning, etc.
4. Tumors of lymphoreticular tissue (lympholeukemia, thymoma, lymphogranulomatosis), malignant neoplasms of any localization.
5. Metabolic diseases (diabetes mellitus, etc.).
6. Protein loss in intestinal diseases, nephrotic syndrome, burn disease, etc.
7. The action of various types of radiation, especially ionizing radiation.
8. Strong, prolonged stress effects.
9. The action of drugs (immunosuppressants, corticosteroids, antibiotics, sulfonamides, salicylates, etc.).
10. Blockade by immune complexes and antibodies of lymphocytes in some allergic and autoimmune diseases.
Secondary CIDs can be divided into 2 main forms:
1) systemic, developing as a result of systemic damage to immunogenesis (with radiation, toxic, infectious, stress lesions);
2) local, characterized by regional damage to immunocompetent cells (local disorders of the immune apparatus of the mucosa, skin and other tissues, developed as a result of local inflammatory, atrophic and hypoxic disorders).
Physiological immunodeficiencies are associated with specific causes.
The insufficiency of the immune system of newborns is characterized by the inferiority of the cellular and humoral links, as well as factors of nonspecific resistance.
A large number of lymphocytes in the peripheral blood of newborns is combined with a decrease in the functional activity of T- and B-lymphocytes. Synthesis of antibodies to the antigen occurs mainly due to IgM, the content of IgG and IgA is reduced and reaches the levels of adults only by the age of 11-14. There is a low phagocytic activity and opsonizing ability of blood. The complement level is reduced and normalizes by the 3-6th month of life.
The immune status of pregnant women is characterized by a decrease in the number and functions of T- and B-lymphocytes, which can be explained by an increase in the content and activity of T-suppressors. This is necessary to suppress the immune response to fetal alloantigens.
Insufficiency of the immune system during aging is manifested in a decrease in the activity of both humoral and cellular links. The levels of normal antibodies in the blood decrease, the ability to synthesize antibodies to antigenic stimulation decreases. These are mainly low avid IgM antibodies; the production of IgG and IgA antibodies is significantly reduced.
The synthesis of lgE antibodies is inhibited, so the severity of allergic reactions is mitigated. The cellular link of the immune system suffers significantly. The total number of peripheral blood lymphocytes decreases, as well as the relative and absolute number of T- and B-lymphocytes and their functional activity. The phagocytic activity of macrophages, neutrophilic granulocytes, the activity of complement, lysoim and the bactericidal activity of blood serum are reduced. Autoimmune reactions become more frequent and become more intense with age.
Pathological immunodeficiencies, as well as primary (hereditary), are characterized by an increase in the frequency (tens and even hundreds of times) of malignant tumors (reticulosarcoma, lymphosarcoma, etc.), especially leukemia, lymphomas. With secondary immunodeficiencies, as with primary ones, either humoral or cellular immunity may also suffer more. Thus, diseases accompanied by loss of proteins often lead to the development of humoral secondary immunodeficiency: burns, nephrotic syndrome, chronic nephritis, etc.
Severe viral infections (measles, influenza), fungal diseases (external and internal candidiasis) lead to the development of cellular secondary immunodeficiency.
The development of immunodeficiency can also occur through the fault of doctors who have long used organ transplantation and the treatment of various serious diseases, especially tumor, autoimmune (rheumatoid arthritis), inflammatory immunosuppressants:
Corticosteroid hormonal preparations;
Protein synthesis inhibitors;
antibiotics;
Antitumor cytostatics; purine and pyrimidine antimetabolites;
X-ray exposure, etc.
Principles of treatment of secondary IDS
1. Replacement therapy - the use of various immune preparations (g-globulin preparations, antitoxic, anti-influenza, anti-staphylococcal sera, etc.).
2. Correction of the effector link. It includes the impact on the immune system by pharmacological drugs that correct its work (decaris, diucefon, imuran, cyclophosphamide, etc.), hormones and mediators of the immune system (thymus drugs - thymosin, thymalin, T-activin, leukocyte interferons).
3. Removal of inhibitory factors that bind antibodies and block the effect of immunocorrection (hemosorption, plasmapheresis, hemodialysis, lymphopheresis, etc.).
Acquired immunodeficiency syndrome (AIDS) has become increasingly important among secondary immunodeficiencies in the last decade. The latter was first described in the scientific literature in 1981 by American scientists.
According to WHO, in recent years, the number of people with registered cases of AIDS has doubled every six months.
If earlier the number of HIV-infected people was 50-100 times more than the number of people who became ill, then already in 2001 the number of infected people reached 130 million, including 35 million people who had clinical manifestations of AIDS.
4. BRUTON'S DISEASE
Or Bruton's agammaglobulinemia, is a hereditary immunodeficiency that is caused by mutations in the gene encoding Bruton's tyrosine kinase. The disease was first described by Bruton in 1952, after whom the defective gene was named. Bruton's tyrosine kinases are critical in the maturation of pre-B cells to the differentiation of mature B cells. The Bruton tyrosine kinase gene was found on the long arm of the X chromosome in the band from Xq21.3 to Xq22; it consists of 37.5 kilobases with 19 exons that encode 659 amino acids; it is these amino acids that complete the formation of cytosolic tyrosine kinase. In this gene, 341 unique molecular events have already been recorded. In addition to mutations, a large number of variants or polymorphisms have been found.
bruton infectious immunodeficiency syndrome
4.1 Reasons
Mutations in the gene that underlie Bruton's disease interfere with the development and function of B-lymphocytes and their offspring. The basic idea is that in a healthy person, pre-B cells mature into lymphocytes. And in people with this disease, pre-B cells are either in small numbers, or they may have problems in functionality.
4.2 Pathophysiology
In the absence of a normal protein, B-lymphocytes do not differentiate or do not fully mature. Without mature B-lymphocytes, antibody-producing plasma cells will also be absent. As a consequence, the reticuloendothelial and lymphoid organs in which these cells proliferate, differentiate and store are poorly developed. The spleen, tonsils, adenoids, intestines, and peripheral lymph nodes may all be reduced in size or absent altogether in individuals with X-linked agammaglobulinemia.
Mutations in each of the gene regions can lead to this disease. The most common genetic event is the missense mutation. Most mutations result in protein truncation. These mutations affect critical residues in the cytoplasmic protein and are highly variable and evenly distributed throughout the molecule. However, disease severity cannot be predicted using specific mutations. Approximately one third of point mutations affect CGG sites, which typically contain the code for arginine residues.
This important protein is essential for the proliferation and differentiation of B-lymphocytes. Men with protein abnormalities have a complete or near complete absence of lymphocytes in their plasma cells.
4.3 Symptoms and manifestations
Recurrent infections begin in early childhood and persist throughout adulthood.
The most common manifestation of Bruton's disease or Bruton's agammaglobulinemia is an increase in susceptibility to encapsulated purulent bacteria, such as Haemophilus influenzae infections, and certain Pseudomonas species. Skin infections in patients with the disease are mainly caused by group A streptococci and staphylococci, and may present as impetigo, cellulitis, abscesses, or boils.
A form of eczema that resembles atopic dermatitis may be evident, along with an increase in cases of pyoderma gangrenosum, vitiligo, alopecia, and Stevens-Johnson syndrome (due to increased drug use). Other infections that are commonly present in this disease include enterovirus infections, sepsis, meningitis, and bacterial diarrhea. Patients may also have autoimmune diseases, thrombocytopenia, neutropenia, hemolytic anemia, and rheumatoid arthritis. Persistent enterovirus infections very rarely lead to fatal encephalitis or dermatomyositis-meningoencephalitis syndrome. In addition to neurological changes, the clinical manifestations of this syndrome include edema and an erythematous rash on the skin over the extensor joints.
Men may develop unusually severe and/or recurrent otitis media and pneumonia. The most common pathogen is S pneumonia, followed by influenza B virus, staphylococci, meningococci, and moraxella catarrhalis.
In children under 12 years of age, typical infections are caused by encapsulated bacteria. Common infections in this age group include recurrent pneumonia, sinusitis, and otitis media caused by S pneumonia and influenza B virus, which are difficult to treat at this age.
In adulthood, skin manifestations become more common, usually due to staphylococcus aureus and group A streptococcus. Otitis media is replaced by chronic sinusitis, and lung disease becomes a constant problem, both in a restrictive form and in an obstructive form.
Both infants and adults can have autoimmune diseases. Typically, these disorders include arthritis, autoimmune hemolytic anemias, autoimmune thrombocytopenia, autoimmune neutropenia, and inflammatory bowel disease. Inflammatory bowel disease can be very difficult to control and often contribute to chronic weight loss and malnutrition. Diarrhea is common and is caused by Giardia or Campylobacter species. Patients are prone to enterovirus infections, including poliovirus.
Physical examination
Male infants with Bruton's agammaglobulinemia may be physically smaller than male infants without the disease due to stunted growth and development from recurrent infections.
On examination, lymph nodes, tonsils, and other lymphoid tissues may be very small or absent.
The disease is diagnosed when the child repeatedly becomes ill in the presence of various infections, otitis media or staphylococcal skin infections and conjunctivitis that do not respond to antibiotic therapy. These severe infections may be associated with neutropenia.
Pyoderma gangrenosum, for example in the form of ulcers and cellulitis of the lower extremities, may also be seen in some patients.
4.4 Diagnostics
Early detection and diagnosis is essential to prevent early morbidity and death from systemic and pulmonary infections. The diagnosis is confirmed by abnormally low levels or no mature B lymphocytes, and low or no m heavy chain expression on the surface of the lymphocytes. On the other hand, the level of T-lymphocytes will be elevated. The ultimate determinant of disease is molecular analysis. Molecular analysis is also used for prenatal diagnosis, which can be done with chorionic villus sampling or amniocentesis when the mother is known to be a carrier of the defective gene. IgG levels less than 100 mg/dl support the diagnosis.
Rarely, the diagnosis can be made in adults in their second decade of life. This is believed to be due to a mutation in the protein rather than its complete absence.
Lab tests
The first step is to quantify IgG, IgM, immunoglobulin E (IgE), and immunoglobulin A (IgA). IgG levels should be measured first, preferably after 6 months of age when maternal IgG levels begin to decline. Second, IgG levels below 100 mg/dL are usually indicative of Bruton's disease. As a rule, IgM and IgA are not detected.
Once the antibody level has been determined to be abnormally low, confirmation of the diagnosis will be achieved by analysis of B-lymphocyte and T-lymphocyte markers. CD19+ B cell levels below 100 mg/dL. T cell assay values (CD4+ and CD8+) tend to increase.
Further analysis can be carried out by detecting IgG responses to T-dependent and T-independent antigens by immunization, for example after administration of unconjugated 23-valent pneumococcal vaccine or diphtheria, tetanus and H influenza type B vaccines.
Molecular genetic testing can establish an early confirmation of the diagnosis of congenital agammaglobulinemia.
Other tests
Lung function studies are central to the monitoring of lung disease. They should be done annually in children who can perform the test (usually from 5 years of age).
Procedures
Endoscopy and colonoscopy can be used to assess the extent and progression of inflammatory bowel disease. Bronchoscopy can be helpful in diagnosing and tracking chronic lung disease and infections.
4.5 Treatment
The introduction of immunoglobulin is the main method of controlling the disease. Typical doses of 400-600 mg/kg/month should be given every 3-4 weeks. Doses and intervals may be adjusted based on individual clinical responses. Therapy should begin at 10-12 weeks of age. Therapy with IgG should begin with a minimum level of 500-800 mg/dL. Therapy should begin at 10-12 weeks of age.
Antibacterial therapy Episodes of bacterial infectious complications in HHHG require antibiotic therapy, usually parenteral. A prerequisite for the success of antimicrobial therapy for HHHH is its simultaneous use with replacement therapy, however, in this case, the duration of antibiotic therapy is 2-3 times longer than the duration of standard antibiotic therapy for the corresponding inflammatory lesions in immunocompetent patients. Dosages of antibiotics remain age-related, but focused on severe and moderate infections.
Ceftriaxone may be used to treat chronic infections, pneumonia, or sepsis. If possible, clinicians should obtain antibiotic susceptibility cultures, as many organisms are already showing resistance to many antibiotics. Strep infections, in particular, may require ceftriaxone, cefotaxime, or vancomycin.
Bronchodilators, steroid inhalers, and regular lung function tests (at least 3-4 times a year) may be a necessary part of therapy in addition to antibiotics.
Chronic dermatological manifestations of atopic dermatitis and eczema are controlled by daily moisturizing of the skin with special lotions and steroids.
Surgery
Surgery may be limited to severe acute infections. The most common procedures include those used to treat patients with recurrent otitis media and those with chronic sinusitis.
4.6 Complications
Complications include chronic infections, enteroviral infections of the central nervous system, increased incidence of autoimmune diseases, and skin infections. Patients have an increased risk of developing lymphoma.
4.7 Prevention
Since Bruton's agammaglobulinemia is genetic in nature, its prevention is not possible. It is advisable to conduct genetic counseling when planning a pregnancy for couples with a family history of this disease.
CONCLUSION
Bruton's disease has a favorable prognosis with continued administration of immunoglobulins and adequate antibiotic therapy. Untimely use of antibacterial agents during exacerbation of infectious diseases can lead to rapid progression of the pathological process and death.
BIBLIOGRAPHY
1. Allergology and immunology: national guidelines / ed. R.M. Khaitova, N.I. Ilyina. - M.: GEOTAR-media, 2009. - 656 p.
2. Pediatrics, Shabalov N. P., St. Petersburg: Spetslit, 2005.
3. Immunology of childhood: a practical guide to childhood diseases, ed. A. Yu. Shcherbina and E. D. Pashanova. M.: Medpraktika-M, 2006.
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This enzyme takes part in the maturation and differentiation of B-lymphocytes (cells that produce antibodies). With its defect, mature B-lymphocytes are absent in the blood and plasmacytic cells (a type of B-lymphocytes that produce antibodies) and immunoglobulins (antibodies) are almost completely absent.
The disease was discovered by Ogden Bruton, a US pediatrician, in 1952 as one of the first immunodeficiency diseases. The patient was an 8-year-old child with immunosuppression, who over 4 years suffered 14 cases of pneumonia, meningitis, constantly suffered from sinusitis, otitis, and had sepsis. There were practically no antibodies in his blood plasma.
In 1993, scientists discovered the molecular genetic mechanism of pathology, the essence of which was the mutation of the gene encoding the tyrosine kinase enzyme. This enzyme is part of many cells of bone marrow origin (monocytes, erythroblasts, basophils, neutrophils), but its defect causes changes only in B-lymphocytes. Therefore, it received the name "Bruton's tyrosine kinase".
Inheritance
Bruton's agammaglobulinemia is characterized by an X-linked recessive type of inheritance: only boys are ill. Girls are not prone to the disease, even if they are heterozygous (a healthy gene compensates for a mutated X-recessive gene). The incidence of pathology is 10:25,000.
Clinical picture
The disease manifests itself in early infancy, most often at 3-4 months, and is associated with a decrease in the concentration of maternal antibodies in the infant's blood. The characteristic manifestations of the disease are constantly recurring infections provoked by Haemophilus influenzae, streptococci or pneumococci. When vaccinated against polio with a live vaccine, the development of the clinical form of poliomyelitis is possible. Vaccination against hepatitis B can provoke the development of its fulminant (overacute) form. Transferred acute intestinal infections can provoke the development of malabsorption syndrome - malabsorption in the small intestine, which is manifested by chronic diarrhea. Primary lesions occur in the lungs, paranasal sinuses.
- gastrointestinal tract;
- lungs and upper respiratory tract;
- joints;
- leather.
Often there are episodes of the following diseases:
- chronic diarrhea (due to the development of malabsorption);
- conjunctivitis;
- inflammation of the middle ear;
- dermatitis, pyoderma;
- bronchitis, pharyngitis;
- chronic sinusitis (inflammation of the paranasal sinuses);
There are characteristic lesions of the central nervous system in the form of encephalitis, meningitis, a tendency to autoimmune diseases, malignant neoplasms. Another common disease in X-linked agammaglobulinemia is rheumatic manifestations with a characteristic articular syndrome. Arthralgias affect large joints, are migratory in nature, and even with a long course do not provoke the development of radiographic changes in the joints.
Diagnosis
Early diagnosis is essential to prevent the development of secondary infections and reduce the mortality rate from the disease. The diagnosis is confirmed by an abnormally low level of mature B-cells of the lymphocytic series. There are no gamma globulins in the proteinogram. Plasma cells are critically reduced or absent in the bone marrow. In the general blood test, leukopenia or leukocytosis. The levels of IgA, IgM and IgG in blood plasma are greatly reduced. In a molecular genetic study, a defect in the long arm of the X chromosome is determined. This examination is recommended for all women in the family to determine the carriage of pathology.
Morphological changes primarily affect the spleen and lymph nodes (the cortical ball is narrowed in the lymph nodes and the follicles are underdeveloped). The lymphoid tissue of the entire body is either underdeveloped or absent, and the tonsils are also absent.
In rare cases, the diagnosis of Bruton's agammaglobulinemia is made in the second decade of a person's life. In such cases, we are not talking about the absence of tyrosine kinase, but mutations in its structure. Immunosuppression is not complete.
Differential diagnosis is important for Swiss-type agammaglobulinemia. In Bruton's disease, only B-lymphocytes will be absent in the blood, and in Swiss-type agammaglobulinemia, both T- and B-lymphocytes are absent.
Treatment
Pathogenetic treatment of agammaglobulinemia is substitution therapy. Patients are given intravenous or intramuscular injections of immunoglobulins - preparations containing antibodies that the patient's cells are unable to synthesize. This treatment is carried out for life. Symptomatic therapy consists of the introduction of antibiotics and, if necessary, detoxification therapy.
Forecast
The prognosis of untreated agammaglobulinemia is poor, the disease ends in death from severe infections. If the necessary therapy is carried out, then these patients remain prone to the development of autoimmune diseases, relapses of infections, the formation of chronic foci of infections, and a high risk of developing oncological pathology.
Prevention
The cause of Bruton's disease is a genetic defect in the enzyme, so it is impossible to prevent the onset of the disease. The main preventive measures are aimed at avoiding frequent recurrences of secondary infections and complications of the disease. These include:
Agammaglobulinemia
Agammaglobulinemia is a hereditary disease in which a severe primary immunodeficiency develops (a defect in the body's immune defense) with a pronounced decrease in the level of gamma globulins in the blood. The disease usually manifests itself in the first months and years of a child's life, when repeated bacterial infections begin to develop: otitis media, sinusitis, pneumonia, pyoderma, meningitis, sepsis. When examined in peripheral blood and bone marrow, serum immunoglobulins and B-cells are practically absent. Treatment for agammaglobulinemia is lifelong replacement therapy.
Agammaglobulinemia
Agammaglobulinemia (hereditary hypogammaglobulinemia, Bruton's disease) is a congenital defect in humoral immunity caused by mutations in the cell genome, which leads to insufficient synthesis of B-lymphocytes. As a result, the formation of immunoglobulins of all classes is disrupted, and their content in the blood is sharply reduced until it is completely absent. Low reactivity of the immune system leads to the development of severe recurrent purulent-inflammatory diseases of the upper respiratory tract, bronchi and lungs, gastrointestinal tract and meninges. Bruton's disease occurs exclusively in boys and occurs in about 1-5 out of a million newborns, regardless of race or ethnic group.
There are three forms of hereditary agammaglobulinemia:
- linked to the X chromosome (85% of all cases of congenital hypogammaglobulinemia, only boys are affected)
- autosomal recessive sporadic Swiss type (occurs in boys and girls)
- agammaglobulinemia linked to the X chromosome and growth hormone deficiency (very rare and only in boys)
Causes of agammaglobulinemia
X-linked form of hereditary agammaglobulinemia occurs due to damage to one of the genes of the X chromosome (located on Xq21.3-22.2). This gene is responsible for the synthesis of the enzyme tyrosine kinase, which is involved in the formation and differentiation of B cells. As a result of mutations in this gene and blocking the synthesis of Bruton's tyrosine kinase, the formation of humoral immunity is disrupted. In agammaglobulinemia, young forms (pre-B cells) are present in the bone marrow, and their further differentiation and entry into the bloodstream is impaired. Accordingly, the production of all classes of immunoglobulins is practically not produced, and the child's body becomes defenseless when pathogenic bacteria penetrate (most often these are streptococci, staphylococci and Pseudomonas aeruginosa).
A similar mechanism of disorders is noted in the case of another form of hereditary agammaglobulinemia - linked to the X chromosome and growth hormone deficiency. The autosomal recessive form develops as a result of mutations in several genes (µ-heavy chains, the λ5/14.1 gene, the adapter protein gene, and the IgA signal molecule gene).
Symptoms of agammaglobulinemia
Reduced reactivity of humoral immunity in agammaglobulinemia leads to the development of repeated purulent-inflammatory diseases already in the first year of a child's life (usually after cessation of breastfeeding - at 6-8 months). At the same time, protective antibodies from the mother no longer enter the child's body, and their own immunoglobulins are not produced.
By the age of 3-4 years, inflammatory processes become chronic with a tendency to generalization. Purulent infection with agammaglobulinemia can affect various organs and systems.
On the part of the ENT organs, purulent sinusitis, ethmoiditis, otitis media are more common, and purulent otitis media often develops in the first year of a child's life, and sinusitis - in 3-5 years. Of the diseases of the bronchopulmonary system, repeated bronchitis, pneumonia, lung abscesses are observed.
Often there is a lesion of the gastrointestinal tract with persistent diarrhea (diarrhea) caused by chronic infectious enterocolitis (the main pathogens are campylobacter, giardia, rotavirus). Impetigo, microbial eczema, recurrent furunculosis, abscesses and phlegmon are often found on the skin.
Often there is damage to the eyes (purulent conjunctivitis), the oral cavity (ulcerative stomatitis, gingivitis), the musculoskeletal system (osteomyelitis, purulent arthritis). The course of the disease can be complicated by the development of meningitis, viral encephalomyelitis, post-vaccination paralytic poliomyelitis, and sepsis.
The clinical picture of agammaglobulinemia is characterized by a combination of general symptoms observed during a purulent infection (high body temperature, chills, muscle pain and headache, general weakness, sleep and appetite disturbance, etc.) and signs of damage to a specific organ (cough, shortness of breath, difficulty nasal breathing, purulent discharge, diarrhea, etc.). Any infectious and somatic disease in a patient with agammaglobulinemia is severe, prolonged and accompanied by complications.
Diagnosis of agammaglobulinemia
During a clinical examination of a patient with agammaglobulinemia by an allergist-immunologist, signs of a purulent-inflammatory lesion of a particular organ (tissue) and symptoms confirming a reduced reactivity of the immune system are revealed: hypoplasia of the tonsils, a decrease in peripheral lymph nodes. Signs of a lag in the physical development of the child are also expressed.
A laboratory blood test reveals a pronounced decrease in the level of immunoglobulins in the immunogram (IgA and IgM histological examination of lymphoid tissue, germinal (embryonic) centers and plasma cells are absent.
Differential diagnosis of hereditary agammaglobulinemia is carried out with other primary and secondary immunodeficiency states (genetic disorders, HIV and cytomegalovirus infection, congenital rubella and toxoplasmosis, malignant neoplasms and systemic disorders, immunodeficiency due to drug intoxication, etc.).
Treatment of agammaglobulinemia
Lifelong replacement therapy with antibody-containing drugs is required. Usually, intravenous immunoglobulin is used, and in its absence, native plasma from healthy permanent donors. With the first diagnosis of agammaglobulinemia, substitution treatment is carried out in saturation mode until the level of IgG immunoglobulin reaches more than 400 mg / dl, after which, in the absence of an active purulent-inflammatory process in organs and tissues, one can proceed to maintenance therapy with the introduction of prophylactic doses of drugs containing immunoglobulins.
Any episode of a purulent bacterial infection, regardless of the location of the inflammatory process, requires adequate antibiotic therapy, which is performed simultaneously with substitution treatment. More often, with agammaglobulinemia, antibacterial agents from the group of cephalosporins, aminoglycosides, macrolides, as well as penicillin antibiotics are used. The duration of treatment in this case is several times higher than the standard for this disease.
Symptomatic treatment is carried out taking into account the specific lesion of a particular organ (washing the paranasal sinuses with antiseptics, performing a vibration massage of the chest and postural drainage for bronchitis and pneumonia, etc.).
Prognosis for agammaglobulinemia
If agammaglobulinemia is detected at an early age before the onset of severe complications, and replacement therapy adequate to the patient's condition is started in a timely manner, it is possible to maintain a normal lifestyle for many years. However, in most cases, the diagnosis of hereditary disorders of humoral immunity is carried out too late, when irreversible chronic purulent-inflammatory diseases of the organs and systems of the body have already developed. In this case, the prognosis for agammaglobulinemia is unfavorable.
Agammaglobulinemia or Bruton's disease
American pediatrician Ogden Bruton first described the disease in 1952. It was a boy suffering from Bruton's disease who was ill with various infectious diseases. Somewhere since the age of 4, he had pneumonia about 14 times, was treated for otitis media, meningitis, and sepsis. The analysis did not reveal antibodies. A group of scientists independently conducted an experiment in 1993, as a result of which it was proved that the X-linked chromosome arose as a result of a mutation in the gene for a non-receptor tyrosine kinase, later it became known as Bruton's tyrosine kinase.
Agammaglobulinemia (Bruton's disease) is a rather rare disease that mainly affects men, in rare cases it can be a woman. It is provoked at the genetic level, this disease is constrained with the X chromosome, resulting in a blockage in the growth of perfectly healthy immune pre-B cells, the so-called B-lymphocytes. This is directly related to the occurrence of defect tyrosine kinase. It takes part in the transduction of maturation of B-lymphocytes. The gene with the defect is located at the limit of the Xq21 chromosome. In order for immunoglobulins to fully protect the body from a variety of viruses and bacteria, sufficient production of them in the blood is required. But due to this disease, the production of immunoglobulins slows down or stops altogether. As a rule, the disease manifests itself when the child is more than six months old and it has the character of a chronic and recurrent disease of the bronchopulmonary apparatus. Allergic reactions to drugs often occur.
People who are exposed to this disease have a very high risk of infection with bacteria such as: Haemophilus influenzae, streptococci, pneumococci. Very often, as a result of concomitant infections, the gastrointestinal tract, lungs, skin, upper respiratory tract, and joints are affected. There is a high probability that relatives of the patient may also be affected by this disease, since Bruton's disease is hereditary.
The disease can be accompanied by a number of the following symptoms: diseases of the upper respiratory tract, skin lesions, conjunctivitis (inflammation of the eyeball), bronchitis, pneumonia, etc. Most often, these symptoms are observed in children aged 4 years. It can also be noted in a number of symptoms of bronchiectasis - bronchial dilatation and asthma attacks, and for no reason. During the period of illness, patients do not have an increase in lymph nodes, they do not suffer from hyperplasia of the tonsils, adenoids. Agammaglobulinemia occurs due to a mutation of the X chromosome gene encoding Bruton's tyrosine kinase (tkB, Btk - Brutontyrosinekinase). TKB plays a very important role in the development and maturation of B-lymphocytes. Antibodies and B-lymphocytes cannot form without TKB, so boys may have very small tonsils and lymph nodes that do not develop. This disease is usually prone to recurrent purulent infections of the lungs, paranasal sinuses, skin with encapsulated bacteria (Streptococcus pneumoniae, Hemophilus influenzae), and there is also a high probability of damage to the central nervous system, due to vaccination with live oral polio vaccine, Echo and Coxsackie viruses. These infections usually occur as progressive dermatomyositis, which may or may not be accompanied by encephalitis.
Diagnose by flow cytometry to measure the number of B-lymphocytes that circulate in the blood. Serum immunoelectrophoresis is performed, using nephelometry, the amount of immunoglobulins contained in the blood is measured.
During treatment, the patient is given intravenous immunoglobulin preparations 400 mg per 1 kg of body weight to strengthen and maintain the immune system as a whole, and antibiotics are also used, which inhibit and slow down the spread and development of various bacteria. Of particular importance is the timely conduct of antibiotic therapy, if the progression of the infectious process suddenly occurs, and with the replacement of antibiotics, it is desirable to treat bronchiectasis. With intravenous treatment, the well-being of patients suffering from agammaglobulinemia improves sufficiently. The prognosis for recovery will be favorable if adequate and appropriate treatment is prescribed in the early stages of the disease. But if treatment is not started on time, there is a high probability that severe concomitant diseases can lead to the death of the patient.
Hereditary hypogammaglobulinemia requires parenteral antimicrobial therapy. For best results, it should be carried out simultaneously with concomitant or replacement therapy. The duration of antibiotic treatment is approximately days, but can increase up to 21 days. The most common antimicrobial drugs that are used in the treatment are cephalosporins, aminoglycosides, sulfonamides and penicillin antibiotics.
From the medical history
A case that was recorded in 1985. A male baby was born with a normal weight of 3500 g and a height of 53 cm, the birth was successful without deviations from the norm. The mother, being pregnant, suffered ARVI at 4 months. In the first month of life, the boy had conjunctivitis. After 1 year, the boy becomes a regular patient with a diagnosis of acute respiratory infections, bronchitis with a suffocating cough, with stable enterocolitis. At 2 years old, the child suffers pneumococcal meningitis. And he will face generalized edema at the age of 5 years, there is also increased shortness of breath, cyanosis. He has pain in his joints and in his heart. The liver and spleen were examined and their size increased by several times, the baby was urgently hospitalized. After a thorough examination in the laboratory, tests were taken, in which they found severe lymphocytopenia, as well as traces of immunoglobulins of all classes. Before hospitalization, antibiotic treatment was carried out to eliminate the focus of infections. In view of this disease, intravenous immunoglobulin was used, including antibiotic therapy. The patient's condition improved after appropriate treatment, there were almost no foci of infections left in the body. And a year after the illness, the patient was hospitalized again, but with bilateral conjunctivitis, as well as bronchopneumonia. Treatment was repeated with intravenous gamma globulin, simultaneously with antibiotic therapy. After the treatment, the patient was discharged with the following recommendations: continuous intake of gamma globulin under careful monitoring of blood levels. At the same time, the boy's parents are absolutely healthy.
Bruton's disease
One of the diseases that are inherited is characterized by agammaglobulinemia. Also known as agammaglobulinemia, Bruton's disease. This is one of the types of immunodeficiency. The disease is caused by a mutation in the gene encoding Bruton's tyrosine kinase. Agammaglobulinemia is characterized by the almost complete absence of antibodies in the blood that protect the human body from various bacteria and viral infections.
A bit of history
The first mention of the disease agammaglobulinemia, which was recorded in the United States by pediatrician Ogden Bruton, dates back to 1952. The doctor happened to meet an eight-year-old boy who, over the last four years of his life, had been ill with pneumonia fourteen times, had sinusitis and otitis media, suffered meningitis and blood sepsis. After a medical examination, no antibodies were found in the child's blood plasma.
In 1993, scientists, after conducting research, announced the causes of this disease. It turned out that X-linked agammaglobulinemia arises due to mutations in the gene for non-receptor tyrosine kinase, which was later called Bruton's tyrosine kinase. Photos of Bruton's disease were also presented.
Rare genetic mutations
Characteristic features of the disease
What is its peculiarity, how is Bruton's disease characterized? The presence of a mutated protein in the gene is the cause of the disease. Bruton's disease is inherited through an X-linked recessive type. Agammaglobulinemia is diagnosed only in boys, as they have an XY chromosome in their DNA. Having XX chromosomes, girls cannot get sick. Even if the females are heterozygous, then the gene with the presence of the mutation is replaced by the normal one.
Bruton's disease can be detected in one boy out of 250 thousand. Women can only be carriers of such a gene and pass it on to their sons.
The first symptoms of Bruton's disease begin before the age of 1 year, at about 3-6 months. During this period, the level of antibodies received from the mother in the baby's blood falls. What will be the manifestations and signs of agammaglobulinemia?
One of the main signs of Bruton's disease is the presence of chronic and recurrent infections caused by pyogenic bacteria. These can be microorganisms of pneumococci, staphylococci, Haemophilus influenzae and others. They have the ability to cause purulent inflammation.
The disease of the child is associated with the ENT organs, the baby may have problems with the skin and subcutaneous fat, disorders in the gastrointestinal tract, respiratory tract.
A boy with Bruton's disease may be physically smaller than his peers who are healthy. This is provoked by slow growth and recurrent infections.
He can get pneumonia, otitis media, sinusitis, meningitis, encephalitis. In a child suffering from agammaglobulinemia, allergies, autoimmune diseases, oncological pathologies, disorders in the structure of connective tissue (arthritis of large joints) are most often present. Vaccination against polio or hepatitis B leads to the development of these diseases. During the examination, the small size of the lymph nodes and tonsils, or their complete absence, can be detected.
Diagnostics
In order to identify Bruton's disease, a number of studies need to be carried out. It is recommended that agammaglobulinemia be diagnosed as early as possible to prevent the development of secondary infections and reduce the number of deaths from the disease. Mandatory examination of the patient, laboratory tests, x-rays.
The results of blood tests carried out in laboratory conditions show that there are no gamma globulins in the proteinogram. There is a hundred-fold decrease in the levels of Ig A and Ig, and Ig G - ten times. Less than the norm and the number of B-lymphocytes. At the stage of pregnancy planning, it is recommended to conduct a molecular genetic examination, which will detect the presence of a defective gene encoding non-receptor tyrosine kinase.
Radiography can reveal the absence of tonsils or their underdevelopment, the pathology of the lymph nodes, as well as changes in the spleen. Children over the age of five need to have lung function tests (bronchoscopy) done in order to diagnose a violation in their work in time. Endoscopy and colonoscopy are also used to assess the extent and progression of inflammatory bowel disease.
Treatment and prognosis
The whole essence of the treatment of Bruton's disease is supportive therapy, that is, gamma globulin preparations are administered to the patient. The dose is selected individually, but the result should be a serum concentration of 3 grams / liter.
Throughout life, medications are used to maintain the functioning of the immune system. That is, the patient is injected with antibodies that his body cannot produce. Therapy should begin at 9 to 12 weeks of age. With exacerbations of infectious diseases, antibiotics are used to remove the symptoms of Bruton's disease. Preparations based on penicillins, cephalosporins, sulfonamides can be used.
With constant therapy with immunoglobulins and antibiotics, agammaglobulinemia has a favorable prognosis. If you violate the mode of administration of gamma globulins and untimely use of antibacterial drugs, this can lead to serious consequences. There is a possibility of the development of a pathological process or the onset of death.
Prevention of agammaglobulinemia
Bruton's disease is characterized by a genetic nature, so prevention is not possible here. If there is a family history of this disease, it is recommended that couples, when planning conception, undergo an examination and consult a geneticist.
If a child has agammaglobulinemia, measures must be taken to prevent complications and recurrence of infections.
- use only inactivated vaccine;
- compliance with adequate treatment of diseases;
- prophylactic, long-term antibiotic therapy.
Agammaglobulinemia Bruton. Symptoms, diagnosis, treatment
Bruton's disease, or Bruton's agammaglobulinemia, is an inherited immunodeficiency that is caused by mutations in the gene encoding Bruton's tyrosine kinase. The disease was first described by Bruton in 1952, after whom the defective gene was named. Bruton's tyrosine kinases are critical in the maturation of pre-B cells to the differentiation of mature B cells. The Bruton tyrosine kinase gene was found on the long arm of the X chromosome in the band from Xq21.3 to Xq22; it consists of 37.5 kilobases with 19 exons that encode 659 amino acids; it is these amino acids that complete the formation of cytosolic tyrosine kinase. In this gene, 341 unique molecular events have already been recorded. In addition to mutations, a large number of variants or polymorphisms have been found.
Agammaglobulinemia Bruton. Causes
Mutations in the gene that underlie Bruton's disease interfere with the development and function of B-lymphocytes and their offspring. The basic idea is that in a healthy person, pre-B cells mature into lymphocytes. And in people with this disease, pre-B cells are either in small numbers, or they may have problems in functionality.
Agammaglobulinemia Bruton. Pathophysiology
In the absence of a normal protein, B-lymphocytes do not differentiate or do not fully mature. Without mature B-lymphocytes, antibody-producing plasma cells will also be absent. As a consequence, the reticuloendothelial and lymphoid organs in which these cells proliferate, differentiate, and store are poorly developed. The spleen, tonsils, adenoids, intestines, and peripheral lymph nodes may all be reduced in size or absent altogether in individuals with X-linked agammaglobulinemia.
Mutations in each of the gene regions can lead to this disease. The most common genetic event is the missense mutation. Most mutations result in protein truncation. These mutations affect critical residues in the cytoplasmic protein and are highly variable and evenly distributed throughout the molecule. However, disease severity cannot be predicted using specific mutations. Approximately one third of point mutations affect CGG sites, which typically contain the code for arginine residues.
This important protein is essential for the proliferation and differentiation of B-lymphocytes. Men with protein abnormalities have a complete or near complete absence of lymphocytes in their plasma cells.
Agammaglobulinemia Bruton. Symptoms and manifestations
Recurrent infections begin in early childhood and persist throughout adulthood.
The most common manifestation of Bruton's disease or Bruton's agammaglobulinemia is an increase in susceptibility to encapsulated purulent bacteria, such as Haemophilus influenzae infections, and certain Pseudomonas species. Skin infections in patients with the disease are mainly caused by group A streptococci and staphylococci, and may present as impetigo, cellulitis, abscesses, or boils.
A form of eczema that resembles atopic dermatitis may be evident, along with an increase in cases of pyoderma gangrenosum, vitiligo, alopecia, and Stevens-Johnson syndrome (due to increased drug use). Other infections that are commonly present in this disease include enterovirus infections, sepsis, meningitis, and bacterial diarrhea. Patients may also have autoimmune diseases, thrombocytopenia, neutropenia, hemolytic anemia, and rheumatoid arthritis. Persistent enterovirus infections very rarely lead to fatal encephalitis or dermatomyositis-meningoencephalitis syndrome. In addition to neurological changes, the clinical manifestations of this syndrome include edema and an erythematous rash on the skin over the extensor joints.
Men may develop unusually severe and/or recurrent otitis media and pneumonia. The most common pathogen is S pneumonia, followed by influenza B virus, staphylococci, meningococci, and moraxella catarrhalis.
In children under 12 years of age, typical infections are caused by encapsulated bacteria. Common infections in this age group include recurrent pneumonia, sinusitis, and otitis media caused by S pneumonia and influenza B virus, which are difficult to treat at this age.
In adulthood, skin manifestations become more common, usually due to staphylococcus aureus and group A streptococcus. Otitis media is replaced by chronic sinusitis, and lung disease becomes a constant problem, both in a restrictive form and in an obstructive form.
Both infants and adults can have autoimmune diseases. Typically, these disorders include arthritis, autoimmune hemolytic anemias, autoimmune thrombocytopenia, autoimmune neutropenia, and inflammatory bowel disease. Inflammatory bowel disease can be very difficult to control and often contribute to chronic weight loss and malnutrition. Diarrhea is common and is caused by Giardia or Campylobacter species. Patients are prone to enterovirus infections, including poliovirus.
Male infants with Bruton's agammaglobulinemia may be physically smaller than male infants without the disease due to stunted growth and development from recurrent infections.
On examination, lymph nodes, tonsils, and other lymphoid tissues may be very small or absent.
The disease is diagnosed when the child repeatedly becomes ill in the presence of various infections, otitis media or staphylococcal skin infections and conjunctivitis that do not respond to antibiotic therapy. These severe infections may be associated with neutropenia.
Pyoderma gangrenosum, for example in the form of ulcers and cellulitis of the lower extremities, may also be seen in some patients.
Agammaglobulinemia Bruton. Diagnostics
Early detection and diagnosis is essential to prevent early morbidity and death from systemic and pulmonary infections. Diagnosis is confirmed by abnormally low levels or no mature B lymphocytes, and low or no μ heavy chain expression on the lymphocyte surface. On the other hand, the level of T-lymphocytes will be elevated. The ultimate determinant of disease is molecular analysis. Molecular analysis is also used for prenatal diagnosis, which can be done with chorionic villus sampling or amniocentesis when the mother is known to be a carrier of the defective gene. IgG levels less than 100 mg/dl support the diagnosis.
Rarely, the diagnosis can be made in adults in their second decade of life. This is believed to be due to a mutation in the protein rather than its complete absence.
The first step is to quantify IgG, IgM, immunoglobulin E (IgE), and immunoglobulin A (IgA). IgG levels should be measured first, preferably after 6 months of age when maternal IgG levels begin to decline. Second, IgG levels below 100 mg/dL are usually indicative of Bruton's disease. As a rule, IgM and IgA are not detected.
Once the antibody level has been determined to be abnormally low, confirmation of the diagnosis will be achieved by analysis of B-lymphocyte and T-lymphocyte markers. CD19+ B cell levels below 100 mg/dL. T cell assay values (CD4+ and CD8+) tend to increase.
Further analysis can be carried out by detecting IgG responses to T-dependent and T-independent antigens, by immunization, for example after administration of unconjugated 23-valent pneumococcal vaccine or diphtheria, tetanus and H influenza type B vaccines.
Molecular genetic testing can establish an early confirmation of the diagnosis of congenital agammaglobulinemia.
Lung function studies are central to the monitoring of lung disease. They should be done annually in children who can perform the test (usually from 5 years of age).
Endoscopy and colonoscopy can be used to assess the extent and progression of inflammatory bowel disease. Bronchoscopy can be helpful in diagnosing and tracking chronic lung disease and infections.
Agammaglobulinemia Bruton. Treatment
There is no cure for this disease. The introduction of immunoglobulin is the main method of controlling the disease. Typical doses of mg/kg/month should be administered every 3-4 weeks. Doses and intervals may be adjusted based on individual clinical responses. Therapy should begin at the age of weeks. Therapy with IgG should start at a minimum level of mg/dl. Therapy should begin at the age of weeks.
Ceftriaxone may be used to treat chronic infections, pneumonia, or sepsis. If possible, clinicians should obtain antibiotic susceptibility cultures, as many organisms are already showing resistance to many antibiotics. Strep infections, in particular, may require ceftriaxone, cefotaxime, or vancomycin.
Bronchodilators, steroid inhalers, and regular lung function tests (at least 3-4 times a year) may be a necessary part of therapy in addition to antibiotics.
Chronic dermatological manifestations of atopic dermatitis and eczema are controlled by daily moisturizing of the skin with special lotions and steroids.
Surgery may be limited to severe acute infections. The most common procedures include those used to treat patients with recurrent otitis media and those with chronic sinusitis.
Agammaglobulinemia Bruton. Complications
Complications include chronic infections, enteroviral infections of the central nervous system, increased incidence of autoimmune diseases, and skin infections. Patients have an increased risk of developing lymphoma.
Agammaglobulinemia Bruton. Forecast
Most patients can survive until the end of their fourth decade of life. The prognosis is good as long as patients are diagnosed and treated early with regular intravenous gamma globulin therapy.
Serious enterovirus infections and chronic lung disease are often fatal in adulthood.
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- This is a hereditary disease in which a severe primary immunodeficiency develops (a defect in the body's immune defense) with a pronounced decrease in the level of gamma globulins in the blood. The disease usually manifests itself in the first months and years of a child's life, when repeated bacterial infections begin to develop: otitis media, sinusitis, pneumonia, pyoderma, meningitis, sepsis. When examined in peripheral blood and bone marrow, serum immunoglobulins and B-cells are practically absent. Treatment for agammaglobulinemia is lifelong replacement therapy.
ICD-10
D80 Immunodeficiencies with predominant antibody deficiency
General information
Agammaglobulinemia (hereditary hypogammaglobulinemia, Bruton's disease) is a congenital defect in humoral immunity caused by mutations in the cell genome, which leads to insufficient synthesis of B-lymphocytes. As a result, the formation of immunoglobulins of all classes is disrupted, and their content in the blood decreases sharply until it is completely absent, and primary immunodeficiency develops. Low reactivity of the immune system leads to the development of severe recurrent purulent-inflammatory diseases of the upper respiratory tract, bronchi and lungs, gastrointestinal tract and meninges. Bruton's disease occurs exclusively in boys and occurs in about 1-5 out of a million newborns, regardless of race or ethnic group.
Causes
X-linked form of hereditary agammaglobulinemia occurs due to damage to one of the genes of the X chromosome (located on Xq21.3-22.2). This gene is responsible for the synthesis of the enzyme tyrosine kinase, which is involved in the formation and differentiation of B cells. As a result of mutations in this gene and blocking the synthesis of Bruton's tyrosine kinase, the formation of humoral immunity is disrupted. In agammaglobulinemia, young forms (pre-B cells) are present in the bone marrow, and their further differentiation and entry into the bloodstream is impaired. Accordingly, the production of all classes of immunoglobulins is practically not produced, and the child's body becomes defenseless when pathogenic bacteria penetrate (most often these are streptococci, staphylococci and Pseudomonas aeruginosa).
A similar mechanism of disorders is noted in the case of another form of hereditary agammaglobulinemia - linked to the X chromosome and growth hormone deficiency. The autosomal recessive form develops as a result of mutations in several genes (µ-heavy chains, the λ5/14.1 gene, the adapter protein gene, and the IgA signal molecule gene).
Classification
There are three forms of hereditary agammaglobulinemia:
- linked to the X chromosome (85% of all cases of congenital hypogammaglobulinemia, only boys are affected)
- autosomal recessive sporadic Swiss type (occurs in boys and girls)
- agammaglobulinemia linked to the X chromosome and growth hormone deficiency (very rare and only in boys)
Symptoms of agammaglobulinemia
Reduced reactivity of humoral immunity in agammaglobulinemia leads to the development of repeated purulent-inflammatory diseases already in the first year of a child's life (usually after cessation of breastfeeding - at 6-8 months). At the same time, protective antibodies from the mother no longer enter the child's body, and their own immunoglobulins are not produced. By the age of 3-4 years, inflammatory processes become chronic with a tendency to generalization. Purulent infection with agammaglobulinemia can affect various organs and systems.
On the part of the ENT organs, purulent sinusitis, ethmoiditis, otitis media are not uncommon, and purulent otitis media often develops in the first year of a child's life, and sinusitis - in 3-5 years. Of the diseases of the bronchopulmonary system, repeated bronchitis, pneumonia, lung abscesses are observed.
Often there is a lesion of the gastrointestinal tract with persistent diarrhea (diarrhea) caused by chronic infectious enterocolitis (the main pathogens are campylobacter, giardia, rotavirus). Impetigo, microbial eczema, recurrent furunculosis, abscesses and phlegmon are found on the skin.
It is not uncommon to damage the eyes (purulent conjunctivitis), the oral cavity (ulcerative stomatitis, gingivitis), the musculoskeletal system (osteomyelitis, purulent arthritis). In general, the clinical picture of agammaglobulinemia is characterized by a combination of general symptoms observed during a purulent infection (high body temperature, chills, muscle pain and headache, general weakness, sleep and appetite disturbance, etc.) and signs of damage to a specific organ (cough, shortness of breath , difficulty in nasal breathing, purulent discharge, diarrhea, etc.).
Complications
Any infectious and somatic disease in a patient with immunodeficiency is severe, prolonged and accompanied by complications. The severe course of agammaglobulinemia can be complicated by the development of meningitis, viral encephalomyelitis, post-vaccination paralytic poliomyelitis, and sepsis. Against the background of the disease, the likelihood of developing autoimmune and oncological diseases is increased. The death of patients often occurs from infectious-toxic shock.
Diagnostics
During a clinical examination of the patient by an allergist-immunologist, signs of a purulent-inflammatory lesion of a particular organ (tissue) and symptoms confirming a reduced reactivity of the immune system are revealed: tonsil hypoplasia, a decrease in peripheral lymph nodes. Signs of a lag in the physical development of the child are also expressed.
A laboratory blood test reveals a pronounced decrease in the level of immunoglobulins in the immunogram (IgA and IgM< 20 мг/дл – снижение в сто раз, IgG < 200 мг/дл – в десять раз) или их полное отсутствие. В периферической крови обнаруживается глубокий дефицит B-клеток (менее 1%), в костном мозге практически отсутствуют плазмоциты. Что касается клеточного иммунитета, то содержание T-лимфоцитов может быть в норме. При гистологическом исследовании лимфоидной ткани герминативные (зародышевые) центры и плазматические клетки отсутствуют.
Differential diagnosis of hereditary agammaglobulinemia is carried out with other primary and secondary immunodeficiency conditions (genetic disorders, HIV and cytomegalovirus infection, congenital rubella and toxoplasmosis, malignant neoplasms and systemic disorders, immunodeficiency due to drug intoxication, etc.).
Treatment of agammaglobulinemia
Lifelong replacement therapy with antibody-containing drugs is required. Usually, intravenous immunoglobulin is used, and in its absence, native plasma from healthy permanent donors. With the first diagnosis of agammaglobulinemia, substitution treatment is carried out in saturation mode until the level of IgG immunoglobulin reaches more than 400 mg / dl, after which, in the absence of an active purulent-inflammatory process in organs and tissues, one can proceed to maintenance therapy with the introduction of prophylactic doses of drugs containing immunoglobulins.
Any episode of a purulent bacterial infection, regardless of the location of the inflammatory process, requires adequate antibiotic therapy, which is performed simultaneously with substitution treatment. More often, with agammaglobulinemia, antibacterial agents from the group of cephalosporins, aminoglycosides, macrolides, as well as penicillin antibiotics are used. The duration of treatment in this case is several times higher than the standard for this disease.
Symptomatic treatment is carried out taking into account the specific lesion of a particular organ (washing the paranasal sinuses with antiseptics, performing a vibration massage of the chest and postural drainage for bronchitis and pneumonia, etc.).
Forecast
If agammaglobulinemia is detected at an early age before the onset of severe complications, and replacement therapy adequate to the patient's condition is started in a timely manner, it is possible to maintain a normal lifestyle for many years. However, in most cases, the diagnosis of hereditary disorders of humoral immunity is carried out too late, when irreversible chronic purulent-inflammatory diseases of the organs and systems of the body have already developed. In this case, the prognosis for agammaglobulinemia is unfavorable.
Bruton's disease is a variant of primary humoral immunodeficiency caused by mutations in the gene encoding Bruton's tyrosine kinase. The disease is characterized by impaired maturation of B-lymphocytes and an almost complete absence of plasma cells and immunoglobulins.
Clinic. The first symptoms of the disease appear, as a rule, at the age of less than 1 year, most often after 3-4 months of life. This is due to a gradual decrease in the amount of antibodies received from the mother. Patients suffer from recurrent infections caused by pneumococci, staphylococci, and other pyogenic bacteria. Vaccination against poliomyelitis can be complicated by poliomyelitis, etc. The lungs, paranasal sinuses are primarily affected. The clinical picture shows fever, malabsorption syndrome, conjunctivitis, CNS lesions (encephalitis), autoimmune diseases, and malignant neoplasms.
Laboratory diagnostics. A laboratory blood test reveals the absence of a gamma globulin fraction in the proteinogram. The level of Ig A and Ig M is reduced by 100 times, and the level of Ig G - by 10 times. The number of B-lymphocytes is reduced. The number of plasma cells in the bone marrow is reduced to the point of complete absence. In the peripheral blood, leukopenia or leukocytosis are noted. The thymus is not changed, but the structure of the lymph nodes and spleen is disturbed.
Treatment - replacement therapy with gammaglobulin, plasma. Gamma globulin must be administered throughout life. During periods of exacerbation, antibiotics are used, more often penicillins and cephalosporins in normal dosages.
4. Selective IgA deficiency
Pathogenesis. Selective IgA deficiency is diagnosed in patients older than 4 years whose serum IgA level is less than 0.07 g/l with normal serum IgG and IgM levels. Partial IgA deficiency is detected if the IgA level is reduced by more than 2 times compared to the age norm. The defect occurs as a result of the disruption of isotype switching to IgA or the maturation of IgA producers. It has been shown that with IgA deficiency, there is a violation of the processes of terminal differentiation of B-lymphocytes that synthesize IgA, but are not able to secrete it.
Clinical manifestations. Recurrent and chronic diseases of the respiratory tract and ENT organs (otitis media, sinusitis, bronchitis, pneumonia), and the sensitivity of patients to viral rather than bacterial infectious diseases is more pronounced. Respiratory infections rarely become chronic. A characteristic feature of this type of immunodeficiency is the presence of diseases of the digestive tract.
Treatment. Patients with asymptomatic permanent treatment is not required. Patients with manifestations of infectious diseases are prescribed antibiotics for prophylactic purposes. Therapeutic measures are reduced to symptomatic therapy of infectious, allergic and autoimmune diseases. Immunotropic drugs are prescribed mainly in connection with the manifestation of increased infectious morbidity.
5. Hyper - igm syndrome.
Pathogenesis. According to the clinical picture, the syndrome is similar to the syndrome of hypogammaglobulinemia. The difference lies in the increased content of IgM in such patients against the background of low concentrations of IgG and IgA or their complete absence. The syndrome is linked to the X chromosome. Its development is associated with a mutation in the gene encoding the production of a specific CD40L protein on activated T-lymphocytes.
Clinic. Patients are hypersensitive to opportunistic infections, especially to pneumocystis pneumonia and enteritis caused by Criptosporidium. Patients are prone to autoimmune diseases: hemolytic anemia, thrombocytopenic purpura, neutropenia.
Treatment. Symptomatic. Antimicrobial therapy. The use of immunoglobulin preparations for intravenous administration. Lifelong replacement therapy with antibody-containing drugs.
