CHAPTER 3. IMMUNODEFICIENCY STATES
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 in any other system of the body, disturbances which lead to the development of diseases (that are primarily
characteristic of this system) may occur. 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.
IDS with a predominant lesion of the B-cell component of adaptive immunity is 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 component of adaptive immunity, in addition to many bacterial infections, occurrence of infectious
diseases may be caused by such opportunistic flora as Candida fungi, viruses (herpes, cytomegalovirus, adenoviruses), pneumocysts, intracellular bacteria
(mycobacteria, ureaplasmas and 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 (TAPs) 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 manifest 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 for this condition.
● Defects in the phagocytic system are clinically more often manifested in the form of infectious lesions of the skin and parenchymal organs, for
example, lesions 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. 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 immunodeficiency states 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 is due to predominant defects in its B-cell and T-cell link(content, in many cases there are combined lesions of both
links. The 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 IDS, as a rule, are hereditary in nature, so they are also called genetically determined IDS. Most often, primary CIDs are inherited in a recessive
manner. 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 immunodeficiency states are diverse, and their description and classification in the literature are 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 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.).
VI
Tt Tp
II
Intrathymic Peripheral
I
СК T-lyphocytes T-lymphocytes
III
Hematopoietic IV V
stem cell
IgM B
IgG IgA B B
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 slightly reduced. Hypogammaglobulinemia with macroglobulinemia, since IgM synthesis is preserved or
even increased, while the level of IgG and IgA is sharply reduced.
Block V. There is a 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 IDS-s 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 IDS-s for 1997, the frequency of registered primary IDS-s 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 IDSs 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 muco-cutaneous 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.
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 in any other system of the body, disturbances which lead to the development of diseases (that are primarily
characteristic of this system) may occur. 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.
IDS with a predominant lesion of the B-cell component of adaptive immunity is 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 component of adaptive immunity, in addition to many bacterial infections, occurrence of infectious
diseases may be caused by such opportunistic flora as Candida fungi, viruses (herpes, cytomegalovirus, adenoviruses), pneumocysts, intracellular bacteria
(mycobacteria, ureaplasmas and 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 (TAPs) 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 manifest 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 for this condition.
● Defects in the phagocytic system are clinically more often manifested in the form of infectious lesions of the skin and parenchymal organs, for
example, lesions 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. 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 immunodeficiency states 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 is due to predominant defects in its B-cell and T-cell link(content, in many cases there are combined lesions of both
links. The 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 IDS, as a rule, are hereditary in nature, so they are also called genetically determined IDS. Most often, primary CIDs are inherited in a recessive
manner. 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 immunodeficiency states are diverse, and their description and classification in the literature are 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 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.).
VI
Tt Tp
II
Intrathymic Peripheral
I
СК T-lyphocytes T-lymphocytes
III
Hematopoietic IV V
stem cell
IgM B
IgG IgA B B
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 slightly reduced. Hypogammaglobulinemia with macroglobulinemia, since IgM synthesis is preserved or
even increased, while the level of IgG and IgA is sharply reduced.
Block V. There is a 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 IDS-s 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 IDS-s for 1997, the frequency of registered primary IDS-s 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 IDSs 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 muco-cutaneous 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.
