Immunodeficiencies due to insufficiency of the humoral part of the immune system

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Characteristic signs of weakening in the functioning of the humoral link of the immune system is the inability of the body to produce antibodies that have the ability to: a) inactivate bacteria and toxins in the body fluids - IgM and IgG; b) prevent the penetration of pathogens through the mucous membranes of the respiratory and digestive tracts - IgA. As a consequence, patients with this form of immunodeficiency are susceptible to pyogenic infections caused by encapsulated microorganisms (Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus and various types of Pseudomonas). At the same time, insufficiency of the humoral link of the immune system does not have a significant effect on the susceptibility to diseases caused by protozoa, fungi intracellular bacterial pathogens (Mycobacteria) and viruses. An exception to this rule are diseases caused by enteroviruses.

The mechanism of increased susceptibility to pyogenic infections in persons with disorders of the humoral link of the immune system is due to the fact that pyogenic bacteria having a lipopolysaccharide shell can not be receptor-mediated by neutrophils and macrophages. That is why this type of pathogen deviates from the cellular factors of natural resistance. Effective elimination of this type of pathogens from the body entirely depends on their preliminary opsonization (antibody, complement protein), which ensures their subsequent phagocytosis. The inadequacy of antibody production in the mucous membranes (IgA) reduces the likelihood of neutralization of viruses, which makes people with an impaired humoral immune response susceptible to enterovirus infections.

A. Primary immunodeficiency of the humoral unit

1. Transient agammaglobulinemia in children - develops between 1 and 2 years of life, due to the gradual destruction of maternal IgGs that have passed through the placental barrier. It is the result of blockade of B-LYMPHOCYTE maturation in plasma cells (normal serum IgM and IgA level and reduced IgG level) due to intercellular interactions between T and B-LYMPHOCYTE. The result of the failure of the humoral link of the immune system are frequent infections of the upper respiratory tract and middle ear. The IgG level usually normalizes to 2-4 years of a child's life.

2. Agammaglobulinemia, linked to the X chromosome (Bruton's disease) - manifests a sharp decrease (up to complete absence) in the serum of all classes of immunoglobulins. It is the result of blockade of differentiation and maturation of pre-B cells, which leads to the absence of B-Lymphocyte and plasma cells in the body. The reason for the absence of antibody producing cells is the mutation of the gene encoding tyrosine kinase btk (Bruton's tyrosine kinase), which normally normalizes the expression of the corresponding receptor on pre-B cells, which makes them sensitive to factors that ensure their subsequent differentiation. The T-LYMPHOCYTE function is not violated. Symptoms of the disease begin to develop after the expiration of the life of the parent antibodies (IgG) that have passed the placental barrier. Therapy of this disease can consist in the introduction of immunoglobulins and antibiotic therapy in the presence of bacterial infections.

3. General variable immunodeficiency - manifested in a significant decrease in the level of serum immunoglobulins against a background of normal B-LYMPHOCYTE content, the absence of germinal centers and plasma cells in the lymph nodes and spleen. It is the result of blockade of maturation of B-Lymphocyte in plasma cells (ie, the maturation block occurs at a later stage in comparison with agammaglobulinemia linked to the X chromosome). Symptoms of the disease are typical for this group - frequent sinusitis, otitis, respiratory disease caused by encapsulated pathogens). Nevertheless, the symptoms develop gradually and reach a maximum by 15-20 years of life. People with common variable immunodeficiency have a tendency to develop autoimmune diseases, chronic respiratory diseases, diarrhea and malabsorption. 1/3 of patients with variable immunodeficiency have also disorders of the cell link. Principles of therapy of persons with this pathology are similar to those of persons with hypogammaglobulinemia linked to the X chromosome.

4. Selective deficiencies of IgA, IgM and subclasses of IgG

Among the selective deficiencies of immunoglobulin isotypes, IgA deficiency is the most frequent. With this pathology in the body there are B-lymphocytes carrying membrane IgA (ie, the process of switching isotypes is carried out). Nevertheless, the formation of plasma cells secreting IgA does not occur. It is the result of a block of differentiation of mature B-Lymphocyte in IgA-producing plasma cells. Perhaps the cause of this defect is the inadequacy of signaling from T-lymphocytes, other microcirculation cells and a deficiency of the factors produced by them, especially those that contribute to the production of IgA (TGF-b and IL-5). Persons with this form of immunodeficiency are most sensitive to the development of chronic respiratory diseases. In 1/3 patients with a slight decrease in the level of IgA, these symptoms are absent, which is probably due to the compensatory capabilities of the humoral immune system in the presence of a normal level of IgG and IgM in the serum of this group of people. In individuals with a significant decrease in IgA, frequent recurrences of respiratory and gastrointestinal tract infections, an increased incidence of bronchial asthma, and autoimmune diseases are observed. It should be noted that the pronounced IgA deficiency in these patients predisposes to the production of anti-IgA antibodies, which can play a role in the development of anaphylactic reactions in the transfusion of blood or its components. Therefore, for transfusions, only "purified" erythrocytes or sera from patients with a similar pathology are suitable. Individuals with moderate selective IgA deficiency do not need specific treatment, since normal levels of IgG and IgM "close" the gap in the immune response. The introduction of IgA is not effective because of: a) a short halymphocyte-life, b) its inability to penetrate the mucous membranes, c) the risk of developing anaphylactic reactions.

Selective IgG deficiency can affect all subclasses of IgG and can occur against a background of normal or even elevated levels of total IgG in serum. Normally, IgG1 and IgG2 are 70% and 20% of total serum IgG. The production of each subclass of IgG depends on the type and structure of the antigen. For example, the synthesis of IgG1 and IgG3 occurs on protein antigens, while IgG2 is produced by antigens that include polysaccharide and / or carbohydrate components. Consequently, in individuals with selective IgG2 deficiency there is a greater likelihood of developing sinusitis, otitis and pneumonia, the causative agents of which are bacteria whose liposuction is lipopolysaccharides (S. pneumoniae, H. influenzae type b and N. meningitidis). Children with a moderate form of selective IgG deficiencies are advisable prophylactic courses of antibiotic therapy, and with severe form-intravenous immunoglobulin.

5. Hyper-IgM syndrome. The basis of the pathology in this case is a violation of the expression on the T-cells of the molecule CD154 (CD40L), which is a ligand of the CD40 receptor on the surface of B cells. As a result, a signal responsible, in particular, for switching immunoglobulin isotypes is not transmitted to the B cell, and only IgM antibodies are formed. In this disease, the function of T cells that do not receive signals of the opposite direction is also defective due to the absence of the CD40L molecule. Formally located in the group of immunodeficiencies of the humoral unit, hyper-IgM-syndrome is actually a consequence of violations of the T-cell link of the immune system. Persons with hyper-IgM syndrome are prone to frequent recurrent diseases of the respiratory tract, tonsillitis, sinusitis, otitis. A number of people have a tendency to develop opportunistic infections (for example, pneumonia caused by Pneumocystis carinii). It is known that normally this pathogen is effectively eliminated from the body by macrophages receiving the CD40-mediated activation signal from the T-cells side.

B. Secondary immunodeficiency of the humoral link

Reduction of the level of immunoglobulins of different classes can be due to their losses through the gastrointestinal and / or urogenital tracts. For example, in persons with nephrotic syndrome, due to increased filtration in urine, a significant increase in IgA and IgG levels is observed. The serum IgM content is not changed, because of its large size, preventing the passage of IgM glomerular membrane.