Primary immunodeficiencies
Primary immunodeficiencies arise as a result of genetic disorders in the development and maturation of cells of the immune system, which increases the sensitivity of the organism to infections.
Classification of primary immunodeficiencies
■ Primary defects in AT products.
□ Agammaglobulinemia linked to the chromosome.
□ Deficiency of IgA and IgG with an increase in IgM synthesis.
□ Total variable immunodeficiency.
□ Selective deficiency of AT with normal Ig level.
. □ Selective deficiency of subclasses of IgG.
□ Selective IgA deficiency.
□ Transitional hypogammaglobulinemia in newborns.
□ Lymphoproliferative syndrome linked to the chromosome X.
■ Primary disorders of cellular immunity leading to combined immunodeficiency.
□ Thymic hypoplasia.
□ Multiple combined immune deficiencies associated with the X chromosome;
□ Deficiency of adenosine deaminase.
□ Defective expression of HLA Ag.
□ Deficiency of T-cell antigen receptors.
□ Cellular immunodeficiency with normal Ig content.
■ Immunodeficiencies associated with other defects.
□ Chronic granulomatous disease( Wiskott-Aldrich syndrome).
□ Ataxia-telangiectasia.
X-linked agammaglobulinemia( Bruton's disease) - immunodeficiency due to blockage of B-cell differentiation( * 300300, Xq21.2-q22, AGMX1 gene defect encoding tyrosine kinase, key regulator of B-cell development, K).The severity of immunodeficiency can vary from the total absence of all Ig and B-lymphocyte isotypes in the blood to moderate depression. The number of T-lymphocytes and their functional activity( cellular immunity) is normal. The disease manifests persistent purulent infections in children 9-12 months after birth.
Deficiency of IgA and IgG with increasing IgM synthesis, or M hyperimmo-noglobulinemia syndrome,( * 308230, Xq26, ligand defect to CD40).
A genetic defect is the presence of a mutation in the CD40 ligand gene( CD40L) expressed on activated T lymphocytes. Defective expression of CD40L results in the absence of a secondary immune response( Ig synthesis by B lymphocytes) on T-dependent Ar. In the serum, very high concentrations of IgM( up to 10 g / l), undetectable IgA and IgE and very low IgG( less than 1.5 g / l) are detected. The number of B-lymphocytes may be normal( but they are represented only by B-lymphocytes bearing IgM).Clinically, the disease is manifested by purulent infections, increased risk of autoimmune pathology.
General Variable Immunodeficiency. The term "general variable immunodeficiency" is used to describe immunodeficiency states caused by a violation of the ability of B-lymphocytes to transform into plasma cells. This is a very heterogeneous group of diseases with different types of inheritance. The most frequent clinical manifestations are recurrent pulmonary infections, herpes, giardiasis, meningo-encephalitis;characterized by a high incidence of malignant tumors.
Selective deficiency of AT with normal Ig level is characterized by selective deficiency of immune response to certain Ar( tetanus, diphtheria, group Ar blood, pneumococcal polysaccharides and bacteriophages).Most of these people are healthy, and only some suffer from repeated infections. Concentrations of IgM and IgG in the serum are usually normal, in some patients the concentration of IgG2 can be reduced. Reduction of the immune response to polysaccharide Ar is often detected in patients with sickle-cell anemia, asplenia, Wiskott-Aldrich syndrome, Di-Georgi.
The selective deficiency of subclasses of IgG is selective with a decrease in the concentration of IgG1-4 in the blood at a normal level of total IgG.Deficiency of IgG2 can be accompanied by a decrease in the concentration of IgA in the blood and is often associated with recurrent infections. With the deficiency of IgGj, IgG3 and IgG4, sinusitis, pneumonia and bronchiectasis develop. Simultaneous deficiency of IgG2 and IgG3 is often combined with juvenile diabetes mellitus, idiopathic thrombocytopenic purpura and SLE.
Selective IgA deficiency in the European population is detected at a frequency of 1 to 500. IgA concentration in serum is less than 0.1 g / l. Presumably, the defect develops as a result of impaired maturation of IgA-producing B-lymphocytes. Clinical manifestations may be absent,
in some cases, frequent infectious diseases, atopy, inflammatory diseases of the gastrointestinal tract, autoimmune pathology.
Transient hypogammaglobulinemia in newborns - delay in the formation of their own ATs in infants( normally begin to be actively synthesized from the 3rd to 12th month of life), which is associated with delayed differentiation of T and B lymphocytes. With transient hypogammaglobulinemia, the onset of production of intrinsic ATs can be delayed up to 3 years of age. Some patients report an increased incidence of infectious diseases.
Lymphoproliferative syndrome linked to chromosome X is characterized by a selective inability to respond to infection with the Epstein-Barr virus, leading to serious, and sometimes fatal, infectious diseases and acquired immunodeficiency. The genes responsible for this disease have not yet been identified. T-cell immunity is slightly impaired, an inverted CD4 / CD8 ratio and a decreased proliferative response to mitogens are observed, in most patients the number of NK cells is reduced.
DiGordji anomaly is a genetic syndrome characterized by heart defects, cleft palate, hypocalcemia, facial skeletal pathology and T-cell immunodeficiency due to thymic hypoplasia. Most cases of the disease( 80-90%) are associated with deletion of the locus 22q11.2( ED).
Multiple combined immunodeficiencies are a group of diseases, both with autosomal recessive and with X-linked inheritance. The most frequent X-linked form( # 312863, IL-2 receptor-chain mutations, K is recessive) is due to a defect in the receptor for IL-2, which leads to a disruption in the development and differentiation of T-lymphocytes and, to a lesser extent, B-lymphocytes. In the study of blood in these patients noted lymphopenia, mainly due to T-lymphocytes. Since the first months of life, candidiasis of the oral mucosa, recurrent septic states, interstitial pneumonia, otitis, chronic diarrhea develop.
Adenosine deaminase deficiency( * 102700, 20q12-q13.11, ADA gene defect).As a result of the decrease in the activity of adenosine deaminase, metabolites( in particular, deoxyadenosine triphosphate) accumulate in the lymphoid cells. Deoxyadenosine triphosphate depresses the enzyme ribonucleotide reductase necessary for DNA synthesis, as a result of which the proliferation of lymphocytes is impaired. A significant decrease in the number of T-lymphocytes is detected in the blood. Clinical manifestations of immunodeficiency are similar to those of multiple combined immune deficiencies, in addition, skeletal anomalies are possible.
Defective expression of HLA( nude lymphocyte syndrome) is a group of immunodeficiencies, characterized by the absence of HLA I and II class expression on the surface of T and B lymphocytes, monocytes and other mononuclear phagocytes, which may be associated with pathology of a number ofgenes( # 209920, 600005, 600006, 601863, 601861, defects of the genes MHC2TA, RFX5, RFXAP, C2TA, all p).Clinically, the disease manifests itself as persistent diarrhea, malabsorption syndrome, candidiasis, bacterial infections, interstitial pneumonia. In laboratory studies of
, mammoglobulinemia, absence of Ag-stimulated proliferation of lymphocytes and cell-mediated cytotoxicity are detected.
Deficiency of T-cell antigen receptors is characterized by the absence of T-lymphocytes of antigenic receptors( included in the group of CD3 proteins of the complex).Clinical manifestations are variable. Deficits and anomalies in the structure of the y and e chains of CD3 are described.
Cellular immunodeficiency with normal Ig content( He-zelof syndrome, * 242700, p) is characterized by a decrease in T-cell function and a decrease in the number of CD4 and CD8 lymphocytes;the concentration of Ig in the serum is within the normal range. Clinical manifestations - kandi-doses of skin and mucous membranes, herpetic infection, chronic pneumonia, sepsis and urinary tract infections.
Chronic granulomatous disease( Wiskott-Aldrich syndrome) manifests itself in infancy or early childhood with eczema, recurrent and resistant to treatment of infections, and thrombocytopenia. All three types of inheritance are described: basically X-linked( * 301000, Xp11.23-p11.22, WAS, IMD2, THC), less recessive( 277970, p) and dominant( * 600903).In the study of the immune status, progressive lymphopenia is detected, mainly due to T-lymphocytes, the number of B-lymphocytes is increased, the blood concentration of IgM decreases significantly, and the levels of IgA and IgE increase. To the initial clinical manifestations can be attached autoimmune diseases( vasculitis, glomerulonephritis) and malignant lymphorrhythmic tumors.
Ataxia-telangiectasia( 208900, ATM gene, 11q22-q23, p) is characterized by progressive cerebellar ataxia, the appearance of small telangiectasies( on earlobes and sclera) and, in most patients, recurrent infections. The disease is associated with defects of DNA-then-isomerase, leading to disturbances in the regulation of the cell cycle. In lymphocytes, frequent breakdowns of chromosomes, inversions and translocations, affecting sections of the genes of the T-cell receptor and the complex of Ig genes, are revealed. In the study of immune status, a variable decrease in the concentrations in the blood of IgG2, IgG4, IgA and IgE may be absent altogether. This form of immunodeficiency is characterized by a high concentration of AFP in the blood.