Immunodeficiencies due to combined defects of the cellular and humoral parts of the immune system

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A. Primary

Single and / or multiple mutations of the genes responsible for the development of the immune response (receptors of lymphocytes, main complexion antigens, adhesion, cytokine synthesis, etc.) can lead to combined immunodeficiency of the cellular and humoral parts of the immune system.

1. Severe combined immunodeficiency (TCID). There are 2 variants of inheritance of TCID:

A) linked to the X chromosome (about 50% of cases). The basis of pathogenesis is mutations of genes encoding the general g chain of receptors of cytokines (IL-2, 7, 15, etc.), necessary for differentiation and maturation of T and B-lymphocyte. Mutations are recessive, so the pathology is manifested only in men and women heterozygous for this indication. The onset of manifestations is already in the first 3 months of life. Characterized by: pertussis-like cough, korepodobnoj a rash, not giving in to treatment by a diarrhea, visceral candidiasis. Coripiform rash is associated with a reaction of incompatibility to the maternal lymphocytes that enter the bloodstream of the child through the placenta. The clinical picture is also characterized by a delay in weight gain up to grade II - III hypotrophy, anxiety, anorexia, high sensitivity to infections, including opportunistic pathogens; Pneumocystis pneumonia, malabsorption, progressive encephalitis, generalization in vaccination with live vaccines. The generalization of the infectious process (viruses, bacteria, fungi, protozoa, live vaccine strains) leads to the death of the child. In the septic process, deterioration of the condition and death of the child can occur within 24 hours. . Laboratory indicators - extremely low values of T-Lymphocyte and NK cells and an elevated level of B-LYMPHOCYTE. However, B-LYMPHOCYTE is not able to produce antibodies due to the lack of intercellular interactions between T and B-LYMPHOCYTE.

B) autosomal recessive. About half of the cases are the cause of adenosine deaminase deficiency, which leads to the formation of metabolites of purine bases, toxic to immunocompetent cells (see above). Laboratory indicators - lymphopenia is even more pronounced (in comparison with the previous type of inheritance), the number of T and B-LYMPHOCYTE <500 mm3. The number of NK cells is also reduced, but their function is preserved. The characteristic clinical signs (in addition to those indicated in a) are various deformations of the skeleton, in particular the chest.

The prognosis for all variants of TCID is unfavorable - death occurs either in the first months or in the first 2 years of life. Treatment is not very effective and is directed, first of all, to arresting the infectious process (antibacterial therapy, detoxification, immunoglobulin replacement therapy, etc.). The greatest hope for TCID is associated with transplantation of bone marrow purified from T-lymphocytes in combination with immunoglobulin replacement therapy. Promising methods of treatment of these conditions are bone marrow transplantation and gene therapy (for the first version of TCID) and enzyme replacement therapy (for the second version of TCID).

2. Combined immunodeficiency (CID)

A distinctive feature is the higher (in comparison with TCID) values of T-Lymphocyte, as well as low levels of antibodies (in the case of TCID antibodies are practically absent). There are 2 variants of CID

A) Wiskott-Aldrich Syndrome. It occurs in boys. The pathogenetic basis is a violation of the structure of cell membranes of lymphocytes, processes of tromocytogenesis, IgM deficiency, IgE excess. This immunodeficiency reveals a specific protein WASP (Wiscott-Aldrich syndrome protein), which is associated with a violation of the transmission of intercellular signals and the lack of response to thymus-dependent antigens. The disease begins in early childhood, sometimes in the newborn period with petechiae, ecchymosis, bleeding from the mucous membranes (similar to thrombocytopenic purpura), then the persistent recurrent eczema and infectious syndrome (purulent otitis, pyoderma, pneumonia, colitis) necessarily join. It is characteristic to join allergic diseases (more often atopic dermatitis), lagging physical development up to dystrophy, multiple abscesses. Hemorrhagic syndrome often leads to a lethal outcome (intestinal bleeding, cerebral hemorrhage, parenchymal organs). With cerebral bleeding - paralysis, neurological symptoms. This syndrome is characterized by a tendency to lymphoproliferative diseases. In a laboratory study, the most characteristic is thrombocytopenia with impaired platelet characteristics, low IgM level, a sharp increase (sometimes hundreds of times) of IgE, an increase in IgA and IgD, a normal IgG content, a progressive decrease in T-lymphocytes and an increase in B cells, a decrease in the specific response to Polysaccharide antigens, which makes individuals with this pathology susceptible to infections caused by encapsulated bacteria. Complications often occur in the form of septicemia (30%) and meningitis. The outlook is unfavorable. In severe cases, death occurs in the first 10 years of life. In less severe cases, life expectancy is longer, since dysfunction of T cells at the early stages of development is less pronounced. Nevertheless, it is characterized by a steady tendency towards progression, which is clinically manifested in the tendency to develop malignant neoplasms of the lymphatic system (lymphogranulomatosis, leukemia). Treatment: replacement therapy with immunoglobulins, thymus preparations, correction of hemorrhagic syndrome, antibacterial therapy. Chicken pox often ends in a fatal outcome. Bone marrow transplantation is considered to be a promising method of treatment. If this procedure is not possible, splenectomy is advisable to prevent a steady decline in platelets and the development of a hemorrhagic syndrome.

B) Ataxia-telangiectasia (Louis-Bar syndrome) - There is no explicit sexual benefit. The disease begins at the age of 2 - 3 years and later. Pathogenetic basis is loss of cerebellar function (death of Purkinje cells), subcortical ganglia, diencephalic cortex of the hemispheres, hypoplasia of the thymus, lymph nodes, spleen; Deficiency of IgA, cellular immunity. The disease begins with a disorder of gait and balance, often in combination with hyperkinesis, symptoms of parkinsonism, slowing down of voluntary movements, progressive dementia. Such patients are often diagnosed with cerebral palsy or Friedreich ataxia. A significant difference between the Louis-Bar syndrome and these diseases is the appearance, either simultaneously with neurological symptoms, or soon after it, of characteristic changes in the skin and vessels (telangiectasias): a freckle-like rash on the face, whose color resembles "coffee with milk", a characteristic "butterfly" on the face After exposure to the sun, vitiligo and hyperpigmentation; Telangiectasia on conjunctiva of the eyeball, more in the zone close to the eyelids. Teleangiectasias are associated with IgA deficiency. Neurological symptoms and vascular disorders are the main clinical markers, which determine the name of the syndrome (ataxia - telangiectasia). Against this background, the development of severe recurrent and sluggish infections is typical: pneumonia, sinusitis, sinusitis, etc. Pneumonia usually leads to a decrease in the function of external respiration, the development of atelectasis, bronchiectasis, pneumosclerosis. Characteristic for the syndrome of Louis-Bar is a high predisposition to oncopathology and sensitivity to radiation. At laboratory research absence or sharp depression of IgA, depression of IgG2, IgG4, IgE is defined; Decrease in the number of lymphocytes and their response to stimulation of PHA. The prognosis is unfavorable: at an early age, death comes from the generalization of infectious processes; In the distant period - from malignant neoplasms. At the same time, cases of surviving patients up to 40-50 years are described. The treatment is similar to that described in TCID.

B. Secondary

1. Chronic non-specific lung diseases can cause combined immunodeficiency (mainly humoral) due to the polyclonal activation of immunocompetent cells and the enhancement of suppressor factors as a result of prolonged action of inflammatory factors and toxins.

2. Deficiency of microelements causes combined immunodeficiency (mainly cellular) due to the disturbance of signaling pathways involved in gene reanimation, protein activation and contributing to the formation of different populations of Lymphocyte. For example, a deficiency of Zn can lead to defects in the development of T cells, a decrease in the activity of T and NK cells, and neutrophils. Deficiency of Cu - hypofunction of T-cells, defects of phagocytosis.

3. Fasting leads to total (mainly cellular) immunodeficiency due to lymphopenia and hypofunction of immunocompetent cells as a result of protein deficiency and energy supply disorders of cells.

4. Chemotherapy and irradiation lead to combined immunodeficiency due to cytotoxic effects on immunocompetent cells, induction of their apoptosis or necrosis, and suppression of lympho- and myelopoiesis.