Primary immunodeficiency is a group of pathological conditions, mainly of an innate nature, in which there is a violation of the work of certain parts of the immune system. Symptoms vary, depend on the type of disease, mainly there is an increased susceptibility to bacterial and viral agents. Pathology is diagnosed by means of laboratory research methods, molecular genetic analysis (with hereditary forms), studying the patient’s anamnesis. Treatment includes substitution therapy, bone marrow transplantation, and infection control measures. Some forms of immunodeficiency are incurable.
Primary immunodeficiency has been actively studied since the 50s of the XX century – after the first condition of this type was described by the American pediatrician Ogden Bruton in 1952, which received his name. At the moment, more than 25 varieties of pathology are known, most of them are genetically determined diseases. The occurrence of different types of immunodeficiency ranges from 1:1,000 to 1:5,000,000. The vast majority of patients are children under the age of 5 years, mild forms may be detected for the first time in adults. In some cases, an immunodeficiency condition is detected only by the results of laboratory tests. Some types of the disease are combined with numerous malformations, have a high lethality.
Immunodeficiency conditions of a primary nature begin to form at the stage of intrauterine development under the influence of various factors. Often they are combined with other defects (dystrophies, abnormalities of tissues and organs, fermentopathies). There are three main groups of congenital pathologies of the immune system based on etiological characteristics:
- Due to genetic mutations. The vast majority of diseases occur due to defects in the genes responsible for the development and differentiation of immunocompetent cells. Autosomal recessive or gender-linked inheritance is usually noted. There is a small proportion of spontaneous and germinative mutations.
- As a result of teratogenic exposure. The effect of toxins of various nature on the fetus can lead to innate problems with immunity. Immunodeficiency often accompanies malformations caused by TORCH infections.
- Unclear etiology. This group includes cases when it is not possible to identify the cause of the weakness of the immune system. These may be unexplored genetic anomalies, weak or unidentified teratogenic effects.
The study of the causes, pathogenesis and search for methods of treatment of primary immunodeficiency continues. There are already indications of a whole group of similar conditions that do not manifest themselves as pronounced symptoms, but under certain conditions can provoke infectious complications.
The mechanism of development of immunity deficiency depends on the etiological factor. In the most common genetic variant of pathology, due to mutation of some genes, the proteins encoded by them are either not synthesized or have a defect. Depending on the functions of the protein, the processes of lymphocyte formation, their transformation (into T- or B-cells, plasmocytes, natural killers) or the release of antibodies and cytokines are disrupted. Some forms of the disease are characterized by a decrease in the activity of macrophages or a complex insufficiency of many links of immunity. Varieties of immunodeficiency caused by the influence of teratogenic factors most often occur due to damage to the rudiments of immune organs – thymus, bone marrow, lymphoid tissue. The underdevelopment of individual elements of the immune system leads to its imbalance, which is manifested by the weakening of the body’s defenses. Primary immunodeficiency of any genesis causes the development of frequent fungal, bacterial or viral infections.
The number of types of primary immunodeficiency is quite large. This is due to the complexity of the immune system and the close integration of its individual links, as a result of which the disruption or “shutdown” of one part contributes to the weakening of the entire body’s defenses as a whole. To date, a complex branched classification of such conditions has been developed. It consists of five main groups of immunodeficiency, each of which includes several of the most common types of pathology. In a simplified version , this classification can be represented as follows:
- Primary deficits of cellular immunity. The group combines conditions caused by insufficient activity or low levels of T-lymphocytes. The cause may be thymus insufficiency, fermentopathy and other (mainly genetic) disorders. The most common forms of immunodeficiency of this type are Di Giorgi and Duncan syndromes, orotaciduria, and lymphocyte enzyme deficiency.
- Primary deficits of humoral immunity. A group of conditions in which the function of mainly B-lymphocytes is reduced, the synthesis of immunoglobulins is disrupted. Most forms belong to the category of dysgammaglobulinemia. The most well-known syndromes are Bruton, West, IgM or transcobalamin II deficiencies.
- Combined primary immunodeficiency. An extensive group of diseases with reduced activity of both cellular and humoral links of immunity. According to some data, this type includes more than half of all types of immune insufficiency. Among them, there are severe (Glanzmann-Rinicker syndrome), moderate (Louis-Bar disease, autoimmune lymphoproliferative syndrome) and minor immunodeficiency.
- Primary phagocyte insufficiency. Genetic pathologies that cause reduced activity of macro- and microphages – monocytes and granulocytes. All diseases of this type are divided into two large groups – neutropenia and defects in the activity and chemotaxis of leukocytes. Examples are Kostman’s neutropenia, the syndrome of “lazy leukocytes”.
- Deficiencies of complement proteins. A group of immunodeficiency conditions, the development of which is caused by mutations of genes encoding complement components. As a result, the formation of the membrane-attacking complex is disrupted, other functions in which these proteins participate suffer. This causes complement-dependent primary immunodeficiency, autoimmune conditions or hereditary angioedema.
The clinical picture of various forms of immune deficiency is very diverse, may include not only immunological disorders, but also malformations, tumor processes, dermatological problems. This allows pediatricians or immunologists to differentiate different types of pathology at the stage of physical examination and basic laboratory tests. Nevertheless, there are certain common symptoms that are similar in diseases of each group. Their presence indicates which link or part of the immune system was affected to a greater extent.
With primary deficits of cellular immunity, viral and fungal diseases prevail. These are frequent colds, more severe than normal, the course of childhood viral infections (chickenpox, mumps), pronounced herpetic lesions. Candidiasis of the oral cavity, genitals often occurs, there is a high probability of fungal lesions of the lungs, gastrointestinal tract. Individuals with deficiencies of the cellular link of the immune system have an increased risk of developing malignant neoplasms – lymphomas, cancer of various localization.
Weakening of the humoral protection of the body is usually manifested by increased sensitivity to bacterial agents. Patients develop pneumonia, pustular skin lesions (pyoderma), often taking on a severe character (staphyloderma or streptoderma, erysipelas). With a decrease in the level of secretory IgA, mainly the mucous membranes (conjunctiva of the eyes, the surfaces of the oral and nasal cavities), as well as the bronchi and intestines are affected. Combined immunodeficiency is accompanied by both viral and bacterial complications. Often, it is not the manifestations of a lack of immunity that come to the fore, but other, more specific symptoms – megaloblastic anemia, malformations, tumors of the thymus and lymphoid tissue.
Congenital neutropenia and weakening of phagocytosis of granulocytes are also characterized by frequent occurrence of bacterial infections. Purulent-inflammatory processes with the formation of abscesses in various organs are not uncommon, in the absence of treatment, the formation of phlegmon, sepsis is possible. The clinical picture of complement-associated immunodeficiency is presented either as a decrease in the body’s resistance to bacteria, or in the form of autoimmune lesions. A separate variant of complement-dependent immunity disorder – hereditary ANO – is manifested by recurrent edema of various parts of the body.
All types of primary immunodeficiency are united by an increased risk of severe infectious complications. Due to the weakening of the body’s defenses, pathogenic microbes cause severe lesions of various organs. The lungs (pneumonia, bronchitis, bronchiectasis), mucous membranes, skin, organs of the gastrointestinal tract are most often affected. In severe cases of the disease, it is the infection that causes death in infancy. Concomitant disorders – megaloblastic anemia, abnormalities of the development of the heart and blood vessels, damage to the spleen and liver can lead to an aggravation of the pathology. Some forms of immunodeficiency conditions in the long term may cause the formation of malignant tumors.
In immunology, a huge number of techniques are used to determine the presence and identification of the type of primary immunodeficiency. More often, immunodeficiency conditions are congenital, so they can be detected already in the first weeks and months of a child’s life. The reason for contacting a specialist are frequent bacterial or viral diseases, a burdened hereditary history, the presence of other malformations. Varieties of weakly manifested immunodeficiency can be determined later, often discovered by chance during laboratory tests. The main methods of diagnosis of hereditary and congenital disorders of immunity are considered to be:
- General examination. It is possible to suspect the presence of pronounced immunodeficiency even when examining the skin. In sick children, pronounced dermatomycosis, pustular lesions, atrophy and erosion of the mucous membranes are often detected. Some forms are also manifested by swelling of subcutaneous fat.
- Laboratory tests. The leukocyte formula in the general blood test is violated – leukopenia, neutropenia, agranulocytosis and other anomalies are noted. In some varieties, it is possible to increase the level of individual classes of leukocytes. Biochemical blood analysis in primary immunodeficiency of the humoral type confirms dysgammaglobulinemia, the presence of unusual metabolites (with fermentopathies).
- Specific immunological studies. To clarify the diagnosis, a number of techniques are used to determine the activity of the immune system. These include analysis for activated leukocytes, phagocytic activity of granulocytes, the level of immunoglobulins (in general and individual fractions – IgA, E, G, M). Also, the level of complement fractions, interleukin and interferon statuses of the patient are studied.
- Molecular genetic analysis. Hereditary varieties of primary immunodeficiency can be diagnosed by sequencing genes whose mutations lead to a particular form of the disease. This is how the diagnosis is confirmed for Di Giorgi, Bruton, Duncan, Wiskott-Aldrich syndromes and a number of other immunodeficiency conditions.
Differential diagnosis is primarily performed with acquired secondary immunodeficiency, which can be caused by radioactive contamination, poisoning with cytotoxic substances, autoimmune and oncological pathologies. It is especially difficult to distinguish the cause of the deficiency with smoothed forms, determined mainly in adults.
There are no treatment principles that are uniform for all forms of pathology due to differences in etiology and pathogenesis. In the most severe cases (Glanzmann-Rinicker syndrome, Kostman’s agranulocytosis), any therapeutic measures are temporary, patients die due to infectious complications. Some types of primary immunodeficiency are treated by bone marrow transplantation or embryonic thymus tissue. The insufficiency of cellular immunity can be weakened by the use of special colonies-stimulating factors. With fermentopathies, therapy is performed using missing enzymes or metabolites – for example, biotin preparations.
With dysglobulinemia (primary humoral immunodeficiency), substitution therapy is used – the introduction of immunoglobulins of the missing classes. In the treatment of all forms, it is extremely important to pay attention to the elimination and prevention of infections. At the first signs of bacterial, viral or fungal infection, patients are prescribed a course of appropriate medications. Often, increased dosages of medicines are required for the complete cure of infectious pathologies. In children, all vaccinations are canceled – they are ineffective in most cases, and some are even dangerous.
Prognosis and prevention
The prognosis of primary immunodeficiency varies greatly with different types of pathology. Severe forms can be incurable, lead to death in the first months or years of a child’s life. Other varieties can be successfully controlled through substitution therapy or other treatment methods, only slightly impairing the patient’s quality of life. Mild forms do not require regular medical intervention, however, patients should avoid hypothermia and contact with sources of infection, and contact a specialist if there are signs of viral or bacterial infection. Preventive measures, given the hereditary and often congenital nature of primary immunodeficiency, are limited. These include medical and genetic counseling of parents before conception of a child (with burdened heredity) and prenatal genetic diagnosis. During pregnancy, women should avoid contact with toxic substances or sources of viral infections.