Pediatric Medical Genetics - S.I. Smiian 2003

Primary immunodeficiencies

The Immune System, acting as the body's central regulatory hub, coordinates the interaction among vital Organs. Immunity ensures and maintains antigenic Homeostasis. Immunodeficiencies can be hereditary in nature. Primary Immunodeficiencies (PIDs) attract particular attention from researchers and clinicians because they determine a child's quality and life expectancy.

Etiology. Primarily, these conditions stem from a primary defect in Chromosomes 8, 14, 18, or 20 caused by Gene Mutations, chromosomal translocation, METABOLISM/31.html">Transcription, or deletion. A genetic defect may occur at the level of the stem Cell, T- and B-lymphocyte differentiation, plasma cell maturation, or their cooperation in the Immune Response due to defective specific receptors, adhesion molecules, CYTOKINES AND THEIR receptors, as well as mutated genes encoding secondary Intracellular Signaling Enzymes. Lawton A. (1986) identifies the following molecular-genetic defects underlying primary PIDs: 1) deletions of genes encoding immunoglobulin heavy chains and T-lymphocyte receptors, along with chromosomal mutations; 2) mutations disrupting the contact between immunoglobulin genes and T-cell receptors; 3) defects in alternative RNA splicing (excessive excision of non-coding enzyme genes during transcription); 4) X-chromosome gene mutations regulating lymphocyte differentiation and maturation; 5) mutations causing the loss of Histocompatibility Antigens; 6) mutations impairing T-lymphocyte maturation and differentiation in the Thymus; 7) mutations in genes encoding interleukin synthesis; 8) mutations in genes controlling the synthesis of enzymes and Complement components.

The evolution of Molecular Genetics continually expands our understanding of The Link Between clinical polymorphism and the Selection/32.html">Genetic heterogeneity of PIDs, which deepens our knowledge while simultaneously demanding refinement of current classifications.

The Classification of Primary PIDs is systematically updated in accordance with the latest advances in clinical immunology. The most widely accepted classification is the one proposed by Stephani D.V. and Veltischev Y.E. (1996), which aligns with the latest recommendations adopted by the WHO working group.

Hereditary primary forms of PIDs:

I. Deficiencies of the HUMORAL IMMUNE RESPONSE (B-lymphocyte system).

1. Agammaglobulinemia, Bruton's disease.

2. Dysgammaglobulinemias:

a) common variable hypogammaglobulinemia;

b) selective IgA deficiency;

c) IgA and IgG deficiency with increased IgM synthesis (hyper-IgM syndrome);

d) IgG subclass deficiency.

II. Deficiencies of cellular immune responses (T-lymphocyte systems):

1. Lymphocytic dysgenesis (Nezelof syndrome).

2. Hypoplasia of the thymus and Parathyroid glands (DiGeorge syndrome).

III. Combined immunodeficiencies:

1. Reticular dysgenesis.

2. Hereditary alymphocytosis, lymphocytophthisis.

3. Bare lymphocyte syndrome.

4. PID with thymoma.

5. Wiskott-Aldrich syndrome.

IV. Impairments in the interleukin system and cell cooperation during the immune response.

V. Complement system deficiency.

VI. Phagocytic dysfunction.

VII. PIDs associated with inherited Metabolic Disorders.

VIII. Pathology of mucosal and local immunity.

IX. Minor Anomalies of the immune system.

However, the classification given above has since been modified. Shabalov N.B. (2000), following the guidelines of the WHO Committee on Primary Immunodeficiencies (1995), already distinguishes 5 groups of primary immunodeficiencies: 1) combined immunodeficiencies; 2) predominantly antibody deficiencies (B-cell system insufficiency); 3) predominantly T-cell deficiencies; 4) complement system deficiency; 5) phagocytic defects. A significant difference in this classification is that the combined group also includes immunodeficiency states associated with other major defects.

The prevalence of immunodeficiency states across various populations worldwide is not uniform. This is due to differences in the levels of immunological Diagnostics in particular, and healthcare as a whole. Furthermore, the lack of standardized classification approaches for immunodeficiencies contributes to inaccurate registration of this pathology. Available medical statistics indicate that the frequency of immunodeficiencies is approximately 2:1000. Among children with primary immunodeficiencies, B-system pathology predominates (75%), while localized T-cell impairment is diagnosed less frequently.

General clinical manifestations of immunodeficiencies. In clinical practice, a pediatrician relies on certain generalizations. That is, by analyzing a child's development from birth, the physician attempts to determine the cause of specific deviations and disorders, and to ascertain whether a relationship exists between them. Therefore, if the following criteria are present, the possibility of congenital immunodeficiency should be ruled out:

1) recurrent and chronic infections of the Respiratory system, Skin, mucous membranes, and gastrointestinal tract characterized by systemic spread (septicemia) and Treatment resistance;

2) prolonged digestive disorders, persistent (recurrent) diarrhea, malabsorption syndrome;

3) type I allergic reactions (such as eczema, angioedema, allergic reactions to medications, administration of IMMUNOGLOBULINS, or Blood products);

4) unusual reactions to vaccination;

5) hematological deficiencies (leukopenia, thrombocytopenia, hemolytic and megaloblastic anemias);

6) autoimmune conditions: scleroderma, chronic hepatitis, thyroiditis, Arthritis, systemic lupus erythematosus (SLE)-like syndrome;

7) tumors and lymphoproliferative disorders.

The presence of several criteria simultaneously in a single patient significantly increases the likelihood of an immunodeficiency Diagnosis. In particular, a combination of growth retardation and weight loss, eczema, diarrhea, and hematological abnormalities is most often a manifestation of immunodeficiency. Physicians should be alerted by repeated (or recurrent) Infections caused by Fungi, Protozoa, or unusual microorganisms. Subsequently, the type of pathogen can indirectly suggest a deficiency in the cellular or humoral branches of immunity. For instance, the isolation of Mycoplasmas, mycobacteria, Viruses, or protozoa provides evidence of T-cell deficiency. Conversely, the B-cell branch regulates the inactivation of microbes by phagocytes, meaning persistent bacterial infections demonstrate humoral immunity incompetence. The probability of an immunodeficiency diagnosis increases if There is a family history of immunodeficiency or early childhood deaths.

Diagnostic Methods. Clinical symptoms of suspected immunodeficiency represent only the first step toward a diagnosis, after which the following algorithm should be applied:

1) quantitative screening analysis (T- and B-lymphocytes, granulocytes, monocytes, immunoglobulins A, M, G);

2) analysis of immune effector systems (complement, phagocytic system, and inflammatory response);

3) complete blood count (occasionally myelogram);

4) immunohistological examination of intestinal biopsies in selective IgA deficiency;

5) special diagnostic methods: determination of erythrocyte adenosine deaminase and purine nucleoside phosphorylase levels (combined or cellular immunodeficiencies); blood alpha-fetoprotein determination (in ataxia-telangiectasia); chromosomal analysis; expression of Major Histocompatibility Complex molecules.