Classification and epidemiology
Immunological insufficiency is divided into two large groups based on origin:
- Primary immunodeficiencies: genetically determined disorders in which the immune system itself is initially impaired. They are relatively rare (except for IgA deficiency).
- Secondary immunodeficiencies: acquired conditions developing secondary to other diseases. They are widely prevalent. For example, about 90% of viral infections are accompanied by transient immunosuppression or altered responses to heterologous antigens.
Based on the level of impairment, a distinction is made between specific defects (selective impairment of B lymphocytes, T lymphocytes, or their combined damage) and nonspecific defects (malfunction of the complement system, phagocytes, natural killers).
Humoral immunity (B-cell) defects
- Bruton agammaglobulinemia. An X-linked disease affecting males. Serum immunoglobulins are virtually absent in the blood (sometimes with traces of IgG), along with B lymphocytes and plasma cells. T lymphocytes remain normal. Morphologically, germinal centers are absent in lymph nodes and the spleen, and palatine tonsils are rudimentary. Patients suffer from pyogenic flora (staphylococci) causing recurrent otitis media, bronchitis, pneumonia, and skin infections. In 50% of children, autoimmune disorders resembling rheumatoid arthritis develop, along with systemic lupus erythematosus (SLE) and dermatomyositis.
- Common variable immunodeficiency (CVID). A heterogeneous group with a variable inheritance pattern (congenital, acquired, sporadic, or familial). Characterized by hypogammaglobulinemia (all antibody classes or only IgG are decreased). Unlike Bruton disease, morphological examination reveals hyperplasia of B-cell areas (lymphoid follicles). Clinical features include bacterial and severe enteroviral infections, recurrent herpes, and persistent diarrhea (pathogen — Giardia lamblia). In 20% of cases, rheumatoid arthritis or pernicious/hemolytic anemia develops concurrently.
- Isolated IgA deficiency. A very common form associated with a defect in B lymphocyte differentiation. It can be familial or acquired (following measles or toxoplasmosis). Due to a lack of secretory IgA, mucosal defense is impaired. This leads to sinopulmonary infections, a high incidence of respiratory allergies, and autoimmune diseases (SLE, rheumatoid arthritis).
T-cell and combined immunodeficiencies
- DiGeorge syndrome. A form of selective T-lymphocyte deficiency. It is important to note that it is not genetically determined: it is the result of intrauterine fetal injury at the 8th week of gestation. Manifests as thymic hypoplasia (complete absence of cellular response), absence of parathyroid glands (leading to tetany), and congenital heart and great vessel defects.
- Severe combined immunodeficiencies (SCID). A combined defect of T and B lymphocytes with autosomal recessive or X-linked inheritance. Morphology depends on the mutation: with adenosine deaminase deficiency, the thymus is small and devoid of lymphoid cells; in other cases, lymphoid tissue hypoplasia is observed. Without bone marrow transplantation, the outcome is fatal within the first years of life.
- Wiskott-Aldrich syndrome. An X-linked recessive disorder. Manifests with the triad of immunodeficiency, thrombocytopenia, and eczema. The morphology of the thymus remains unchanged. Characterized by high susceptibility to infections and early death.
Genetic deficiency of the complement system
Mutations can affect all complement components and inhibitors, disrupting nonspecific defense mechanisms.
- C3 deficiency. A critical condition, as the C3 component is essential for both the classical and alternative activation pathways. Leads to increased susceptibility to pathogenic bacteria.
- Hereditary angioedema. Characterized by localized edema of the affected skin and mucous membranes.
Briefly: answers to topical questions
What genetic mutations cause severe combined immunodeficiencies (SCID)?
Severe combined immunodeficiencies (SCID) are caused by a number of genetic mutations that disrupt lymphocyte development. The main genetic defects include:
- Defect in receptor V-gene rearrangement — includes mutations in the RAG-1 and RAG-2 genes, as well as a mutation in the DNA-dependent protein kinase gene.
- Enzyme deficiencies — absence of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP).
- Receptor apparatus defects — mutation of the common γ(c) chain of cytokine receptors (X-linked form) and deficiency of the IL-7 receptor α chain.
- Jak3 tyrosine kinase deficiency — disrupts intracellular signal transduction from the receptor γ(c) chain.
What is the pathogenesis of hereditary angioedema?
The pathogenesis of hereditary angioedema lies in a hereditary defect of the C1 complement component inhibitor ($C1_{inh}$). Normally, this protein belongs to the serpin family, specifically binds classical pathway components, and acts as a kallikrein inhibitor. Its deficiency results in excessive kallikrein activation, leading to the production of excessive amounts of kinins. As a result, a life-threatening condition develops, characterized by localized edema of the affected skin and mucous membranes.
The acronym TIE helps to remember the manifestations of Wiskott-Aldrich syndrome: Thrombocytopenia, Infection/Immunodeficiency, Eczema. Note that the thymus remains morphologically unchanged in this pathology.
Class and exam questions
At what age do primary immunodeficiencies typically debut?
Clinical onset for most forms occurs between 6 months and 2 years of age. The primary manifestation is increased susceptibility to recurrent infections.
How does DiGeorge syndrome fundamentally differ from other forms?
It is not a genetically determined disease. It is the result of intrauterine fetal injury at the 8th week of gestation, leading to hypoplasia of the thymus and parathyroid glands.
How do lymph nodes change in Bruton agammaglobulinemia?
Germinal centers are completely absent in the lymph nodes and spleen, and the palatine tonsils remain rudimentary.
Why is a deficiency of complement component C3 most dangerous?
The C3 component is critically important because it is required to trigger both the classical and alternative pathways of complement activation.
What else to study on this topic
- Mechanisms of development of autoimmune complications (SLE, rheumatoid arthritis) in the setting of immunodeficiencies.
- The role of Giardia lamblia and enteroviruses in the pathogenesis of infections in common variable immunodeficiency.
- Morphological variants of thymus structure in various genetic forms of SCID.
- Pathogenesis of sinopulmonary infections in isolated IgA deficiency.
- Causes of tetany and congenital heart defects in DiGeorge syndrome.
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