Groups 1 and 2: Combined defects and antibody deficiencies
Combined immunodeficiencies include severe combined immunodeficiency (SCID). The disease is most often associated with point mutations in the IL receptor $\gamma$-chain gene (IL-2, IL-4, IL-9) on the X chromosome. This leads to immunosuppression: the number of T lymphocytes (CD4+, CD8+) and immunoglobulin levels drop. Clinically, SCID manifests in the first weeks of life with skin and mucosal lesions and severe pneumonia. The prognosis is extremely serious due to the risk of sepsis. Treatment includes antibacterial and replacement therapy, with bone marrow transplantation serving as the radical method.
The second group includes predominantly antibody deficiencies (B-cell involvement). It arises from defects in B-lymphocyte differentiation or their interaction with T cells. A classic example is Bruton disease (X-linked agammaglobulinemia). A mutation in the Btk tyrosine kinase gene blocks B-lymphocyte maturation. The patient completely lacks plasma cells, IgG is sharply reduced, and IgA and IgM may be undetectable. The T-cell compartment remains normal. The main treatment method is lifelong immunoglobulin therapy.
Groups 3 and 4: Specific syndromes and dysregulation
Other well-defined syndromes include immunodeficiencies with specific clinical features, for example, Job's syndrome (hyper-IgE syndrome), associated with a mutation in the STAT3 gene (4th chromosome). The disease is characterized by early eczema of the face and extremities, recurrent purulent infections (most commonly coccal or caused by Candida albicans). Laboratory findings show eosinophilia and a sharp increase in IgE. The prognosis is favorable, treatment is symptomatic.
The fourth group includes diseases of immune dysregulation leading to uncontrolled lymphoproliferation.
- X-linked lymphoproliferative syndrome: mutation of the SAP protein gene (locus Xq25). Signal transmission from B cells infected with the Epstein–Barr virus to T lymphocytes and NK cells is disrupted. Activation of B lymphocytes occurs, along with a decrease in CD4+ and an increase in CD8+ T cells. It manifests as tonsillitis, fever, and a high risk of B-cell lymphoma or death from bone marrow aplasia.
- Autoimmune lymphoproliferative syndrome: clinically similar, but caused by a mutation in the PHORSF6 gene (locus 10q23-q24.1).
These conditions are treated with chemotherapy and glucocorticosteroids.
Groups 5 and 6: Phagocyte defects and innate immunity
Congenital phagocyte defects are associated with impaired mobility, chemotaxis, and killing ability. This group includes:
- Chronic granulomatous disease.
- Cyclic neutropenia (defect of the ELA2 gene, locus 19p.13.3) — proceeds with a favorable prognosis, despite periodic agranulocytosis.
- Congenital X-linked neutropenia (defect of the WASP gene, locus Xq11.22) — promyelocyte maturation is impaired. There is a high frequency of bacterial infections and a risk of fatal outcome from acute leukemia.
Therapy is based on lifelong antibiotic administration and genetic engineering.
The sixth group consists of innate immunity defects. Pathologies of the receptor apparatus or effector molecules cause barrier tissue infections (boils, paratonsillar abscesses). Examples: X-linked anhidrotic ectodermal dysplasia (mutation of the NF-$\kappa$B inhibitor gene — iKKBG, locus Xq28) and HBD1 defensin deficiency (decreased protein expression due to a point substitution).
Groups 7 and 8: Autoinflammation and complement disorders
The seventh group combines autoinflammatory disorders — immunodeficiencies with systemic inflammation in the absence of an obvious infectious agent. A typical representative is hyper-IgD syndrome (mutation of the MVK gene, locus 12q24). It manifests with the classic triad: fever, leukocytosis, and hyperimmunoglobulinemia D.
The eighth group comprises complement system defects:
- Deficiency of early components (C1q, C4): leads to autoimmune diseases. For example, C1q defect (locus 1p36.3-p34.1) causes an SLE-like syndrome (similar to systemic lupus erythematosus).
- Deficiency of C3 or C9 components: antibacterial defense and the humoral link suffer, which provokes recurrent infections.
Therapy includes infection management, replacement therapy, and bone marrow transplantation as a last resort.
Briefly: answers to topical questions
Which diseases belong to congenital phagocyte defects?
Congenital phagocyte defects include the following diseases:
- Chronic granulomatous disease — associated with impaired generation of reactive oxygen species.
- Cyclic neutropenia — characterized by a periodic decrease in neutrophils down to agranulocytosis.
- Congenital X-linked neutropenia — accompanied by a sharp decrease in the number of neutrophils due to impaired promyelocyte maturation.
Innate immunity cell defects also include leukocyte adhesion deficiencies (LAD), Chediak–Higashi syndrome, myeloperoxidase deficiency, and glucose-6-phosphate dehydrogenase deficiency.
How does the clinical picture of early complement component deficiency (C1q, C4) differ from that of late components (C3, C9)?
The clinical picture of complement component deficiency depends on the level of system impairment.
| Sign | Deficiency of early components (C1q, C4) | Deficiency of C3 or C9 components |
|---|---|---|
| Clinical presentation | Development of autoimmune pathology, in particular an SLE-like syndrome | Recurrent infections of various nature |
| Pathogenesis | Genetic disruptions in genes encoding complement proteins | Antibacterial defense and the humoral link are compromised |
What clinical and laboratory signs are characteristic of Job's syndrome?
Job's syndrome (hyper-IgE syndrome) is characterized by specific clinical and laboratory manifestations.
- Laboratory markers — a sharp increase in serum IgE levels and eosinophilia.
- Clinical picture — recurrent purulent infections of the skin, subcutaneous tissue, soft tissues, and internal organs caused by coccal flora and fungi (Candida albicans).
- Dermatological manifestations — eczema involving the face and extensor surfaces of the extremities, debuting in the first weeks of life.
Which genes are associated with the development of severe combined immunodeficiency (SCID)?
The development of severe combined immunodeficiency (SCID) is associated with mutations in several genes:
- Receptor $\gamma$-chain gene — point mutations on the long arm of the X chromosome (receptors for IL-2, IL-4, IL-9).
- The ADA gene — leads to adenosine deaminase deficiency.
- IL-7 or IL-7 receptor genes — cause lymphopoietic defects.
- The Tbx1 gene — its loss in DiGeorge syndrome (a variant of SCID) disrupts thymus development.
Jak3 tyrosine kinase deficiency also phenotypically overlaps with SCID.
What treatment methods are used for severe combined immunodeficiency?
Severe combined immunodeficiency (SCID) is treated using the following methods:
- Basic therapy — includes antibacterial therapy to protect against infections and replacement immunotherapy with immunoglobulin preparations.
- Bone marrow transplantation — a radical treatment method involving allogeneic bone marrow transplantation.
- Gene therapy — the most appropriate method, in which the patient's autologous bone marrow cells are transfected with the missing gene (e.g., the ADA gene or the $\gamma$-chain gene) followed by their re-implantation into the body.
Which primary immunodeficiencies are associated with mutations on the X chromosome?
The following primary immunodeficiencies are associated with X-chromosome mutations:
- Severe combined immunodeficiency (SCID).
- X-linked agammaglobulinemia (Bruton disease).
- X-linked lymphoproliferative syndrome (locus Xq25).
- Congenital X-linked neutropenia (locus Xq11.22).
- X-linked anhidrotic ectodermal dysplasia (locus Xq28).
- Chronic granulomatous disease (X-linked form, locus Xp21).
- Wiskott–Aldrich syndrome.
- Innate immunity factor deficiencies — factor D deficiency, glucose-6-phosphate dehydrogenase deficiency, and IRAK factor deficiency.
Many severe syndromes (Bruton disease, SCID, anhidrotic dysplasia, one of the forms of neutropenia) are X-linked.
Class and exam questions
What immunogram parameters are typical for Bruton's disease?
There is a marked decrease in IgG and B lymphocytes, a complete absence of plasma cells and immunoglobulins A and M. The T-cell link remains normal.
What is the essence of hyper-IgD syndrome?
This is an autoinflammatory disease (MVK gene mutation) characterized by systemic inflammation without an infectious agent: fever, leukocytosis, and elevated IgD.
What complications are typical for immune dysregulation diseases?
Major complications include chronic lymphoproliferation, malignancies (e.g., B-cell lymphoma), and autoimmune manifestations (anemia, neutropenia).
What else to study on this topic
- Genetic basis of immunodeficiencies: mutation loci and gene functions (Btk, WASP, ELA2)
- Pathogenesis of X-linked lymphoproliferative syndrome and the role of Epstein–Barr virus
- Clinical presentation of severe combined immunodeficiency (SCID)
- Lupus-like syndrome in early complement component deficiency
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