Innate immune cell defects
These disorders are associated with impaired function of phagocytes (neutrophils, macrophages) at various stages: migration, phagocytosis, or intracellular killing.
- Chronic granulomatous disease: occurs due to mutations (e.g., in the CYBB gene) that impair NADPH oxidase assembly. This blocks the "respiratory burst", preventing bacteria from being killed inside the phagocyte, which leads to granuloma formation.
- Enzyme deficiencies (myeloperoxidase, glucose-6-phosphate dehydrogenase): also reduce the production of reactive oxygen species, impairing pathogen killing.
- Leukocyte adhesion deficiencies (LAD): a group of syndromes in which leukocytes cannot exit the vessel into the focus of inflammation. In LAD I, the integrin β2 chain (CD18) is absent; in LAD II, the sLex receptor required for "rolling" is absent. Clinically, this manifests as infections without pus formation.
- Chediak–Higashi syndrome: a mutation in the CHS/Beige gene disrupts intracellular transport and granule exocytosis. Characteristic features include giant granules in neutrophils and NK cells, recurrent infections, and partial albinism.
- NF-κB signaling pathway defects: mutations in the IKKG (IKKγ kinase) or IRAK1 genes disrupt the activation of the inflammatory response. The IKKγ defect causes X-linked anhidrotic ectodermal dysplasia (absence of hair, teeth, and sweat glands) combined with severe immunodeficiency.
Complement system defects
The complement system is a cascade of plasma proteins that destroys microbes and stimulates inflammation. Deficiency of its various components results in different clinical pictures.
- Early components (C1q, C1r, C1s, C4, C2): their deficiency impairs the activation of the classical pathway. The main consequence is impaired elimination of immune complexes, leading to their deposition in tissues and the development of lupus-like syndrome.
- Late components (C5, C6, C7, C8): their absence makes the assembly of the membrane attack complex impossible. Such patients are extremely vulnerable to infections caused by Neisseria.
- C3 deficiency: the central component of the system. Its defect blocks all activation pathways, combining the symptoms of early and late component deficiencies (immune complex pathology and severe pyogenic infections).
- Inhibitor deficiencies (factor I, factor H): lead to uncontrolled cleavage of C3, its depletion, and frequent bacterial infections.
Hereditary angioedema
A distinct pathology associated with deficiency or dysfunction of the complement C1 inhibitor (C1INH).
Normally, this protein restrains the activity of the complement, coagulation, and kinin systems. When C1INH is defective (e.g., after trauma), uncontrolled activation of kallikrein and excessive production of bradykinin occur. Bradykinin sharply increases vascular permeability, causing unpredictable spontaneous edema (including life-threatening laryngeal edema). An important feature is that such edema is clinically similar to anaphylaxis, but does not respond to antihistamines and glucocorticoids.
Briefly: answers to topical questions
What clinical symptoms are characteristic of Chediak–Higashi syndrome?
Chediak–Higashi syndrome is characterized by a severe immunological defect, recurrent bacterial infections, and partial albinism of the eyes and skin.
Clinical manifestations include:
- Recurrent bacterial infections — occur due to impaired phagocytic activity of neutrophils.
- Partial albinism — caused by the failure to release melanin from giant granules.
- Severe immunological defect — associated with a mutation in the CHS/Beige gene, leading to impaired intracellular transport and weakened perforin-dependent cytolysis.
What are the pathways of complement system activation?
There are three main pathways of complement activation: classical, lectin, and alternative.
- Classical pathway is an antibody-dependent pathway initiated by the recognition of the antigen-antibody complex.
- Lectin pathway — is initiated by the binding of carbohydrates on the pathogen surface to mannose-binding lectin or ficolins.
- Alternative pathway — is triggered via spontaneous hydrolysis of the C3 component to C3(H2O) and stabilized on bacterial membranes.
All three pathways converge into a common terminal pathway leading to target cell lysis.
Which laboratory tests are used to diagnose chronic granulomatous disease?
Diagnosis of chronic granulomatous disease is based on identifying the products of the respiratory burst.
The following laboratory methods are used for this:
- NBT test (nitroblue tetrazolium test) — evaluation of nitroblue tetrazolium dye reduction to indirectly assess bactericidal potential.
- Chemiluminescence assay — determination of reactive oxygen species.
- Cytometric method — determination of intracellular hydrogen peroxide by the induction of a fluorescent dichlorofluorescein diacetate metabolite.
Additionally, this disease shows elevated levels of IgM and IgG immunoglobulins, as well as an increased number of CD4+ T cells.
Class and exam questions
Why do leukocyte adhesion deficiencies (LAD) present with infections without pus formation?
Pus consists predominantly of dead neutrophils. In LAD, neutrophils cannot adhere to the endothelium and exit the bloodstream into the focus of infection due to the lack of necessary adhesion molecules (e.g., CD18 in LAD-I).
Why is deficiency of late complement components (C5–C8) dangerous?
Formation of the membrane attack complex is impaired. This specifically reduces the body's resistance to bacteria of the genus Neisseria (causative agents of meningitis and gonorrhea).
What is the main diagnostic feature of Chediak–Higashi syndrome?
The presence of giant granules in the cytoplasm of cells (neutrophils, NK cells, melanocytes), which form due to a defect in intracellular vesicle transport.
What else to study on this topic
- Immunodiagnostic methods for chronic granulomatous disease (NBT test, chemiluminescence)
- Molecular mechanism of leukocyte rolling and transmigration (role of CD18, sLex)
- Pathogenesis of X-linked anhidrotic ectodermal dysplasia in IKKγ deficiency
- The link between the complement system and the kinin system in the pathogenesis of angioedema
- Severe combined immunodeficiency (SCID) as a defect of adaptive immunity
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