Humoral immunodeficiencies

Impaired B-lymphocyte maturation (Bruton's disease)

X-linked agammaglobulinemia, or Bruton's disease, is caused by a mutation leading to a deficiency of the btk protein kinase. Normally, this enzyme is essential for the transition of pre-B cells (bearing a specific receptor) into immature B lymphocytes expressing IgM. In this pathology, the maturation process is completely blocked at the pre-B cell stage.

The clinical presentation manifests with frequent otitis media, sinusitis, and conjunctivitis. A marked susceptibility to mycoplasmas and ureaplasmas is characteristic, which provoke chronic pneumonias, cystitis, arthritis, and subcutaneous soft tissue infections. In addition, these patients frequently develop Th1-dependent autoimmune pathologies (e.g., rheumatoid arthritis, scleroderma-like syndrome, ulcerative colitis). Due to chronic bronchopulmonary inflammation, chest deformity frequently develops.

Costimulation defects: Hyper-IgM syndromes (HIGM)

Hyper-IgM syndrome is a heterogeneous group of disorders caused by the inability of B lymphocytes to undergo immunoglobulin isotype switching. Blood tests reveal low levels of IgG and IgA with normal or elevated IgM levels. The disease manifests with severe recurrent infections as early as the first year of life. Most patients are boys due to the predominance of the X-linked form.

The primary cause is a breakdown in the interaction between T cells and antigen-presenting cells (APCs). For a normal response, the CD40 receptor on the B cell must bind to the CD154 (CD40L) ligand on the T helper cell. Several variants of this pathology are distinguished:

• HIGM1 (X-linked): Defect of the T-cell receptor CD40L. Due to the lack of signaling, B cells fail to undergo class switching. Macrophages and dendritic cells are also not activated, leading to decreased antigen presentation efficiency and secondary suppression of Th1 cells.
• HIGM2 (autosomal recessive): Mutation in the AID (activation-induced cytidine deaminase) gene, which is responsible for hypermutation and isotype switching. CD40L expression remains normal.
• HIGM3 (autosomal recessive): Mutation in the gene encoding the CD40 molecule itself, leading to consequences similar to HIGM1.
• UNG gene mutation: A defect in uracil-N-glycosylase disrupts immunoglobulin class switching, producing a similar clinical picture.

Note: Anhidrotic ectodermal dysplasia, caused by a mutation in the IKKγ molecule, is also associated with signaling pathway defects.

Specific antibody production defects

• Common variable immunodeficiency: A group of defects disrupting B-lymphocyte homeostasis and the differentiation of antibody-secreting cells. Mutations may affect the TNFSF20, BLIMP1, or ICOS genes, impairing the production of survival factors (BAFF), differentiation factors (Blimp-1), or costimulatory molecules (ICOS).
• Selective IgA deficiency: Genetic origin is not fully established. A disruption occurs in the switching of C genes to Cα. Decreased IgA levels critically impair mucosal humoral defense.
• Hyper-IgE syndrome: The cause of the excessive elevation in IgE levels is unknown. The pathology is accompanied by severe allergic manifestations and a predisposition to purulent inflammation.

Combined syndromes with B-cell involvement

Some immunodeficiencies combine humoral and cellular immune defects along with non-immune manifestations:

1. Wiskott–Aldrich syndrome (WAS gene mutation). A defect in the WASP protein disrupts the interaction between signaling molecules and the cytoskeleton. As a result, cell motility, phagocytosis, contact cytolysis, and antigen presentation are impaired.
2. Ataxia-telangiectasia (ATM gene mutation). A defect in the ATM kinase blocks DNA break repair and the initiation of apoptosis. Defective cells accumulate, and lymphocyte development (especially T cells) is impaired.
3. Nijmegen breakage syndrome (NBS1 gene mutation). A breakdown in DNA repair mechanisms leads to immunological disorders fully identical to those seen in ataxia-telangiectasia.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Interaction of costimulatory molecules: the CD80-CD28 and CD40-CD154 axes in normal physiology.
• Pathogenesis of autoimmune processes in Bruton's disease (the role of Th1 cells).
• Molecular mechanism of hypermutation and the function of the AID enzyme.
• The role of WASP, ATM, and NBS1 proteins in the cytoskeleton function and DNA repair of immunocompetent cells.

Other topics in the section "Immunity in defense and damage of the organism. Pathology of immunity"

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