16. Primary Immunodeficiency diseases affecting adaptive immunity

Primary Immunodeficiencies (B-Cell & T-Cell Specific)

Adaptive immunity relies on two arms: Humoral (B-cells/antibodies) and Cell-Mediated (T-cells). While combined defects wipe out both, specific genetic mutations can isolate and destroy just one arm.

B-Cell (Humoral) Immunodeficiencies

• Core Pathophysiology: B-cells fail to develop or fail to secrete antibodies.

• Classic Presentation: Normal at birth (protected by maternal IgG). Recurrent infections begin after 6 months of age.

• Specific Susceptibilities:

  • Extracellular, encapsulated bacteria (e.g., S. pneumoniae, H. influenzae, N. meningitidis) because antibodies are required for opsonization.

  • Enteroviruses (e.g., Polio, Coxsackie) and Giardia lamblia (because IgA is missing in the gut).

EXAMPLES:

A. X-Linked Agammaglobulinemia (Bruton's XLA)

B. Selective IgA Deficiency

C. Common Variable Immunodeficiency (CVID)

A. X-Linked Agammaglobulinemia (Bruton's XLA)

• Genetics: X-linked recessive (affects boys). Mutation in the BTK gene (Bruton Tyrosine Kinase).

• Pathogenesis: BTK is essential for B-cell maturation. Without it, B-cells are permanently stuck in the "pro-B" to "pre-B" stage in the bone marrow.

• Clinical:

  • Profoundly decreased numbers of circulating B-cells (CD19^+, CD20^+).

  • Absent or extremely low levels of ALL classes of immunoglobulins (IgG, IgA, IgM, IgE).

  • Absent/scant lymph nodes and tonsils (no germinal centers).

B. Selective IgA Deficiency

• The most common primary immunodeficiency (1 in ~500 people).

• Pathogenesis: Unknown defect leads to a failure of B-cells to class-switch specifically to IgA. All other Ig levels are normal.

• Clinical:

  • Often completely asymptomatic.

  • May present with recurrent sinopulmonary mucosal infections and GI infections (Giardia).

  • Highly Tested Complication: Patients can develop severe anaphylaxis to blood transfusions if the donor blood contains IgA (the patient's immune system sees IgA as a foreign antigen and attacks it).

C. Common Variable Immunodeficiency (CVID)

• Pathogenesis: A defect in B-cell differentiation. B-cells are produced in normal numbers but fail to mature into plasma cells and secrete antibodies.

• Clinical:

  • Similar to XLA (low Ig levels, recurrent bacterial infections), but onset is much later (typically 20s to 30s).

  • High-Yield Association: High risk of autoimmune diseases, bronchiectasis, and lymphomas.

T-Cell (Cell-Mediated) Immunodeficiencies

• Core Pathophysiology: Defective T-cell development or function.

• Specific Susceptibilities: Recurrent infections with intracellular pathogens (Viruses, Fungi, Mycobacteria).

• Note: Because Helper T-cells are needed to fully activate B-cells, pure T-cell defects often cause secondary antibody deficiencies.

EXAMPLES:

A. DiGeorge Syndrome (Thymic Aplasia)

B. Hyper-IgE Syndrome (Job Syndrome)

A. DiGeorge Syndrome (Thymic Aplasia)

• Genetics: Microdeletion at chromosome 22

• Pathogenesis: Failure of the 3rd and 4th pharyngeal pouches to develop.

• Clinical Mnemonic (CATCH-22):

  • Cardiac abnormalities (Tetralogy of Fallot, Truncus arteriosus).

  • Abnormal facies.

  • Thymic hypoplasia $\rightarrow$ T-cell deficiency (absent thymic shadow on CXR).

  • Cleft palate.

  • Hypocalcemia/Hypoparathyroidism $\rightarrow$ Tetany/seizures (due to lack of parathyroid glands, which also develop from the 3rd/4th pouches).

B. Hyper-IgE Syndrome (Job Syndrome)

• Genetics: Autosomal dominant mutation in the STAT3 gene.

• Pathogenesis: STAT3 mutation leads to a deficiency of Th17 cells. Th17 cells normally secrete IL-17 to recruit neutrophils to sites of infection. Without them, neutrophils fail to respond to chemotactic signals.

• Clinical Mnemonic (FATED):

  • Facies (coarse facial features).

  • Abscesses (cold, non-inflamed staphylococcal abscesses because neutrophils aren't there to create pus/inflammation).

  • Teeth (retained primary/baby teeth).

  • Eosinophilia and IgE excess.

  • Dermatologic issues (severe eczema).

The Crossover: Hyper-IgM Syndrome

This is a classic "class-switching" defect that perfectly illustrates T-cell and B-cell cooperation.

• Genetics: Usually X-linked recessive.

• Pathogenesis: Mutation in the CD40L (CD40 Ligand) on Helper T-cells.

• Mechanism: To change from producing IgM (the default) to producing IgG, IgA, or IgE, a B-cell requires two signals. Signal 2 is the binding of CD40 on the B-cell to CD40L on the T-cell.

• Clinical: Without CD40L, B-cells are structurally fine but can only make IgM.

  • Labs show severely elevated IgM, and near-zero IgG, IgA, and IgE.

  • Presents with severe pyogenic infections and opportunistic infections (like Pneumocystis jirovecii, because CD40L is also needed for macrophages to clear it).