A 28-year-old man with recurrent severe bacterial infections (Streptococcus pneumoniae, Haemophilus influenzae) since infancy has absent serum immunoglobulins of all isotypes and absent B cells on flow cytometry. T-cell counts and function are normal. BTK gene mutation is confirmed. Which immunodeficiency is this, and why does it spare T-cell immunity?

• A Common variable immunodeficiency (CVID); BTK deficiency prevents B-cell activation in germinal centers only, leaving naïve B cells intact
• B SCID; BTK deficiency abrogates both the RAG1/2 recombinase complex in T and B cells simultaneously
• C Bruton's X-linked agammaglobulinemia (XLA); BTK (Bruton's tyrosine kinase) is required for pre-B cell receptor signalling to drive B-cell maturation from pro-B to pre-B stage in bone marrow; T-cell development proceeds normally via the thymus independently of BTK ✓
• D Hyper-IgM syndrome type 1; BTK prevents CD40L expression on T cells, causing failure of isotype switching despite normal B-cell numbers

Explanation

Bruton's XLA is caused by mutations in the BTK gene encoding Bruton's tyrosine kinase, an essential signalling kinase downstream of the pre-B cell receptor (pre-BCR). BTK is required for the transition from pro-B cell to pre-B cell stage in bone marrow. Without BTK signalling, B-cell maturation is arrested at the pro-B cell stage and no mature B cells or plasma cells are produced, resulting in profound agammaglobulinemia. T-cell development is entirely BTK-independent and proceeds normally in the thymus. Boys are predominantly affected (X-linked). CVID is acquired/late-onset and retains some B cells. SCID affects both lineages. Hyper-IgM type 1 is CD40L deficiency.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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Written and medically reviewed by the StethoPrep medical team.