B Cell Primary Immunodeficiencies
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Direct answer
B cell primary immunodeficiencies are inherited defects in B cell development or antibody production that leave patients prone to recurrent bacterial infections. Bruton agammaglobulinaemia, caused by a BTK mutation, is the classic X-linked form with almost no circulating B cells. Common variable immunodeficiency and selective IgA deficiency are the commoner antibody defects, and both usually present in older children or adults.
What you must remember
- Bruton agammaglobulinaemia: X-linked BTK mutation that arrests B cell development at the pre-B stage, leaving very few circulating B cells and very low immunoglobulins.
- Presentation: boys become symptomatic after about six months, when maternal IgG wanes, with recurrent pneumonia, otitis and sepsis from encapsulated bacteria.
- Enterovirus risk: patients with Bruton disease are prone to chronic enteroviral meningoencephalitis, and Giardia infection is common.
- Treatment of Bruton disease: lifelong immunoglobulin replacement, given as IVIG or subcutaneous immunoglobulin.
- CVID: a heterogeneous group with low IgG and IgA, poor vaccine responses, recurrent sinopulmonary infection and sometimes autoimmune cytopenias.
- CVID complications: granulomatous disease, enteropathy and a raised risk of lymphoma.
- Selective IgA deficiency: the most common primary immunodeficiency, with absent or very low serum IgA and normal IgG and IgM, often asymptomatic.
- Transfusion risk: patients with anti-IgA antibodies can have anaphylaxis from IgA-containing blood products, so IgA-deficient or washed products are used.
Work-up of a suspected antibody defect
Antibody deficiencies are identified by pattern rather than by one result, so the work-up moves from clinical clues to quantification and then to genetics. The steps below follow the usual order in a paediatric or adult immunology clinic.
- Clinical clue: recurrent sinopulmonary infections with encapsulated organisms, or infections that persist despite standard antibiotics.
- Quantify immunoglobulins: serum IgG, IgA and IgM are measured against age-matched reference ranges, because infant values differ from adult values.
- Functional response: titres to tetanus toxoid and pneumococcal polysaccharide vaccines show whether specific antibody can be made.
- Lymphocyte count: flow cytometry for CD19 or CD20 B cells, where absent B cells in a boy point strongly to Bruton disease.
- Genetic confirmation: BTK sequencing confirms Bruton disease, while CVID is investigated with a wider panel that includes TACI.
- Treatment: immunoglobulin replacement with IVIG or subcutaneous immunoglobulin, with antibiotics for active infection. Replacement is started for clinically significant disease, not for a low value alone.
Where the exam tries to catch you
Immunodeficiency questions often hinge on a single number, such as the B cell count or the age of onset, so the signal word matters.
- Trap: expecting normal B cell counts in Bruton disease Correct: B cells are absent from the blood in X-linked agammaglobulinaemia because development stops at the pre-B stage.
- Trap: planning IgA replacement in selective IgA deficiency Correct: replacement is not needed, and the real danger is anaphylaxis from anti-IgA antibodies during transfusion of IgA-containing products.
- Trap: diagnosing CVID in a young child with low IgG Correct: CVID usually presents in adolescence or adulthood, so low IgG in infancy more often reflects Bruton disease or transient hypogammaglobulinaemia.
Frequently asked questions
Why do boys with Bruton agammaglobulinaemia usually present after six months of age?
Boys with Bruton agammaglobulinaemia usually present after six months because maternal IgG crossing the placenta protects them in early infancy. Once that IgG wanes, the absent B cell response leaves them open to recurrent bacterial infections such as pneumonia, otitis and sepsis.
Which investigation confirms Bruton agammaglobulinaemia?
Flow cytometry showing very few circulating CD19-positive B cells, together with markedly low immunoglobulins, supports Bruton agammaglobulinaemia. Confirmation comes from mutation analysis of the BTK gene, which encodes a tyrosine kinase needed for B cell development.
What is the main transfusion risk in selective IgA deficiency?
The main transfusion risk in selective IgA deficiency is anaphylaxis, because some patients have antibodies against IgA that react with the IgA in donor plasma. Patients with known anti-IgA antibodies should receive IgA-deficient or washed blood products, and this should be documented.
How does common variable immunodeficiency differ from Bruton disease?
Common variable immunodeficiency differs from Bruton disease because it usually presents in adolescence or adulthood, and some B cells are present. It is also linked to autoimmunity, granulomatous disease and lymphoma, whereas Bruton disease causes absent circulating B cells from early life.