STEPTRACKERIMMUNOLOGY + PEDIATRICS | IMMUNODEFICIENCY | HIGH-YIELD REVIEW

B-Cell Deficiencies

Antibody defects show up after maternal IgG fades (around 6 months) as recurrent sinopulmonary infections with encapsulated bacteria, plus enteroviruses and Giardia.

FOCUS ON

X-linked (Bruton) agammaglobulinemia: BTK defect → no mature B cells, all Ig ↓, absent tonsils and lymph node germinal centers; boys after 6 months; enteroviral meningoencephalitis, Giardia; no live vaccines; IVIG. CVID: B cells present but fail to become plasma cells → ↓ IgG, IgA ± IgM; onset teens–adults; ↑ autoimmunity, granulomas, lymphoma. Selective IgA deficiency: most common; mostly asymptomatic or sinopulmonary/GI infections, celiac, atopy; anaphylaxis to IgA-containing blood; false-negative IgA tTG. Hyper-IgM: CD40L (X-linked) or AID (AR) → can't class switch → ↑ IgM, ↓ others; CD40L form adds Pneumocystis, Cryptosporidium, Cryptococcus. Transient hypogammaglobulinemia of infancy: delayed own IgG, resolves.

DISORDER

DEFECT

FINDINGS

CLUE · TREATMENT

X-linked agammaglobulinemia

BTK (X-linked recessive) → pre-B cells can't mature

Absent CD19⁺ B cells; all Ig ↓; no tonsils, small nodes

Boy > 6 months with otitis, pneumonia, sinusitis, echovirus encephalitis · IVIG, no live vaccines

Common variable immunodeficiency

Heterogeneous (e.g., TACI, ICOS); plasma cells don't form

Normal B-cell count; ↓ IgG and IgA (± IgM); poor vaccine responses

Onset 20s–30s · bronchiectasis, autoimmune cytopenias, granulomas, lymphoma, gastric cancer · IVIG

Selective IgA deficiency

B cells can't switch to IgA

↓ IgA, normal IgG/IgM

Often silent · sinus/lung/GI infections, Giardia, celiac, atopy, autoimmunity · anaphylaxis to transfusion

X-linked hyper-IgM

CD40L on T cells

↑ or normal IgM, ↓ IgG/IgA/IgE; no germinal centers

Pneumocystis, Cryptosporidium (sclerosing cholangitis), Histoplasma · neutropenia · stem cell transplant

AR hyper-IgM

AID, UNG (or CD40)

Same Ig pattern; large lymphoid follicles

Bacterial infections; fewer opportunists than CD40L form

Transient hypogammaglobulinemia of infancy

Delayed onset of own IgG

Low IgG after maternal IgG wanes; normal vaccine responses

Resolves by 2–4 years

Specific antibody deficiency

Poor response to polysaccharide antigens

Normal Ig levels; low titers after PPSV23

Recurrent sinopulmonary infections

Physiologic nadir

Maternal IgG falls, own IgG rising

IgG lowest at 3–6 months

Why antibody defects present after 6 months

Secondary hypogammaglobulinemia

Loss or underproduction

Nephrotic syndrome, protein-losing enteropathy, CLL, myeloma, rituximab

Exclude before diagnosing CVID

Typical organisms

Antibody needed to opsonize capsules and neutralize

S pneumoniae, H influenzae, Moraxella, S aureus; enteroviruses; Giardia; Campylobacter; Mycoplasma

Viral infections otherwise handled (T cells intact)

Laboratory workup

Quantitative IgG, IgA, IgM; vaccine titers; flow cytometry for B cells

—

Check total IgA with celiac serology

Picture it — where each defect blocks the pathway

Lymphocyte development and its failuresSCID genes stop lymphocytes at the progenitor stage; DiGeorge removes the thymus; BTK loss halts B cells at pre-B (XLA); CD40L or AID loss blocks class switching (hyper-IgM); CVID fails at the plasma-cell step; IL-12/IFN-γ and STAT3 defects cripple Th1 and Th17 effector arms.

Schematic diagrams, not to scale.

Mechanism — where B-cell development stops

Pre-B cellBTK needed → XLA stops here

→

Mature B cell

→

Class switchCD40L/AID → hyper-IgM; IgA switch → IgA deficiency

→

Plasma cellCVID fails here

Antibody defects compared

DISORDER

B CELLS

IMMUNOGLOBULINS

ONSET

XLA

Absent

All ↓

> 6 months, boys

CVID

Normal

IgG, IgA ↓

Teens–adults

IgA deficiency

Normal

IgA ↓

Any

Hyper-IgM

Normal

IgM ↑, others ↓

Infancy

How it's tested

COMMON CONFUSIONXLA (no B cells, early childhood, boys) vs CVID (B cells present, later onset, either sex, with autoimmunity).

THE TRAPIgA-deficient patients can make anti-IgA antibodies — transfuse washed or IgA-deficient products, and IVIG must be IgA-depleted.

YOUR APPROACHRecurrent encapsulated infections after 6 months → quantitative Ig → B-cell count → isotype pattern → specific defect.

If you see… think…

Boy, 9 months, recurrent otitis and pneumonia, no tonsils → XLA (BTK)

XLA child with chronic meningoencephalitis → enterovirus

Adult with bronchiectasis, low IgG, normal B cells, autoimmune anemia → CVID

Anaphylaxis during first transfusion → selective IgA deficiency

Celiac serology negative but biopsy positive → check for IgA deficiency

High IgM, absent IgG, Pneumocystis in a boy → CD40L deficiency

Recurrent Giardia → antibody deficiency (IgA, CVID, XLA)

Why antibody defects appear after 6 months → maternal IgG wanes

Low IgG with heavy proteinuria → secondary loss (nephrotic)

Treatment for XLA and CVID → IVIG