Antibody Structure and Function

• Fab (fragment, antigen binding) contains the variable regions of heavy and light chain and determines specificity. Diversity is generated by V(D)J recombination, junctional diversity, and later somatic hypermutation in germinal centres, which raises affinity.
• Fc (fragment, crystallisable) is the constant heavy region. It determines isotype, fixes complement (classical pathway, via C1q), binds Fc receptors on phagocytes and NK cells, and carries the sites for opsonisation and antibody-dependent cellular cytotoxicity.
• Isotypes and their jobs:
• IgM — first produced in a primary response; pentamer with high avidity; the best complement fixer; too large to cross the placenta, so IgM in a neonate indicates congenital infection.
• IgG — most abundant; the main antibody of the secondary response; opsonises, fixes complement, neutralises toxins, and is the only isotype that crosses the placenta, giving passive neonatal immunity.
• IgA — mucosal secretions, saliva and breast milk; a dimer with a secretory component that resists proteolysis; prevents attachment at mucosal surfaces. Selective IgA deficiency is the commonest primary immunodeficiency and risks anaphylaxis on transfusion of IgA-containing products.
• IgE — binds mast cells and basophils, mediating type I hypersensitivity and defence against helminths.
• IgD — a naive B cell surface receptor of uncertain function.
• Class switching is directed by T cell help and cytokines and changes the Fc region while preserving specificity.

Intrinsic (primary) defects, grouped by where B-cell maturation fails

• Arrest before mature B cells exist: loss-of-function of Bruton tyrosine kinase (BTK) blocks pre-B receptor signalling → X-linked agammaglobulinaemia; all isotypes are absent because no Fab-bearing plasma cell is ever made.
• Failure of class switching (Fc region cannot be swapped): CD40 ligand deficiency on T cells (X-linked), CD40 deficiency, and AID (AICDA) or UNG deficiency (autosomal recessive) → hyper-IgM syndromes. AID is also required for somatic hypermutation, so affinity maturation fails too.
• Failure of terminal differentiation/antibody output: common variable immunodeficiency, a heterogeneous group with variants in TACI (TNFRSF13B), ICOS, BAFF-R in a minority; selective IgA deficiency, which shares genetic background with CVID and can progress to it.
• Complement/Fc-receptor limb defects blunt what antibody does after binding, even when immunoglobulin levels are normal.

Acquired (largely modifiable) causes

• Loss of immunoglobulin: nephrotic syndrome, protein-losing enteropathy, severe burns.
• Drugs: anti-CD20 agents (rituximab), anti-CD38 (daratumumab), chronic corticosteroids, antiepileptics — phenytoin and carbamazepine are the classic causes of drug-induced IgA deficiency, which may remit on withdrawal.
• Malignancy and marrow failure: chronic lymphocytic leukaemia and multiple myeloma produce functionally useless immunoglobulin with suppression of normal clones.
• Splenectomy or functional asplenia removes the site where opsonised encapsulated organisms are cleared.

• Timing follows maternal IgG decay: transplacental IgG protects for the first months, so intrinsic antibody defects become symptomatic around 6 months of life as the passive supply is catabolised and the infant's own IgG fails to rise.
• Loss of Fc-dependent effector function drives the organism list: encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae type b, Neisseria meningitidis) resist direct phagocytosis because their polysaccharide capsule blocks contact. They are cleared only when IgG coats them and engages Fcγ receptors, and when C1q-fixed IgG/IgM deposits C3b for complement receptor uptake in the spleen. Without functional antibody, opsonisation fails and recurrent sinopulmonary and invasive pyogenic infection results.
• Loss of secretory IgA removes the mucosal barrier: without dimeric IgA and its protease-resistant secretory component, organisms adhere to gut and airway epithelium — hence Giardia lamblia infection, chronic diarrhoea and recurrent otitis/sinusitis.
• Class-switch defects explain the isotype pattern: when CD40L–CD40 signalling or AID is lost, B cells can still make the germline µ heavy chain but cannot rearrange to γ, α or ε. Serum IgM is normal or high while IgG, IgA and IgE are low — the antibody made is high-avidity but poorly opsonising and cannot cross the placenta or protect mucosa.
• CD40L deficiency is not purely humoral: the same interaction licenses macrophages and dendritic cells, so opportunistic infection (Pneumocystis jirovecii, Cryptosporidium) and neutropenia occur — a T-cell phenotype in a "B-cell" disease.
• Neutralisation loss explains the viral exception: cell-mediated immunity handles most viruses, but enteroviruses require neutralising antibody, so chronic enteroviral meningoencephalitis and vaccine-derived poliovirus occur in agammaglobulinaemia.
• Absent germinal centres mean no somatic hypermutation, no memory, and, anatomically, no tonsillar or nodal lymphoid tissue.

The classic stem — recurrent pyogenic infection with a normal-appearing child between episodes

• Recurrent otitis media, sinusitis, pneumonia from encapsulated organisms; repeated courses of antibiotics; failure to thrive. Bacterial, not fungal or viral, infections dominate in pure antibody defects.
• Chronic productive cough with daily sputum and coarse crackles signals established bronchiectasis from repeated pneumonias.
• Chronic watery diarrhoea and malabsorption from Giardia — the mucosal IgA clue.

Pattern by disorder

• X-linked agammaglobulinaemia: boy, onset after 6 months, and the physical finding examiners love — absent tonsils and no palpable lymph nodes despite active infection, because germinal centres never form.
• Hyper-IgM syndrome: boy with pyogenic sinopulmonary infection plus Pneumocystis pneumonia (hypoxia out of proportion to exam, diffuse interstitial infiltrates), oral ulcers from neutropenia, and sclerosing cholangitis from Cryptosporidium.
• Common variable immunodeficiency: presentation in the 20s–40s (bimodal, can be childhood), sinopulmonary infection accompanied by splenomegaly, non-caseating granulomas, autoimmune cytopenias (immune thrombocytopenia, autoimmune haemolytic anaemia) and nodular lymphoid hyperplasia of the gut.
• Selective IgA deficiency: usually asymptomatic and found incidentally; otherwise mucosal infections, atopy, coeliac disease, and the exam trigger — urticaria, wheeze and hypotension minutes into a transfusion from anti-IgA antibodies.

Step 1 — quantify the product

• Serum IgG, IgA, IgM (and IgE), interpreted against age-matched norms, plus CBC with differential and albumin (to exclude protein loss). This is the initial test in any child with recurrent sinopulmonary infection.

Step 2 — count the cells

• Flow cytometry for CD19/CD20 B cells: absent or <1–2% with all isotypes low is X-linked agammaglobulinaemia; present B cells with low IgG/IgA and normal-to-high IgM is a class-switch (hyper-IgM) defect; present B cells with low IgG plus low IgA and/or IgM in an adult is CVID.

Step 3 — test function, not just level

• Specific antibody titres before and after vaccination: response to protein antigens (tetanus, diphtheria) tests T-dependent help; response to pneumococcal polysaccharide tests T-independent responses and is the discriminating test when immunoglobulin levels are borderline. Poor conversion of titres defines a functional antibody deficiency.

Step 4 — confirm

• Genetic testing (BTK, CD40LG, AICDA) is the gold standard for the monogenic forms; CD40L expression on activated T cells by flow cytometry is a rapid surrogate.
• CVID is a diagnosis of exclusion by ESID criteria: reduced IgG with reduced IgA and/or IgM, impaired vaccine response or low switched memory B cells, age generally over 4 years, and secondary causes excluded.
• Selective IgA deficiency: serum IgA below about 7 mg/dL with normal IgG and IgM after age 4.

Immediate

• Treat the acute infection with culture-directed antibacterials; do not wait for immunologic workup, but draw baseline immunoglobulins and titres before giving any immunoglobulin product.
• Transfusion anaphylaxis in IgA deficiency is the emergency: stop the transfusion and give epinephrine 0.3 mg IM; subsequent products must be washed red cells or from IgA-deficient donors.

First-line maintenance

• Immunoglobulin replacement — IVIG or subcutaneous IG is the cornerstone for agammaglobulinaemia, hyper-IgM syndromes and CVID. The AAAAI/ACAAI Joint Task Force practice parameter frames dosing as titrated to a trough and, more importantly, to freedom from infection rather than to a single universal level. It supplies IgG only — it does not replace secretory IgA.
• Isolated selective IgA deficiency is not treated with immunoglobulin: it cannot restore mucosal IgA and exposes the patient to anti-IgA reactions.

Adjuncts and escalation

• Prophylactic antibiotics (e.g. a macrolide such as azithromycin) for breakthrough sinopulmonary infection, with airway clearance and pulmonary rehabilitation for bronchiectasis.
• **Trimethoprim-sulfamethoxazole for Pneumocystis prophylaxis** in CD40L/CD40 deficiency, plus boiled or filtered water to avoid Cryptosporidium.
• Immunosuppression (corticosteroids, rituximab) for CVID autoimmune cytopenias and granulomatous-lymphocytic interstitial lung disease, guided by specialist care.

Definitive

• Allogeneic haematopoietic stem cell transplantation is curative for CD40 ligand deficiency and other severe combined phenotypes; it is not standard for CVID or XLA.

Contraindicated

• Live attenuated vaccines — oral polio, live attenuated influenza, MMR/varicella and rotavirus in severe humoral or combined defects, per ACIP and the IDSA guideline for vaccination of the immunocompromised host. Household contacts should receive inactivated polio vaccine.
• Blood products should be irradiated and CMV-safe when T-cell function is impaired.

Of the disease

• Bronchiectasis: repeated unopposed bacterial pneumonias destroy airway wall elastin and cartilage. Signalled by daily purulent sputum and tram-track or signet-ring opacities on high-resolution CT; it is the main determinant of long-term morbidity and is largely preventable by early immunoglobulin replacement.
• Chronic otitis and conductive hearing loss from recurrent middle-ear disease.
• Chronic enteroviral meningoencephalitis in agammaglobulinaemia — an emergency; presents as progressive cognitive decline, ataxia and dermatomyositis-like syndrome because neutralising antibody is absent.
• Vaccine-derived poliomyelitis after inadvertent live oral polio exposure — also an emergency.
• Sclerosing cholangitis and cholangiocarcinoma in CD40L deficiency from chronic Cryptosporidium infection; rising alkaline phosphatase and GGT with beaded ducts on MRCP.
• CVID-specific: autoimmune cytopenias (isolated thrombocytopenia or Coombs-positive anaemia), granulomatous-lymphocytic interstitial lung disease (restrictive spirometry, reduced DLCO), and an increased risk of non-Hodgkin lymphoma and gastric carcinoma — unexplained weight loss or lymphadenopathy demands imaging and biopsy.
• Selective IgA deficiency: coeliac disease, atopy, and progression to CVID in a minority.

Of treatment

• IVIG infusion reactions: headache, flushing, myalgia during rapid infusion; aseptic meningitis post-infusion (neck stiffness with sterile CSF pleocytosis).
• Thrombosis from infusion-related hyperviscosity and product procoagulant content — stroke or venous thromboembolism, higher risk in older patients with vascular disease.
• Haemolysis from passively transferred isohaemagglutinins, and acute kidney injury with older sucrose-stabilised preparations.
• Anaphylaxis in IgA-deficient patients with anti-IgA antibodies — an emergency.
• Rituximab: prolonged hypogammaglobulinaemia, hepatitis B reactivation (screen HBsAg and anti-HBc first), and progressive multifocal leukoencephalopathy, an emergency presenting as subacute focal neurologic deficits.

• **Fab decides what, Fc decides what happens next. A stem describing failed opsonisation, failed complement fixation or failed placental transfer is pointing at the Fc/constant region**, not at specificity.
• **Boy over 6 months, recurrent pyogenic infections, *absent tonsils and lymph nodes* = X-linked agammaglobulinaemia (BTK). Single best next step: flow cytometry for CD19+ B cells** after quantitative immunoglobulins — B cells are absent.
• Normal or high IgM with low IgG, IgA and IgE = class-switch defect. If the same patient also has Pneumocystis pneumonia, neutropenia or cryptosporidial cholangitis, the lesion is CD40 ligand, because that pathway also licenses macrophages.
• Anaphylaxis during transfusion in an otherwise well adult = selective IgA deficiency with anti-IgA antibodies; give washed red cells or IgA-deficient donor products. The common distractor is treating isolated IgA deficiency with IVIG — it does not replace secretory IgA and can precipitate reactions.
• **Adult in the 20s–40s with recurrent sinopulmonary infection plus autoimmune cytopenias, splenomegaly and granulomas = CVID; remember the increased risk of lymphoma and gastric cancer**.
• IgM in a neonate means the neonate made it — IgM cannot cross the placenta, so detectable IgM indicates congenital infection, whereas IgG may simply be maternal.
• Live vaccines are contraindicated in significant antibody deficiency (ACIP); the classic trap is oral polio or rotavirus in an infant with an undiagnosed humoral defect.
• Functional testing beats levels: normal total IgG with failure to mount post-pneumococcal-polysaccharide titres still defines an antibody deficiency, and TREC newborn screening will be normal in these patients.