What are primary immunodeficiency disorders and how are they grouped?
A primary immunodeficiency (PID) is a genetic defect in part of the immune system, as opposed to a secondary (acquired) one such as HIV or chemotherapy. For exams, sort each disorder by the arm of immunity that fails, because that predicts the organisms and the age at presentation. Among all PIDs, antibody deficiency is the most common type; complement deficiencies make up only about 5%.
| Defective arm | Typical infections | Examples |
|---|---|---|
| B cell / antibody | Recurrent sinopulmonary infection with encapsulated bacteria after maternal IgG wanes; enteroviruses; Giardia | Bruton XLA, hyper-IgM |
| T cell | Viral, fungal and opportunistic infections; problems with live vaccines | Complete DiGeorge |
| Combined (T + B) | Severe infections of all kinds in early infancy, failure to thrive, chronic diarrhoea | SCID, Wiskott–Aldrich |
| Phagocyte | Bacterial and fungal abscesses, catalase-positive organisms, poor pus formation | CGD, leukocyte adhesion deficiency |
| Complement | Early components: autoimmunity (SLE); C3: pyogenic infection; C5–C9: Neisseria | C2, C3, C5–C9, properdin deficiency |
What is Bruton X-linked agammaglobulinaemia?
X-linked agammaglobulinaemia (XLA) is caused by mutation of the Bruton tyrosine kinase (BTK) gene on Xq21.3–q22. BTK drives the final stages of B-cell maturation, so B-cell development is arrested at the pre-B-cell stage in the marrow. Mature circulating B cells are profoundly reduced and all immunoglobulin classes are very low or undetectable. T cells are normal.
- Who: boys, healthy at birth; recurrent infections from about 6–9 months. Average age at diagnosis about 2.5 years.
- Infections: encapsulated bacteria (S. pneumoniae, H. influenzae, S. aureus) — otitis, sinusitis, pneumonia; enteroviruses (polio, coxsackie, echo); chronic diarrhoea from *Giardia*.
- Examination: hypoplastic tonsils and impalpable lymph nodes — spleen, nodes, tonsils and Peyer patches are underdeveloped.
- Tests: low IgG, IgA and IgM; CD19/CD20-positive B cells markedly reduced; absent BTK protein; BTK gene sequencing.
- Treatment: lifelong immunoglobulin replacement and prompt antibiotics; avoid live vaccines.
What are the features of DiGeorge syndrome?
About 90% of DiGeorge syndrome is due to a 22q11.2 microdeletion (typically about 3 Mb, around 90 genes), most often de novo. Haploinsufficiency of TBX1 disturbs development of the third and fourth pharyngeal pouches and the cardiac neural crest. It is the commonest microdeletion syndrome, about 1 in 2,000–4,000 live births. Embryology is covered in pharyngeal arches and pouches.
| Letter | Feature | Basis |
|---|---|---|
| C | Conotruncal cardiac anomalies — tetralogy of Fallot, truncus arteriosus, interrupted aortic arch, VSD; right aortic arch in about 20% | Abnormal cardiac neural crest migration |
| A | Abnormal facies | Pharyngeal arch maldevelopment |
| T | Thymic hypoplasia/aplasia → T-cell deficiency | Third pouch |
| C | Cleft palate / palatal anomalies | Arch derivatives |
| H | Hypocalcaemia — neonatal seizures, tetany | Parathyroid hypoplasia (third and fourth pouches) |
| 22 | 22q11.2 deletion | TBX1 haploinsufficiency |
Most children have partial DiGeorge, with T-cell counts that often improve with age. Complete DiGeorge (no thymic tissue, fewer than 50 naive T cells/µL) affects under 1% of 22q11.2 deletions and behaves like SCID: it needs reverse isolation, irradiated CMV-negative blood, no live vaccines, prophylaxis and definitive thymus transplantation. Adults with the deletion carry a raised risk of schizophrenia-spectrum disorders. See also chromosomal syndromes and tetralogy of Fallot.
What is severe combined immunodeficiency (SCID)?
In SCID both T- and B-cell function are absent or severely disturbed. Without treatment, infants rarely survive beyond one year. Presentation is early: recurrent pneumonia (66% in one series), failure to thrive (60%) and chronic diarrhoea (35%). Population-based newborn screening for SCID and T-cell lymphopenia now picks up many cases before infection.
| Phenotype | Defect | Note |
|---|---|---|
| T− B+ NK− | Common gamma chain shared by several interleukin receptors; JAK3 deficiency gives the same picture | Can be X-linked |
| T− B− NK− | Adenosine deaminase (ADA) deficiency — toxic metabolites kill T, B and NK cells; reticular dysgenesis | Autosomal recessive |
| T− B− NK+ | RAG1/RAG2 (cannot cut DNA for V(D)J recombination); Artemis | Autosomal recessive |
| T− B+ NK+ | IL-7 receptor α chain defect | Failure of T-cell differentiation |
What are Wiskott–Aldrich syndrome and hyper-IgM syndrome?
Wiskott–Aldrich syndrome (WAS) is X-linked, caused by mutations in the gene for WAS protein (WASp), a cytoskeletal regulator of lymphocytes and platelets. Its classic triad is immunodeficiency, thrombocytopenia with small platelets, and eczema. Milder alleles give X-linked thrombocytopenia (XLT) only.
- Immunoglobulins: IgG normal, IgM low, IgA and IgE high.
- Bleeding: petechiae, bruising, serious haemorrhage — any boy with thrombocytopenia and small platelets should be tested for WASp.
- Late problems: autoimmunity and malignancy — EBV-positive B-cell lymphoma and leukaemia, mainly in adolescents and young adults.
- Definitive therapy: bone marrow transplantation is listed as beneficial.
Hyper-IgM syndrome is mostly X-linked, due to a defect in CD40 ligand (CD40L) on activated T cells. Without CD40L–CD40 interaction, B cells cannot class-switch, so IgM is normal or high while IgG, IgA and IgE are low or absent; germinal centres do not form. Because macrophage and dendritic-cell activation also needs CD40L, cell-mediated immunity is impaired too. Rarer autosomal recessive forms involve CD40, AID, UNG or NEMO.
How do chronic granulomatous disease and leukocyte adhesion deficiency present?
Chronic granulomatous disease (CGD) results from defective phagocyte NADPH oxidase, so neutrophils and macrophages cannot generate the respiratory burst that kills ingested microbes. About 70% of cases are X-linked (CYBB, gp91phox); the rest are autosomal recessive (e.g. NCF1, p47phox).
- Organisms: typically catalase-positive — Staphylococcus aureus, Burkholderia cepacia complex, Serratia marcescens, Nocardia; *Aspergillus* is the commonest fungus. BCG infection can follow vaccination.
- Presentation: pneumonia, skin abscesses and lymphadenitis, with granuloma formation.
- Diagnosis: dihydrorhodamine-123 (DHR) flow cytometry (measures hydrogen peroxide) or the older nitroblue tetrazolium (NBT) slide test (measures superoxide).
- Prophylaxis: trimethoprim–sulfamethoxazole + itraconazole, with interferon-γ in some countries — cutting severe infections from about one per patient-year to about one per ten years. Avoid live bacterial vaccines.
| Type | Defect | Clinical clues |
|---|---|---|
| LAD I | CD18 (β2 integrin) — LFA-1, Mac-1 deficient | Delayed umbilical cord separation, omphalitis, recurrent S. aureus/Pseudomonas infection, no pus, periodontitis, marked neutrophilia |
| LAD II | Absent sialyl Lewis X (selectin ligand) | Milder, fewer infections |
| LAD III | Kindlin-3 (FERMT3) — integrin activation fails | Infections plus bleeding tendency |
What are the clinical effects of complement deficiencies?
| Deficiency | Main consequence |
|---|---|
| Early classical — C1, C4, C2 | SLE and other autoimmune disease (poor clearance of apoptotic cells); C2 is the commonest after MBL and often silent |
| C3 | Severe recurrent pyogenic infections early in life |
| Late — C5, C6, C7, C8, C9 (membrane attack complex) | Recurrent *Neisseria* infection (meningococcus, gonococcus) |
| Properdin (alternative pathway; X-linked) | Recurrent Neisseria infection |
| Mannan-binding lectin | Pyogenic infection and sepsis in young children; about 5% of White people, often clinically silent |
| C1 inhibitor | Hereditary angioedema |
Screen with CH50 (classical pathway) and AH50 (alternative pathway). Low CH50 with normal AH50 suggests an early classical component (C1, C2, C4); low AH50 with normal CH50 points to factor B, factor D or properdin. For immune-complex disease mechanisms, see hypersensitivity reactions.
How do you tell the main primary immunodeficiencies apart at a glance?
| Disorder | Inheritance | Defect | Key clue | Key test/finding |
|---|---|---|---|---|
| Bruton XLA | X-linked | BTK; arrest at pre-B stage | Boy, infections after 6 months, tiny tonsils | All Ig classes low; CD19+ B cells absent |
| DiGeorge | Mostly de novo 22q11.2 deletion | Third/fourth pouch maldevelopment | Hypocalcaemic seizures + conotruncal defect | Low T cells; chromosomal microarray (first-tier) |
| SCID | X-linked or autosomal recessive | Common gamma chain, ADA, RAG1/2, IL-7Rα | Infant with failure to thrive, diarrhoea, pneumonia | Very low T cells |
| Wiskott–Aldrich | X-linked | WASp | Eczema + bleeding with small platelets | IgM low, IgA/IgE high |
| Hyper-IgM | Mostly X-linked | CD40 ligand | Recurrent infection, no class switch | IgM normal/high, IgG/IgA/IgE low |
| CGD | X-linked (about 70%) or AR | NADPH oxidase | Catalase-positive abscesses, Aspergillus | Abnormal DHR or NBT |
| LAD I | Autosomal recessive | CD18 (β2 integrin) | Delayed cord separation, no pus | Marked neutrophilia |
| Terminal complement | Mostly autosomal recessive | C5–C9 | Recurrent Neisseria | Low CH50 |