STEPTRACKERGENERAL PRINCIPLES | IMMUNOLOGY + PATHOLOGY | HIGH-YIELD REVIEW

Primary Immunodeficiencies

Inherited holes in the immune system — the infection pattern tells you which arm is missing.

FOCUS ON
Infections with encapsulated bacteria after 6 months point to an antibody defect. Viruses, fungi and opportunists point to a T-cell defect. A mix of both means a combined defect. Then use the one extra clue: eczema with small platelets, ataxia, hypocalcemia, transfusion anaphylaxis.
DISORDER
DEFECT
PRESENTATION
LAB CLUE
X-linked (Bruton) agammaglobulinemia
B cell
BTK tyrosine kinase → B cells stop maturing · X-linked
Boy, sinopulmonary infections with encapsulated bacteria after 6 months; enterovirus, Giardia; no tonsils or nodes
All Ig ↓; CD19⁺ B cells absent
Selective IgA deficiency
most common
Failure of IgA-producing B cells
Often silent; sinus/lung/GI infections, Giardia, autoimmunity, celiac; anaphylaxis to blood products
IgA ↓, others normal; tTG-IgA falsely negative
Common variable immunodeficiency
B-cell differentiation
B cells present but fail to become plasma cells
Usually 20s–30s; recurrent infections, autoimmunity, granulomas, lymphoma risk
Ig ↓ with normal B-cell count
DiGeorge syndrome
T cell
22q11.2 deletion → 3rd/4th pharyngeal pouch failure
Thymic aplasia (viral/fungal infections), hypocalcemic tetany, conotruncal heart defects, cleft palate, facial anomalies
Absent thymic shadow; ↓ T cells; ↓ Ca²⁺, ↓ PTH
SCID
B + T
IL-2Rγ (common γ chain, X-linked), ADA deficiency (toxic dATP), RAG defects
Infant: failure to thrive, chronic diarrhea, thrush, recurrent viral, bacterial, fungal and opportunistic infections
Low TRECs on newborn screen; no thymic shadow, no germinal centers
Wiskott-Aldrich syndrome
combined
WAS gene → cytoskeleton defect in leukocytes and platelets · X-linked
Triad: thrombocytopenia (small platelets), eczema, recurrent infections; autoimmunity, lymphoma
↓ IgM, ↑ IgE and IgA
Hyper-IgM syndrome
class switch
CD40L on T helper cells (X-linked most common) → no class switching
Severe pyogenic infections early; Pneumocystis, Cryptosporidium, CMV
↑ IgM; ↓ IgG, IgA, IgE
Ataxia-telangiectasia
DNA repair + immunity
ATM defect → double-strand break repair fails · autosomal recessive
Cerebellar ataxia, telangiectasias, sinopulmonary infections, lymphoma/leukemia risk, radiation sensitivity
↑ AFP; ↓ IgA, IgG, IgE
IL-12 receptor / IFN-γ axis defect
Th1 loop
Macrophages can't drive Th1, or can't respond to IFN-γ
Disseminated mycobacterial (incl. BCG) and Salmonella infections
↓ IFN-γ
Complement deficiencies
plasma proteins
C3 · C5–C9 · C1-esterase inhibitor · early components (C1, C2, C4)
C3: severe pyogenic infections · C5–C9: Neisseria · C1-INH: hereditary angioedema · early: SLE-like disease
CH50 screens the classical pathway

Mechanism — where development stops

Stem cellSCID: ADA, IL-2Rγ, RAG
→
Pre-B → BBruton: BTK
→
Class switchHyper-IgM: CD40L
→
Plasma cellCVID, IgA deficiency
ThymusDiGeorge: no thymus
→
T-cell functionWAS, A-T, IL-12R
→
Help to B cellsCD40L (hyper-IgM)

Infection pattern → arm affected

INFECTIONS
MISSING ARM
Encapsulated bacteria, after 6 months
Antibodies (B cells) — maternal IgG has worn off
Viruses, Candida, Pneumocystis
T cells
Both from early infancy
Combined (SCID, WAS, hyper-IgM)
Catalase-positive, abscesses
Phagocytes (page 2.03)
Recurrent Neisseria
Terminal complement C5–C9

No live vaccines in severe T-cell or combined defects.

How it's tested

COMMON CONFUSIONBruton: B cells absent. CVID: B cells present but immunoglobulins low. Count the CD19⁺ cells.
THE TRAPAnaphylaxis minutes into a first transfusion is selective IgA deficiency. The patient's anti-IgA antibodies react with donor IgA, so use IgA-deficient or washed products.
YOUR APPROACHUse age of onset and infection type to pick the arm, then the extra clue to name the gene.

If you see… think…

Boy, recurrent otitis/pneumonia from 6 months, no tonsils, no B cells → Bruton (BTK)
Anaphylaxis during transfusion → selective IgA deficiency
Neonatal tetany + truncus arteriosus + absent thymus → DiGeorge (22q11.2)
Infant with thrush, diarrhea, no thymic shadow, low TRECs → SCID
Boy with eczema, petechiae, tiny platelets, infections → Wiskott-Aldrich
High IgM, absent IgG, Pneumocystis in infancy → CD40L (hyper-IgM)
Ataxic child with eye telangiectasias and ↑ AFP → ataxia-telangiectasia (ATM)
Adult with sinusitis, low Ig, normal B-cell count → CVID
Disseminated BCG after vaccination → IL-12 / IFN-γ receptor defect
Toxic dATP buildup kills lymphocytes → ADA-deficient SCID