StepWise USMLE
IMMUNOLOGY Β· HOST DEFENSE

Immunodeficiency Β· integrated review

Phagocytes, antibodies, complement, and T cells each protect against a different set of pathogens β€” so each failure has its own signature infection pattern.

πŸ• Big Picture: Reading the Age of Onsetframework

  • Immunodeficiencies can hit any arm of defense β€” innate (phagocytes, complement) or adaptive (B cells, T cells)
  • Most present in infancy/early childhood, and the timing is a clue in itself
  • Maternal IgG crosses the placenta and protects the newborn for the first several months
    • Largely gone by ~6 months, fully gone by ~12–15 months
    • A pure antibody defect often stays clinically silent until maternal IgG runs out
  • A baby who gets sick before 6 months with severe infections (especially fungal/viral) points more toward a T-cell or combined defect, since T-cell immunity isn't covered by maternal antibody
  • Many of these diseases are X-linked β†’ skewed toward males

🧫 Phagocyte Defectsinnate immunity

phagocyte engulfs microbe→ respiratory burst (NADPH oxidase)→ superoxide → H₂O₂→ MPO converts to hypochlorite→ microbial killing
DiseaseWhat's brokenClinical signature
Chronic granulomatous diseaseNADPH oxidase (any of its subunits) β†’ no respiratory burstRecurrent infection with catalase-positive organisms (they neutralize their own peroxide, and the phagocyte can't compensate)
Myeloperoxidase deficiencyCan't convert Hβ‚‚Oβ‚‚ to hypochloriteUsually mild/asymptomatic β€” other killing pathways compensate
G6PD deficiencyHexose monophosphate shunt can't regenerate NADPHCGD-like infection pattern, plus hemolytic anemia
Leukocyte adhesion deficiencyMissing CD18 (shared chain of the Ξ²2-integrins LFA-1, Mac-1, gp150/95)Neutrophils can't firmly adhere/migrate β†’ no pus formation, delayed umbilical cord separation
Chediak-Higashi syndromeLYST gene β†’ abnormal lysosomal vesicle fusion/traffickingRecurrent pyogenic infection, absent NK cytotoxicity, partial albinism (giant granules in melanocytes too)
Hyper-IgE syndrome (Job syndrome)STAT3 pathway defect β†’ impaired Th17 differentiationCoarse facies, "cold" skin abscesses, recurrent pneumonia with pneumatocele formation, retained primary teeth, markedly elevated IgE
Pattern to rememberAnything that cripples the neutrophil's killing machinery shows up as recurrent bacterial/fungal skin and organ infections rather than viral disease.
CGD respiratory burst short video thumbnail
β–Ά CGD & the respiratory burst Β· @StepWiseUSMLE

πŸ…±οΈ Antibody (Humoral) Defectsadaptive immunity

  • Shared theme: B cells fail somewhere along maturation or antibody production β†’ recurrent infection with encapsulated/pyogenic organisms, usually once maternal IgG fades
DiseaseDefectKey featuresTreatment
Bruton (X-linked) agammaglobulinemiaBTK kinase defect β†’ B cells arrest at the pre-B stageAll immunoglobulin isotypes low/absent, few or no circulating B cells; T-cell immunity intactRegular IVIG replacement + antibiotics for infections
X-linked hyper-IgM syndromeCD40 ligand missing on activated T cells β†’ no class switchingHigh IgM only, other isotypes low; normal B- and T-cell counts; susceptible to encapsulated bacteria and opportunistsAntibiotics + immunoglobulin replacement
Selective IgA deficiencyMultiple genetic causes, most common primary immunodeficiency overallLow IgA with normal IgG/IgM; recurrent sinopulmonary and GI infection; increased atopyAntibiotics only β€” not immunoglobulin (anaphylaxis risk, covered earlier)
Common variable immunodeficiencyHeterogeneous group of B-cell maturation defectsLater onset (late teens–20s); B cells present but antibody production falls over time; increased autoimmunityAntibiotics Β± immunoglobulin depending on severity
Transient hypogammaglobulinemia of infancyJust a delay in the infant's own IgG synthesis ramping upNoticed around 5–6 months, resolves by 16–30 months; increased pyogenic infection in the interimUsually supportive; gamma-globulin only if severe

🧩 Complement Pathway Defectsinnate immunity

  • Early classical-pathway components (C1q, C1r, C1s, C4, C2)
    • These normally help clear immune complexes
    • Deficiency β†’ immune-complex disease (lupus-like), plus more pyogenic infection
  • C3 (the convergence point of all pathways)
    • Most severe complement deficiency clinically
    • Recurrent bacterial infection + immune-complex disease
  • Terminal components (C5–C9 β†’ membrane attack complex)
    • MAC is specifically needed to lyse Neisseria
    • Deficiency β†’ recurrent meningococcal/gonococcal infection, otherwise fairly well
  • C1 esterase inhibitor (regulatory protein, not a pathway component)
    • Deficiency = hereditary angioedema
    • Unchecked C1, C4, C2 activation β†’ recurrent episodic mucosal/submucosal swelling without urticaria
Exam trapTerminal complement (C5-9) deficiency = the classic setup for recurrent Neisseria infection, not general pyogenic infection.

🧬 T-Cell & Combined Immunodeficienciesadaptive immunity

  • T cells sit at the center of nearly every adaptive response β€” a T-cell defect ripples outward, so these tend to be more devastating and harder to pin down than an isolated B-cell defect
  • Classic tell: opportunistic fungal/viral infection appearing very early in infancy, before maternal antibody has worn off
CategoryDiseaseMolecular defectClinical picture
Selective T-cell defectDiGeorge syndrome22q11 deletion β†’ failed 3rd/4th pharyngeal pouch development β†’ thymic hypoplasiaCardiac defects, hypocalcemia (absent parathyroids), characteristic facies, thymic aplasia
Selective T-cell defectMHC class I deficiencyTAP transporter failure β€” peptides can't load onto MHC-ICD8+ T cells low, CD4+ normal; recurrent viral infection
Combined (partial)Wiskott-Aldrich syndromeWAS gene β†’ defective actin cytoskeleton remodelingTriad: eczema, thrombocytopenia, recurrent infection (poor response to polysaccharide antigen, low IgM, progressive loss of both B- and T-cell function)
Combined (partial)Ataxia-telangiectasiaATM kinase defect β†’ impaired DNA-damage responseCerebellar ataxia, ocular/skin telangiectasias, low IgA and IgE
Complete combinedSCID β€” X-linkedCommon Ξ³-chain (shared by IL-2,-4,-7,-9,-15 receptors) defectVery low lymphocytes, no response to mitogens, chronic diarrhea, mucocutaneous lesions, opportunistic fungal infection
Complete combinedSCID β€” ADA deficiencyAdenosine deaminase deficiency β†’ toxic metabolite buildup in lymphocytesSimilar to X-linked SCID, plus neurologic involvement
Complete combinedSCID β€” RAG1/RAG2 mutationFailure of V(D)J recombinationEssentially no mature B or T cells at all
Complete combinedBare lymphocyte syndrome (MHC class II deficiency)Transcription-factor defect β†’ no MHC-II expressionCD4+ T cells deficient, hypogammaglobulinemia, no graft-vs-host disease (can't recognize foreign MHC-II)
Why B-cell symptoms lag in these diseasesPassive maternal antibody still covers the humoral gap for the first few months, so the B-cell half of a combined defect often isn't apparent until later.

⭐ High-Yield Pearlsexam focus

  • Recurrent infection + no pus + delayed cord separation β†’ leukocyte adhesion deficiency
  • Recurrent infection + catalase-positive organisms β†’ chronic granulomatous disease
  • Partial albinism + giant granules + absent NK activity β†’ Chediak-Higashi
  • Coarse face + cold abscesses + sky-high IgE β†’ hyper-IgE (Job) syndrome
  • All isotypes low, no circulating B cells, boy, recurrent bacterial infection β†’ Bruton agammaglobulinemia
  • IgM sky-high, everything else low β†’ hyper-IgM syndrome (CD40L defect)
  • Low IgA + risk of anaphylaxis to blood products β†’ selective IgA deficiency
  • Recurrent Neisseria specifically β†’ terminal complement (C5-9) deficiency
  • Episodic swelling without hives, no response to antihistamines β†’ C1 esterase inhibitor deficiency (hereditary angioedema)
  • Cardiac defect + hypocalcemia + absent thymus in a newborn β†’ DiGeorge syndrome
  • Eczema + thrombocytopenia + infections in a boy β†’ Wiskott-Aldrich syndrome
  • Ataxia + telangiectasia + low IgA β†’ ataxia-telangiectasia
  • Profound infection, no lymphocytes, presents in early infancy β†’ SCID