⚡ Defects of phagocytic cells

Overview: Phagocytes (neutrophils, monocytes) rely on oxidative burst, adhesion, and granule fusion. Inherited defects impair pathogen clearance, especially catalase‑positive organisms.

Chronic granulomatous disease (CGD)

  • Defect: NADPH oxidase deficiency (any of 4 subunits) → no superoxide / reactive oxygen species.
  • Infections: catalase‑positive bacteria (Staph. aureus, Burkholderia, Serratia) & fungi (Aspergillus).
  • Diagnosis: DHR (dihydrorhodamine) flow assay or NBT test.
  • Treatment: prophylactic TMP‑SMX, interferon‑γ, antifungal.

Leukocyte adhesion deficiency (LAD)

  • Defect: absence of CD18 (common β chain of integrins LFA‑1, Mac‑1, gp150/95).
  • Features: recurrent soft‑tissue infections, delayed umbilical cord separation, failure to form pus.
  • Lab: marked neutrophilia, absent CD18 on flow cytometry.
  • Management: prompt antibiotics, bone marrow transplant.

Chediak‑Higashi syndrome

  • Defect: LYST mutation → defective lysosomal trafficking, giant granules in leukocytes.
  • Clinical: partial albinism, recurrent pyogenic infections, peripheral neuropathy, absent NK function.
  • Accelerated phase: hemophagocytic lymphohistiocytosis (HLH).

Other phagocyte defects

  • G6PD deficiency: impaired HMP shunt → similar to CGD (plus hemolytic anemia).
  • Myeloperoxidase deficiency: mild or asymptomatic; impaired H2O2 → hypochlorite.
  • Hyper‑IgE (Job) syndrome: STAT3 mutation → impaired Th17, elevated IgE, retained primary teeth, eczema, bone fractures.
📌 High‑yield: CGD → catalase‑positive organisms (because catalase destroys H2O2 that other bacteria might produce). LAD → delayed umbilical cord separation.

🧪 Defects of humoral immunity

B‑cell disorders lead to recurrent infections with encapsulated bacteria (e.g., Streptococcus pneumoniae, Haemophilus) and enteroviruses.

Bruton (X‑linked) agammaglobulinemia

  • Defect: mutation in Bruton tyrosine kinase (BTK) → block at pre‑B cell stage.
  • Clinical: recurrent sinopulmonary infections after 6 months (maternal IgG wanes).
  • Lab: absent B cells, very low all Ig isotypes; T‑cell immunity intact.
  • Treatment: IVIG replacement, antibiotics.

X‑linked hyper‑IgM syndrome

  • Defect: CD40L deficiency on T cells → failure of class switching.
  • Lab: high IgM, low IgG/IgA; normal B and T cell counts.
  • Infections: encapsulated bacteria + opportunistic (PCP, Cryptosporidium).
  • Treatment: IVIG, prophylaxis.

Selective IgA deficiency

  • Most common: IgA < 7 mg/dL with normal IgG/IgM (IgE often elevated).
  • Associations: atopy, autoimmune disease, GI infections.
  • Caution: anaphylaxis to blood products (anti‑IgA antibodies).
  • Often asymptomatic; treat infections, avoid immunoglobulin.

Common variable immunodeficiency (CVID)

  • Onset: late teens – 20s; reduced IgG, IgA, and/or IgM.
  • B cells present but fail to differentiate into plasma cells.
  • Features: recurrent infections, autoimmune cytopenias, granulomatous disease.
  • Treatment: IVIG, antibiotics.
⚠️ Transient hypogammaglobulinemia of infancy: physiologic delay in IgG production, resolves by 16–30 months. Treat only severe infections.

🧬 Complement deficiencies & regulation

Classic pathway (C1q, C1r, C1s, C4, C2)

  • Presentation: immune‑complex diseases (SLE‑like), pyogenic infections.
  • C2 deficiency is the most common classic pathway defect.

C3 deficiency

  • Severe recurrent bacterial infections + immune‑complex disease (both pathways affected).

Terminal pathway (C5–C9)

  • Recurrent meningococcal & gonococcal infections (due to loss of membrane attack complex).
  • Consider in patients with recurrent Neisseria.

Regulatory defects

  • C1‑INH deficiency (hereditary angioedema): overactivation of C1, C4, C2 → mucosal edema (larynx, GI), normal urticaria.
  • Treatment: bradykinin antagonists, C1‑INH concentrate.

🛡️ T‑cell defects & severe combined immunodeficiency

T‑cell defects have broad consequences because T cells orchestrate adaptive immunity. SCID presents within first months with failure to thrive, opportunistic infections, and absence of T cells.

DiGeorge syndrome (22q11.2 deletion)

  • Defect: 3rd/4th pharyngeal pouch failure → thymic aplasia, hypoparathyroidism.
  • Triad: cardiac anomalies, hypocalcemia, hypoplastic thymus.
  • Immunity: low T cells (CD4+ & CD8+); B cells normal.

MHC class I deficiency (TAP defect)

  • Defective peptide transport → low CD8+ T cells; recurrent viral infections.
  • DTH and antibody responses are preserved.

Wiskott‑Aldrich syndrome (WAS)

  • X‑linked: WASp defect → impaired actin cytoskeleton.
  • Triad: eczema, thrombocytopenia, recurrent infections.
  • Low IgM, elevated IgA/IgE; defective response to polysaccharides.

Ataxia‑telangiectasia

  • ATM kinase defect → ataxia, telangiectasias (ocular), IgA & IgE deficiency.
  • High risk of malignancy, radiosensitivity.

Severe combined immunodeficiency (SCID) variants

TypeDefectKey features
X‑linked SCIDCommon γ‑chain (IL‑2,‑4,‑7,‑9,‑15 receptors)Absent T & NK cells; B cells present but nonfunctional
Adenosine deaminase (ADA) deficiencyPurine metabolism → toxic dATPSCID + neurologic abnormalities, bony abnormalities
RAG1/RAG2 deficiencyV(D)J recombination failureAbsent T and B cells (T− B− NK+), Omenn syndrome possible
Bare lymphocyte syndrome (MHC II)Defective MHC II expressionCD4+ T‑cell deficiency, hypogammaglobulinemia, viral/fungal infections
🧠 Clinical pearl: SCID infants often present with Pneumocystis jirovecii pneumonia, oral thrush, and chronic diarrhea. Avoid live vaccines (BCG, rotavirus, MMR).

📊 Comparison table · high‑yield defects

DiseaseDefectInfections / hallmark
CGDNADPH oxidaseCatalase‑positive bacteria, fungi
LADCD18 integrinDelayed cord separation, no pus
Bruton agammaglobulinemiaBTKEncapsulated bacteria, enteroviruses
Hyper‑IgMCD40LOpportunistic infections + low IgG/A
Selective IgA deficiencyMultiple genesAtopy, GI infections, anti‑IgA risk
DiGeorge22q11.2Hypocalcemia, cardiac, absent thymus
Wiskott‑AldrichWASpEczema, thrombocytopenia, low IgM
SCID (X‑linked)γ‑chain IL‑2RAbsent T & NK, infections early

🧩 High‑yield pearls & recall

🔹 X‑linked immunodeficiencies (males predominance): Bruton, Wiskott‑Aldrich, X‑SCID, X‑linked hyper‑IgM.
🔹 Maternal IgG protects until ~6 months; therefore, B‑cell defects often present after that age.
🔹 Encapsulated bacteria (S. pneumoniae, H. influenzae, Neisseria) → defect in antibody / complement (C3, C5–C9, B‑cell defects).
🔹 Opportunistic infections (PCP, fungi, viruses) → T‑cell defect / SCID.

❓ Recall question

Increased susceptibility to encapsulated bacteria and bloodborne viruses is predominantly seen in which condition?

  • CGD
  • Bruton agammaglobulinemia ✅
  • Chediak‑Higashi
  • Leukocyte adhesion deficiency
  • Wiskott‑Aldrich
  • Ataxia‑telangiectasia

Answer: Bruton agammaglobulinemia (B‑cell defect → impaired response to encapsulated bacteria & enteroviruses).

📖 Treatment & management details

Management principles

  • Antibiotic prophylaxis: TMP‑SMX for CGD, azithromycin for some.
  • Immunoglobulin replacement: IVIG (or SCIG) for Bruton, CVID, hyper‑IgM.
  • Hematopoietic stem cell transplant: curative for SCID, WAS, LAD, CGD.
  • Gene therapy: ADA‑SCID, X‑SCID (clinical trials).
  • Avoid live vaccines in T‑cell defects / SCID.
Defect identified → Prophylaxis / IVIG → HSCT if severe → Monitor for autoimmunity/malignancy
END