• B-cell immunodeficiencies (pyogenic and sinopulmonary infections, especially by encapsulated bacteria. See Asplenia)
  • X-linked (Bruton) agammaglobulinemia
    • Patho: Defect in BTK gene (tyrosine kinase) -> Blocks B-cell maturation.
    • T: Normal, B: ↓↓/Absent.
    • Feature: Absent B cells/Igs, absent tonsils, bacterial infx after 6mo.
  • Selective IgA deficiency
    • Patho: Unknown defect impairing class switching to IgA.
    • T: Normal, B: Normal # but no IgA secretion.
    • Feature: Most common; IgA anaphylaxis risk.
  • Common variable immunodeficiency
    • Patho: Defect in B-cell differentiation into plasma cells (heterogeneous causes).
    • T: Normal, B: Normal #, ↓plasma cells/Igs.
    • Feature: Late onset, ↓IgG/A/M, lymphoma/autoimmune risk.
• T-cell immunodeficiencies (more abnormalities)
  • DiGeorge syndrome
    • Patho: 22q11.2 deletion -> Failure of 3rd/4th pharyngeal pouch development.
    • T: ↓↓/Absent (thymic aplasia), B: Normal #.
    • Feature: CATCH-22 (Thymic/Parathyroid aplasia).
  • Autosomal dominant hyper-IgE syndrome (Job syndrome)
    • Patho: AD STAT3 mutation -> Impaired Th17 differentiation -> Impaired neutrophil recruitment.
    • T: ↓Th17, B: ↑↑IgE.
    • Feature: FATED (Cold abscesses, retained teeth, eczema, ↑IgE).
  • IL-12 receptor deficiency
    • Patho: Defective IL-12 receptor -> Reduced Th1 response, ↓IFN-γ production.
    • T: ↓Th1 function, B: Normal.
    • Feature: Disseminated mycobacteria/fungi.
  • Chronic mucocutaneous candidiasis
    • Patho: T-cell dysfunction specifically against Candida antigens (various genetic causes, e.g., AIRE).
    • T: Anti-Candida defect, B: Normal.
    • Feature: Persistent Candida (skin/mucosa only).
  • IPEX syndrome
    • Patho: FOXP3 mutation (X-linked) -> Defective regulatory T cells (Tregs).
    • T: ↓Tregs, B: Normal #.
    • Feature: Severe Autoimmunity (Enteropathy, Endocrinopathy).
• Combined immunodeficiencies
  • Severe combined immunodeficiency
    • Patho: Various defects (e.g., IL-2R gamma chain [X-linked], ADA deficiency [AR]) -> Failure of T-cell +/- B/NK cell development.
    • T: ↓↓/Absent, B: ↓↓/Non-functional.
    • Feature: Severe infections early, absent thymus shadow, live vaccine contraindicated.
  • Wiskott-Aldrich syndrome (WAS)
    • Patho: WAS gene mutation (X-linked) -> Defective WASp protein impairs actin cytoskeleton in hematopoietic cells.
    • T: ↓Progressive, B: ↓IgM, ↑IgA/E.
    • Feature: WATER (Thrombocytopenia with small platelets, Eczema, Infections).
  • Hyper-IgM syndrome
    • Patho: Most commonly CD40L defect (T-cell, X-linked) -> Failure of T-cell help for B-cell class switching.
    • T: No CD40L function, B: No class switch.
    • Feature: ↑IgM, ↓Others; Pneumocystis risk.
  • Ataxia telangiectasia
    • Patho: ATM gene mutation (AR) -> Defective DNA double-strand break repair.
    • T: ↓, B: ↓ (esp. IgA).
    • Feature: Triad (Ataxia, Telangiectasias, Infections); ↑AFP, radiation sensitivity.
• Neutrophil and phagocyte disorders
  • Chronic granulomatous disease (CGD)
    • Patho: Defect in NADPH oxidase (e.g., CYBB gene) → Impaired generation of reactive oxygen species → Defective killing of catalase-positive organisms.
    • Cells: Phagocytes ingest but can't kill certain pathogens.
    • Feature: Recurrent infections (catalase+ bacteria/fungi like S. aureus, Aspergillus), granulomas. DHR test for diagnosis.
  • Leukocyte adhesion deficiency type 1 (LAD-1)
    • Patho: Defect in β2 integrin (CD18) (ITGB2 gene) → Impaired leukocyte adhesion and migration.
    • Cells: ↑↑Neutrophils in blood (leukocytosis) as they can't exit vessels.
    • Feature: Recurrent bacterial/fungal infections without pus, delayed umbilical cord separation, impaired wound healing.
  • Chédiak-Higashi syndrome
    • Patho: LYST gene mutation → Defective lysosomal trafficking → Impaired phagosome-lysosome fusion; abnormal giant granules.
    • Cells: Neutropenia, defective degranulation/chemotaxis, giant granules in leukocytes.
    • Feature: Recurrent pyogenic infections, partial albinism, neuropathy, bleeding tendency, risk of lymphoproliferative phase.
  • Myeloperoxidase deficiency
    • Patho: MPO gene defect → Deficient myeloperoxidase → Reduced hypochlorous acid production.
    • Cells: Impaired killing of Candida and some bacteria by neutrophils.
    • Feature: Mostly asymptomatic; increased risk of Candida infections (especially disseminated in diabetics).
• Complement system#Complement deficiencies

Common Pathogens and Mechanisms

Clinical Pearls:

• Recurrent sinopulmonary infections with encapsulated bacteria suggest antibody deficiency
• Mucocutaneous candidiasis points toward T-cell dysfunction
• Severe, life-threatening infections beginning in early infancy suggest SCID
• Deep-seated abscesses with catalase-positive organisms suggest chronic granulomatous disease
• Recurrent Neisserial infections are hallmarks of terminal complement deficiencies