• 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)
  • Leukocyte adhesion deficiency type 1
  • Chédiak-Higashi syndrome
  • Myeloperoxidase deficiency
• Complement system > Complement deficiencies

Common Pathogens and Mechanisms

Immunodeficiency Type	Common Pathogens	Common Infection Sites	Underlying Mechanism
B-cell Deficiencies	- Encapsulated bacteria (S. pneumoniae, H. influenzae, M. catarrhalis) - Giardia lamblia - Nonenveloped viruses (enterovirus, rotavirus)	- Sinuses - Ears - Lungs - Bloodstream - GI tract	Decreased or absent antibody production impairs opsonization and neutralization of pathogens, especially encapsulated bacteria that require antibody-mediated clearance
T-cell Deficiencies	- Viruses (CMV, EBV, VZV, HSV) - Fungi (Candida, P. jirovecii) - Mycobacteria - Intracellular parasites	- Skin/mucous membranes - Lungs - CNS - Systemic dissemination	Impaired cell-mediated immunity against intracellular pathogens, defective cytokine production, and decreased killing of infected cells
Combined Immunodeficiencies	- Broad spectrum of pathogens - Bacteria, viruses, fungi, protozoa - Opportunistic infections - Live vaccine strains	- Multiple organ systems - Lungs - GI tract - Skin - Systemic infections	Profound defects in both cellular and humoral immunity, affecting both adaptive and innate immune functions
Neutrophil/Phagocyte Disorders	- Catalase-positive bacteria (S. aureus, Burkholderia, Serratia, Nocardia) - Fungi (Aspergillus, Candida) - Gram-negative bacteria	- Skin/soft tissue abscesses - Lungs - Liver abscesses - Lymph nodes - GI tract	Defective phagocyte recruitment, ingestion, or killing of pathogens; impaired respiratory burst (in CGD); defective chemotaxis
Complement Deficiencies	- Encapsulated bacteria - Neisseria species (meningitidis, gonorrhoeae) - S. pneumoniae - H. influenzae	- Meninges - Bloodstream - Respiratory tract - Urogenital tract	Impaired opsonization and bacterial killing (like B cell deficiency)

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