Immunodeficiency, Innate System

Diagnosis

Indications for Testing

• Child with recurrent infections after more common immunodeficiencies have been ruled out

Laboratory Testing

• Screen for more common immunodeficiencies
  • Immunoglobulin testing
    • If hypogammaglobulinemia is present, consider ectodermal dysplasia
  • Complement testing
  • Cell-mediated immunity testing
  • Neutrophil function testing
  • See Immunodeficiency Evaluation for Chronic Infections in Adults and Older Children and Immunodeficiency Evaluation for Chronic Infections in Infants and Children algorithms
• If all above screening tests are normal, order IRAK4 and TLR function testing
  • If IRAK4  and TLR are negative, consider other genetic types (MYD88, TLR3, UNC93B1)

Differential Diagnosis

• Neutropenic disorders
• Chronic granulomatous disease
• Chédiak-Higashi
• Ectodermal dysplasia
• Job syndrome
• Leukocyte adhesion deficiency

Clinical Background

Immunodeficiencies associated with impaired innate immunity (nuclear factor kappa B signaling) include disruptions to signaling pathways for IRAK4, MYD88, and TLR3 and may be associated with recurrent pyogenic bacterial infections.

Epidemiology

• Incidence
  • IRAK4 – rare; <30 affected individuals worldwide as of 2006
  • MYD88 – rare
  • TLR3 – 1/250,000

Inheritance

• Autosomal recessive inheritance – all are familial syndromes

Pathophysiology

• Toll-like receptor (TLR) activation involves adapter genes MYD88 and IRAK4
  • IRAK4 – plays an essential role in TLR and IL-1A receptor-mediated signaling
  • TLR3 triggers activation of IL1A
• Broad defect in nuclear factor kappa B signaling with impaired TLR function
• TLRs function as recognition factors for microbial and viral ligands
  • Enables innate immunity to induce appropriate cytokine pathways (by stimulating TNFα, IL-1B and IL-6) to prevent infection

Clinical Presentation

• Severe recurrent infections occur in deficiency
  • IRAK4/MYD88
    • Normal appearance
    • Particular susceptibility to Streptococcus pneumoniae, Shigella sonnei, Staphylococcus aureus
      • All invasive infections occur before age 14
    • TLR3, UNC93B1 – selective susceptibility to herpes encephalitis 

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Diagnostic Algorithm

  Immunodeficiency Evaluation for Chronic Infections in Adults and Older Children Testing Algorithm

  Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm