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

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-1β and IL-6) to prevent infection

Clinical Presentation

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
Test Name and Number Recommended Use Limitations Follow Up
Toll-Like Receptor Function 0051589
Method: Cell Culture/Quantitative Multiplex Bead Assay

Assist in diagnosis of innate immunodeficiencies when genetic defects of the innate immune system are suspected in individuals negative for other immunodeficiencies (eg, no detectable abnormality of antibody function, complement activity, neutrophil function, or cell mediated immunity)

Results should be interpreted in light of the individual’s clinical status

 
Interleukin-1-Receptor-Associated Kinase-4 (IRAK-4) Deficiency Screen 0051393
Method: Cell Culture/Quantitative Multiplex Bead Assay

Screen for IRAK4 deficiency in patients negative for other immunodeficiencies

Not a first-line test for immunodeficiency evaluation

Results should be interpreted in light of the individual’s clinical status