Immunodeficiency, TLR-Signaling Defects

Diagnosis

Indications for Testing

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

Laboratory Testing

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

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 deficiency – rare
    • MYD88  deficiency – rare
    • TLR3 deficiency – 1/250,000

Inheritance

  • Autosomal recessive inheritance – all are familial syndromes

Pathophysiology

  • Toll-like receptor (TLR) activation involves adapter proteins 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

  • Severe recurrent infections occur, often with pus
  • Normal appearance
  • TLR3, UNC93B1, TRAF3, TRIF, TBK1 – 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
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 or MYD88 deficiency in children with recurrent life-threatening bacterial infections with weak signs of inflammation or negative evaluation for other more common immunodeficiencies

Not a first-line test for immunodeficiency evaluation

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