Immunodeficiency, TLR-Signaling Defects

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.

Diagnosis

Indications for Testing

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

Laboratory Testing

Differential Diagnosis

Background

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
    • Particular susceptibility to Streptococcus pneumoniaeShigella sonnei, Staphylococcus aureus, and Pseudomonas aeruginosa
    • All invasive infections occur before age 14 with spontaneous improvement for most after age 14
    • Normal resistance to other common organisms
  • Normal appearance
  • TLR3, UNC93B1, TRAF3, TRIF, TBK1 – selective susceptibility to herpes encephalitis

ARUP Laboratory Tests

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)

Medical Experts

Contributor

Hill

Harry R. Hill, MD
Professor of Clinical Pathology, Pediatrics, and Medicine, University of Utah
Medical Director, Cellular and Innate Immunology, ARUP Laboratories

References

Additional Resources