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
  • Refer to 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 toll-like receptor (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

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

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 pneumoniae, Shigella 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