Immunodeficiency, TLR-Signaling Defects

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

Indications for Testing

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

Laboratory Testing

Differential Diagnosis

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
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.

Toll-Like Receptor Function 0051589
Method: Cell Culture/Quantitative Multiplex Bead Assay

Limitations 

Defects in TLR3 associated with herpes simplex encephalitis may not be detected in this assay based on the reported instance of a patient with compound heterozygous mutations in TLR3 leading to decreased cytokine production in response to Poly I:C in fibroblasts but not PBMCs1

Guidelines

Picard C, Al-Herz W, Bousfiha A, Casanova J, Chatila T, Conley ME, Cunningham-Rundles C, Etzioni A, Holland SM, Klein C, Nonoyama S, Ochs HD, Oksenhendler E, Puck JM, Sullivan KE, Tang ML, Franco JL, Gaspar B. Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J Clin Immunol. 2015; 35(8): 696-726. PubMed

General References

Immune Deficiency Foundation. Towson, MD [Accessed: May 2017]

Picard C, Casanova J, Puel A. Infectious diseases in patients with IRAK-4, MyD88, NEMO, or IκBα deficiency. Clin Microbiol Rev. 2011; 24(3): 490-7. PubMed

Puel A, Picard C, Ku C, Smahi A, Casanova J. Inherited disorders of NF-kappaB-mediated immunity in man. Curr Opin Immunol. 2004; 16(1): 34-41. PubMed

Suzuki N, Saito T. IRAK-4--a shared NF-kappaB activator in innate and acquired immunity. Trends Immunol. 2006; 27(12): 566-72. PubMed

Yavuz I, Baskan Z, Ulku R, Dulgergil TC, Dari O, Ece A, Yavuz Y, Dari KO. Ectodermal dysplasia: Retrospective study of fifteen cases. Arch Med Res. 2006; 37(3): 403-9. PubMed

Medical Reviewers









Last Update: May 2017