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

  • 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

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

Recommended Use 

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)

Limitations 

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

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

Al-Herz W, Bousfiha A, Casanova J, Chatila T, Conley ME, Cunningham-Rundles C, Etzioni A, Franco JL, Gaspar B, Holland SM, Klein C, Nonoyama S, Ochs HD, Oksenhendler E, Picard C, Puck JM, Sullivan K, Tang ML. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2014; 5: 162. PubMed

General References

Immune Deficiency Foundation. Towson, MD [Accessed: Nov 2015]

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

Hill, Harry R., MD, Medical Director, Immunology and Infectious Disease at ARUP Laboratories; Professor of Clinical Pathology and Pediatrics; Adjunct Professor, Internal Medicine, University of Utah

Kumanovics, Attila, MD, Assistant Medical Director, Co-Director, Immunology Laboratory, Immunogenetics at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

Agammaglobulinemia
Chronic Granulomatous Disease - CGD
Common Variable Immune Deficiency Syndromes - CVID
Complement Deficiency
Congenital Neutrophil Disorders
Immunoglobulin Disorders
Leukocyte Adhesion Deficiency
Severe Combined Immunodeficiencies - SCID
T-Cell Deficiency Disorders, Inherited

Last Update: August 2016

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