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.

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Clinical Overview

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

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

ARUP Lab Tests

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

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

Medical Experts

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

References

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

Testing Algorithms

Immunodeficiency Evaluation for Chronic Infections in Adults and Older Children Testing Algorithm

Read more about Immunodeficiency Evaluation for Chronic Infections in Adults and Older Children Testing Algorithm

Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm

Read more about Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm

Educational Videos

Last Update: July 2018