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.
Quick Answers for Clinicians
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
- Quantitative immunoglobulin testing
- 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
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)
Cell Culture/Quantitative Multiplex Bead Assay
Medical Experts
Hill

References
Immune Deficiency Foundation
Immune Deficiency Foundation. [Accessed: Mar 2020]
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Picard C, Casanova JL, Puel A. Infectious diseases in patients with IRAK-4, MyD88, NEMO, or IκBα deficiency. Clin Microbiol Rev. 2011;24(3):490-497.