SUMMARY
1. TLR3 Deficiency is an autosomal dominant defect in innate immunity which results in increased susceptibility to HSV encephalitis.
2. To date, 3 patients with TLR3 deficiency have been reported. Two patients presented solely with HSV meningo-encephalitis. A Japanese patient presented with influenza associated encephalopathy.
3. Toll-like receptors are type I transmembrane proteins that recognize a broad spectrum of pathogen associated molecular patterns to initiate innate immune responses. TLR3 recognizes double-stranded RNA (dsRNA) that is produced by RNA and DNA viruses during replication.
4. TLR3 signaling occurs via a MyD88-independent pathway and leads to induction of type I interferons (alpha and beta). Type I interferons trigger the transcription of antiviral proteins, increase viral antigen presentation by MHC class I molecules and activate NK cells.
5. Conventional tests for humoral and cell-mediated immunity are normal in patients. Screening of patients can be performed by the measurement of type I interferon induction following stimulation by a TLR3 agonist. Sequencing of the TLR3 gene can confirm the diagnosis.
6. HSV infections should be aggressively treated with acyclovir. The addition of IFN-alpha may be of therapeutic benefit for treatment of severe acute viral infections.
OVERVIEW
TLR3 Deficiency is an autosomal dominant defect in innate immunity which results in increased susceptibility to HSV encephalitis.
To date, 3 patients with TLR3 deficiency have been reported. Two patients presented solely with HSV meningo-encephalitis. A Japanese patient presented with influenza associated encephalopathy.
PATHOGENESIS
Toll-like receptors are type I transmembrane proteins that recognize a broad spectrum of pathogen associated molecular patterns to initiate innate immune responses. TLR3 recognizes double-stranded RNA (dsRNA) that is produced by RNA and DNA viruses during replication.
TLR3 signaling occurs via a MyD88-independent pathway and leads to induction of type I interferons (αalpha and betaβ). Type I interferons trigger the transcription of antiviral proteins, increase viral antigen presentation by MHC class I molecules and activate NK cells.
EVALUATION
The diagnosis of TLR3 deficiency should be considered in patients with HSV encephalitis or influenza encephalopathy.
Step 1: Immune Evaluation
-Quantitative immunoglobulins (IgG, IgM, IgA)
-Antibody titers to vaccine antigens
-Flow cytometry for B cell, T cell, and NK cell enumeration
-Lymphocyte proliferation to mitogens
-NK cell functional assay
-The above tests will be normal in patients with TLR3 deficiency. However, they should be performed to screen for T cell or NK cell defects that could result in life-threatening HSV or influenza infections.
Step 2: TLR screening assay
-TLR3 Functional Assay
-Measurement of Type I Interferons following stimulation with TLR3 agonists can be a useful screening tool for TLR3 deficiency. This test is currently only available at specialized research centers.
Step 3: Genetic Testing
-TLR3 gene sequencing
-This test is currently only available at specialized research centers.
MANAGEMENT
HSV infections should be aggressively treated with acyclovir. The addition of IFN-alpha may be of therapeutic benefit for treatment of severe acute viral infections.
RESOURCES
Literature Resources
1. Zhang 2007
TLR dependent induction of Interferons and immunity to viruses
2. Hidaka 2006
TLR3 mutation in a patient with Influenza-associated encephalopathy