Toll-like Receptor 3 Deficiency in a Child with Recurrent Infections and Diabetes Mellitus

There are more than 400 different primary immune deficiencies worldwide. Amongst them, patients with humoral immunodeficiency are more common. Most of the innate immune defects, affect the phagocytic system. There are a few cases of toll-like receptor deficiency with innate immune defects, like TLR3 mutations, which usually present with Herpes simplex encephalitis. Herein, we report a two-year old boy with TLR3 deficiency, who was presented with recurrent infections and type one diabetes mellitus.

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Functional IRF3 deficiency in a patient with herpes simplex encephalitis

Journal of Experimental Medicine ◽

10.1084/jem.20142274 ◽

2015 ◽

Vol 212 (9) ◽

pp. 1371-1379 ◽

Cited By ~ 98

Author(s):

Line Lykke Andersen ◽

Nanna Mørk ◽

Line S. Reinert ◽

Emil Kofod-Olsen ◽

Ryo Narita ◽

...

Keyword(s):

Herpes Simplex ◽

Autosomal Dominant ◽

Viral Infections ◽

Herpes Simplex Encephalitis ◽

Type I ◽

Toll Like Receptor ◽

Loss Of Function ◽

Impaired Ability ◽

Increased Susceptibility ◽

Hsv 1

Herpes simplex encephalitis (HSE) in children has previously been linked to defects in type I interferon (IFN) production downstream of Toll-like receptor 3. Here, we describe a novel genetic etiology of HSE by identifying a heterozygous loss-of-function mutation in the IFN regulatory factor 3 (IRF3) gene, leading to autosomal dominant (AD) IRF3 deficiency by haploinsufficiency, in an adolescent female patient with HSE. IRF3 is activated by most pattern recognition receptors recognizing viral infections and plays an essential role in induction of type I IFN. The identified IRF3 R285Q amino acid substitution results in impaired IFN responses to HSV-1 infection and particularly impairs signaling through the TLR3–TRIF pathway. In addition, the R285Q mutant of IRF3 fails to become phosphorylated at S386 and undergo dimerization, and thus has impaired ability to activate transcription. Finally, transduction with WT IRF3 rescues the ability of patient fibroblasts to express IFN in response to HSV-1 infection. The identification of IRF3 deficiency in HSE provides the first description of a defect in an IFN-regulating transcription factor conferring increased susceptibility to a viral infection in the CNS in humans.

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Chronic granulomatous herpes encephalitis: a rare entity posing a diagnostic challenge

Journal of Neurosurgery Pediatrics ◽

10.3171/2011.7.peds10393 ◽

2011 ◽

Vol 8 (4) ◽

pp. 402-406 ◽

Cited By ~ 6

Author(s):

Matthew A. Adamo ◽

Lisa Abraham ◽

Ian F. Pollack

Keyword(s):

Herpes Simplex ◽

Herpes Simplex Encephalitis ◽

Disease Process ◽

Toll Like Receptor ◽

Herpes Encephalitis ◽

Diagnostic Challenge ◽

Intractable Seizures ◽

History Of ◽

Simplex Virus ◽

Chronic Disease State

Herpesviruses can cause an acute, subacute, or chronic disease state in both immunocompetent and immunocompromised individuals. Herpes simplex virus (HSV) encephalitis is most often an acute monophasic disease process. Rarely, however, it may progress to a chronic state, and more rarely still to a granulomatous encephalitis. Prior studies have suggested that antiviral immunity with Toll-like receptors determines susceptibility to herpesviruses. The authors report the case of a 14-year-old girl with a remote history of treated HSV encephalitis, who had intractable seizures and worsening MR imaging changes that were concerning for either a neoplastic or an inflammatory process. She was found to have granulomatous herpes simplex encephalitis and had a low cytokine response to Toll-like receptor 3 stimulation.

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