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Published on: July 12, 2021
Diminished toll-like receptor response in febrile infection-related epilepsy syndrome (FIRES)
Meng-Ying Hsieh1, Jainn-Jim Lin2, Shao-Hsuan Hsia2
1Division of Pediatrics, Chang Gung Memorial Hospital at Taipei, Taipei, Taiwan; Division of Pediatric Neurology, Department of Pediatrics, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Primary Immunodeficiency Care and Research (PICAR) Institute, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Insights
Children with febrile infection-related epilepsy syndrome (FIRES) exhibit impaired Toll-like receptor (TLR) responses, particularly TLR3, TLR4, TLR7/8, and TLR9. This immune dysfunction may be linked to reduced phagocytosis and T regulatory cells in these patients.
Area of Science:
- Immunology
- Neurology
- Pediatrics
Background:
- Defective Toll-like receptor (TLR) signaling is implicated in recurrent herpes simplex encephalitis.
- Children experiencing febrile infection-related epilepsy syndrome (FIRES) with refractory seizures may present with compromised TLR responses.
Purpose of the Study:
- To investigate Toll-like receptor (TLR) 1-9 responses in children with febrile infection-related epilepsy syndrome (FIRES).
- To compare TLR responses in patients with FIRES against controls with febrile seizures or non-refractory epilepsy.
Main Methods:
- Evaluated TLR1-9 responses (cytokine profiles: IL-6, IL-8, IL-12p40, INF-α, INF-γ, TNF-α) in peripheral blood mononuclear cells (PBMCs) and monocyte-derived dendritic cells (MDDCs).
- Compared immune cell responses between children with FIRES and control groups.
Main Results:
- Patients with FIRES showed impaired TLR responses, specifically reduced cytokine production for TLR3, TLR4, TLR7/8, and TLR9.
- Despite normal TLR expression, patients had decreased naïve T and T regulatory cells, and weakened phagocytosis.
- Common viral and bacterial infections were identified, but pathogens and autoantibodies were not consistently detected in cerebrospinal fluid.
Conclusions:
- Children with FIRES may experience impaired TLR3, TLR4, TLR7/8, and TLR9 responses.
- Weakened phagocytosis and reduced T regulatory cells could be associated with the observed TLR dysfunction in FIRES.
Background:
Defective human TLR3 signaling causes recurrent and refractory herpes simplex encephalitis/encephalopathy. Children with febrile infection-related epilepsy syndrome with refractory seizures may have defective TLR responses.
Methods:
Children with febrile infection-related epilepsy syndrome were enrolled in this study to evaluate TLR1-9 responses (IL-6, IL-8, IL-12p40, INF-α, INF-γ, and TNF-α) in their peripheral blood mononuclear cells (PBMCs) and monocyte-derived dendritic cells (MDDCs), compared to those with febrile seizures and non-refractory epilepsy with/without underlying encephalitis/encephalopathy.
Results:
Adenovirus and enterovirus were found in throat cultures of enrolled patients (2-13 years) as well as serologic IgM elevation of mycoplasma pneumonia and herpes simplex virus, although neither detectable pathogens nor anti-neural autoantibodies in the CSF could be noted. Their PBMCs and MDDCs trended to have impaired TLR responses and significantly lower in cytokine profiles of TLR3, TLR4, TLR7/8, and TLR9 responses but not other TLRs despite normal TLR expressions and normal candidate genes for defective TLR3 signaling. They also had decreased naïve T and T regulatory cells, and weakened phagocytosis.
Conclusion:
Children with febrile infection-related epilepsy syndrome (FIRES) could have impaired TLR3, TLR4, TLR7/8, and TLR9 responses possibly relating to their weakened phagocytosis and decreased T regulatory cells.
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