The present study aimed to determine whether granzymes are implicated in the pathogenesis of infection-associated acute encephalopathy (AE).
Methods:
We investigated granzyme and cytokine levels in the cerebrospinal fluid of patients with acute encephalopathy or complex febrile seizures (cFS). A total of 24 acute encephalopathy patients and 22 complex febrile seizures patients were included in the present study. Levels of granzymes A and B were measured using enzyme-linked immunosorbent assay, and levels of tumor necrosis factor α (TNF-α), interferon-γ (IFN-γ), interleukin 1β (IL-1β), IL-1 receptor antagonist (IL-1RA), IL-4, IL-6, IL-8, and IL-10 were assessed using the Bio-Plex suspension array system.
Results:
Cerebrospinal fluid levels of granzyme A were significantly higher, and those of TNF-α and IL-1RA were significantly lower in the AE group than in the cFS group; however, no significant differences in the levels of granzyme B, IFN-γ, IL-1β, IL-4, IL-6, IL-8, and IL-10 were observed between the 2 groups. In addition, no significant differences in granzyme A, granzyme B, or cytokine levels were observed between acute encephalopathy patients with and those without neurologic sequelae.
Conclusions:
Our findings indicate the involvement of granzyme A in the pathogenesis of acute encephalopathy.
MizuguchiMYamanouchiHIchiyamaTShiomiM. Acute encephalopathy associated with influenza and other viral infections. Acta Neurol Scand Suppl. 2007;186:45–56.
2.
TakanashiJObaHBarkovichAJ, et al.Diffusion MRI abnormalities after prolonged febrile seizures with encephalopathy. Neurology. 2006;66(9):1304–1309; discussion 1291.
3.
YamanakaGMorishitaNOanaS, et al.Single-photon emission computed tomography is an ambiguous imaging method on initial diagnosis for acute encephalopathy. Neuropediatrics. 2016;47(1):39–45.
4.
MorichiSMorishitaNTakeshitaM, et al.Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) levels in the cerebrospinal fluid of children with influenza-associated encephalopathy. J Infect Chemother. 2017;23(2):80–84.
5.
YamanakaGIshidaYMorichiS, et al.Spinal fluid cytokine levels and single-photon emission computed tomography findings in complex febrile seizures. J Child Neurol. 2018;33(6):417–421.
6.
HoshinoASaitohMOkaA, et al.Epidemiology of acute encephalopathy in Japan, with emphasis on the association of viruses and syndromes. Brain Dev. 2012;34(5):337–343.
HiraiNYoshimaruDMoriyamaYYasukawaKTakanashiJI. A new infectious encephalopathy syndrome, clinically mild encephalopathy associated with excitotoxicity (MEEX). J Neurol Sci. 2017;380:27–30.
9.
HosoyaMNunoiHAoyamaMKawasakiYSuzukiH. Cytochrome c and tumor necrosis factor-alpha values in serum and cerebrospinal fluid of patients with influenza-associated encephalopathy. Pediatr Infect Dis J. 2005;24(5):467–470.
10.
HosoyaMKawasakiYKatayoseM, et al.Prognostic predictive values of serum cytochrome c, cytokines, and other laboratory measurements in acute encephalopathy with multiple organ failure. Arch Dis Child. 2006;91(6):469–72.
11.
YamanakaGIshiiCKawashimaHOanaSMiyajimaTHoshikaA. Cerebrospinal fluid Diacron-reactive oxygen metabolite levels in pediatric patients with central nervous system diseases. Pediatr Neurol. 2008;39(2):80–84.
12.
VoskoboinikIWhisstockJCTrapaniJA. Perforin and granzymes: function, dysfunction and human pathology. Nat Rev Immunol. 2015;15(6):388–400.
13.
PardoJAguiloJIAnelA, et al.The biology of cytotoxic cell granule exocytosis pathway: granzymes have evolved to induce cell death and inflammation. Microbes Infect. 2009;11(4):452–459.
14.
EwenCLKaneKPBleackleyRC. A quarter century of granzymes. Cell Death Differ. 2012;19(1):28–35.
15.
AnthonyDAAndrewsDMWattSVTrapaniJASmythMJ. Functional dissection of the granzyme family: cell death and inflammation. Immunol Rev. 2010;235(1):73–92.
16.
TakPPSpaeny-DekkingLKraanMCBreedveldFCFroelichCJHackCE. The levels of soluble granzyme A and B are elevated in plasma and synovial fluid of patients with rheumatoid arthritis (RA). Clin Exp Immunol. 1999;116(2):366–370.
17.
BratkeKKlugAJuliusP, et al.Granzyme K: a novel mediator in acute airway inflammation. Thorax. 2008;63(11):1006–1011.
18.
TakahashiYMineJKubotaYYamazakiEFujiwaraT. Asubstantial number of Rasmussen syndrome patients have increased IgG, CD4+ T cells, TNFalpha, and Granzyme B in CSF. Epilepsia. 2009;50(6):1419–1431.
19.
LeePRJohnsonTPGnanapavanS, et al.Protease-activated receptor-1 activation by granzyme B causes neurotoxicity that is augmented by interleukin-1beta. J Neuroinflamm. 2017;14(1):131.
20.
OlahZKalmanJTothME, et al.Proteomic analysis of cerebrospinal fluid in Alzheimer’s disease: wanted dead or alive. J Alzheimers Dis. 2015;44(4):1303–1312.
21.
BergATBerkovicSFBrodieMJ, et al.Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010;51(4):676–685.
22.
FiserDH. Assessing the outcome of pediatric intensive care. J Pediatr. 1992;121(1):68–74.
WensinkACKempVFermieJ, et al.Granzyme K synergistically potentiates LPS-induced cytokine responses in human monocytes. Proc Natl Acad Sci U S A. 2014;111(16):5974–5979.
25.
MatsudaTMuraoNKatanoY, et al.TLR9 signalling in microglia attenuates seizure-induced aberrant neurogenesis in the adult hippocampus. Nat Commun. 2015;6:6514.
26.
ShacharIKarinN. The dual roles of inflammatory cytokines and chemokines in the regulation of autoimmune diseases and their clinical implications. J Leukoc Biol. 2013;93(1):51–61.
27.
ParkYJWarnockGLAoZ, et al.Dual role of interleukin-1beta in islet amyloid formation and its beta-cell toxicity: implications for type 2 diabetes and islet transplantation. Diabetes Obes Metab. 2017;19(5):682–694.
28.
de VriesEEvan den MunckhofBBraunKPvan Royen-KerkhofAde JagerWJansenFE. Inflammatory mediators in human epilepsy: a systematic review and meta-analysis. Neurosci Biobehav Rev. 2016;63:177–190.
29.
VezzaniAContiMDe LuigiA, et al.Interleukin-1beta immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: functional evidence for enhancement of electrographic seizures. J Neurosci. 1999;19(12):5054–5065.
30.
Kenney-JungDLVezzaniAKahoudRJ, et al.Febrile infection-related epilepsy syndrome treated with anakinra. Ann Neurol. 2016;80(6):939–945.
