title: Inflammasome induction in Rasmussen's encephalitis: cortical and associated white matter pathogenesis.
abstract: BACKGROUND
  Rasmussen's encephalitis (RE) is an inflammatory encephalopathy of unknown cause defined by seizures with progressive neurological disabilities. Herein, the pathogenesis of RE was investigated focusing on inflammasome activation in the brain.
  
  
  METHODS
  Patients with RE at the University of Alberta, Edmonton, AB, Canada, were identified and analyzed by neuroimaging, neuropsychological, molecular, and pathological tools. Primary human microglia, astrocytes, and neurons were examined using RT-PCR, enzyme-linked immunosorbent assay (ELISA), and western blotting.
  
  
  RESULTS
  Four patients with RE were identified at the University of Alberta. Magnetic resonance imaging (MRI) disclosed increased signal intensities in cerebral white matter adjacent to cortical lesions of RE patients, accompanied by a decline in neurocognitive processing speed (P <0.05). CD3ϵ, HLA-DRA, and TNFα together with several inflammasome-associated genes (IL-1β, IL-18, NLRP1, NLRP3, and CASP1) showed increased transcript levels in RE brains compared to non-RE controls (n = 6; P <0.05). Cultured human microglia displayed expression of inflammasome-associated genes and responded to inflammasome activators by releasing IL-1β, which was inhibited by the caspase inhibitor, zVAD-fmk. Major histocompatibility complex (MHC) class II, IL-1β, caspase-1, and alanine/serine/cysteine (ASC) immunoreactivity were increased in RE brain tissues, especially in white matter myeloid cells, in conjunction with mononuclear cell infiltration and gliosis. Neuroinflammation in RE brains was present in both white matter and adjacent cortex with associated induction of inflammasome components, which was correlated with neuroimaging and neuropsychological deficits.
  
  
  CONCLUSIONS
  Inflammasome activation likely contributes to the disease process underlying RE and offers a mechanistic target for future therapeutic interventions.
authors: Vijay
authors: V
authors: Ramaswamy
authors: John G
authors: JG
authors: Walsh
authors: D Barry
authors: DB
authors: Sinclair
authors: Edward
authors: E
authors: Johnson
authors: Richard
authors: R
authors: Tang-Wai
authors: B Matt
authors: BM
authors: Wheatley
authors: William
authors: W
authors: Branton
authors: Ferdinand
authors: F
authors: Maingat
authors: Thomas
authors: T
authors: Snyder
authors: Donald W
authors: DW
authors: Gross
authors: Department of Psychiatry, University of Alberta, Edmonton, AB, Canada. chris.power@ualberta.ca.
authors: Christopher
authors: C
authors: Power
mesh_terms: D000293:Adolescent; D015153:Blotting, Western; D001921:Brain / Q000276:immunology* / Q000503:physiopathology*; D002648:Child; D002675:Child, Preschool; D004660:Encephalitis / Q000276:immunology* / Q000503:physiopathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D058847:Inflammasomes / Q000502:physiology*; D008297:Male; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D058847:Inflammasomes