Brain Advance Access originally published online on January 29, 2009
Brain 2009 132(5):1236-1246; doi:10.1093/brain/awp003
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CD8+ T-cell clones dominate brain infiltrates in Rasmussen encephalitis and persist in the periphery
1 Clinical Research Group for Multiple Sclerosis and Neuroimmunology, University of Würzburg, Josef-Schneider-Str. 11, 97080 Würzburg, Germany 2 Department of Epileptology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany 3 Department of Neuropathology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany 4 Department of Neurosurgery, University of Würzburg, Josef-Schneider-Str. 11, 97080 Würzburg, Germany 5 Institute for Clinical Neuroimmunology, Ludwig Maximilian University of Munich, Marchioninistr. 15, 81377 Munich, Germany
Prof. Dr Heinz Wiendl, Department of Neurology, University of Würzburg, Josef-Schneider-Str. 11, 97080 Würzburg, Germany E-mail: heinz.wiendl{at}klinik.uni-wuerzburg.de
Rasmussen encephalitis (RE) is a rare neurological disorder of childhood characterized by uni-hemispheric inflammation, progressive neurological deficits and intractable focal epilepsy. Destruction of neurons and astrocytes by cytotoxic CD8 T cells has been proposed as a pathogenic mechanism underlying this enigmatic disorder. We tested this hypothesis by analysing the clonal composition and T-cell receptor (TCR) repertoire of CD4+ and CD8+ T cells using complementarity determining region 3 (CDR3) spectratyping from peripheral blood and corresponding CNS specimens. Severe perturbations of the TCR repertoire were found in brain infiltrates from all specimens (n = 5). Clonal expansions, as evidenced by peripheral blood analysis (n = 14), belonged to the CD8+ T-cell subset, while CD4+ cells showed normal distributions. Some of those expansions were analysed in the respective CNS specimens by histochemistry. The stainings showed Vβ specific T cells containing the cytotoxic molecule granzyme B and lying in close appositions to NeuN+ neurons and GFAP+ astrocytes. Analysis of corresponding CNS/blood specimens revealed overlapping but also CNS-restricted expansions of certain TCR clonotypes suggesting expansions of T cells within the target organ itself. Longitudinal analysis of peripheral blood samples (n = 5) demonstrated dominance but also longitudinal persistence of specific CD8 T-cell clones over time. The Vβ/Jβ usage, length of the CDR3, and biochemical characteristics of the CDR3 amino acids suggested high similarities putatively related to common driving antigen(s) without shared clones. Taken together, our data strongly support the hypothesis of an antigen-driven MHC class-I restricted, CD8+ T cell-mediated attack against neurons and astrocytes in the CNS dominating the pathogenesis in RE.
Key Words: Rasmussen encephalitis; CDR3 spectratyping; CD8 cytotoxicity; clonal expansion
Abbreviations: CDR3, complementarity determining region 3; HD, healthy donor; NDN, D segment with flanking N sequence; TCR, T-cell receptor; PBMC, peripheral blood mononuclear cells; RE, Rasmussen encephalitis
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Received June 3, 2008. Revised December 22, 2008. Accepted December 29, 2008.
*These authors contributed equally to this work.
Present address: Department of Neurology, University of Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany.
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