CD8+ T-cell clones dominate brain infiltrates in Rasmussen encephalitis and persist in the periphery

Abstract

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 Vbeta 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 Vbeta/Jbeta 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.

Peripheral leukocyte profile in people with temporal lobe epilepsy reflects the associated proinflammatory state

“…Granzyme A is a serine protease involved in several immune functions, including cell death by non-apoptotic pathways [21,24], and mediation of inflammatory cytokine release [25][26][27]. Granzyme A produced by CD8 + and NK cells could be involved in cytokine production and apoptotic response in epilepsy.…”

“…DAMPs generated in the brain after seizures would induce a cascade of events leading to local and systemic inflammation ( Figure 9). Indeed experimental studies have demonstrated that there is continuous recruitment of peripheral cells into the brain following seizures, with a parallel between the activation of immune cells in the CNS and in the periphery [3,[19][20][21][22].…”

Expression of human cytomegalovirus components in the brain tissues of patients with Rasmussen’s encephalitis

“…RE is now confirmed as an inflammatory autoimmune neurological syndrome that can be triggered by exogenous antigens and somehow mediated by Tlymphocyte cytotoxicity as well as autoantibodies (Li et al, 1997;Gahring et al, 2001;Bauer et al, 2002;Bien et al, 2002a;Schwab et al, 2009). However, virus infection, as an important potential initiating factor (Merkler et al, 2006;Chen et al, 2016), has not been carefully studied.…”

Neuroprotective intervention by interferon-γ blockade prevents CD8+ T cell-mediated dendrite and synapse loss

“…At the histopathological level, RE is dominated by putatively antigenspecific CTL infiltrates in close association with CNS neurons (Schwab et al, 2009). Five out of six Rasmussen specimens displayed P-STAT1 + cells.…”