Article

Granzyme B mediates neurotoxicity through a G-protein-coupled receptor.

Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA.
The FASEB Journal (Impact Factor: 5.48). 07/2006; 20(8):1209-11. DOI: 10.1096/fj.05-5022fje
Source: PubMed

ABSTRACT Neuroinflammatory diseases such as multiple sclerosis (MS) are characterized by focal regions of demyelination and axonal loss associated with infiltrating T cells. However, the role of activated T cells in causing neuronal injury remains unclear. CD4 and CD8 T cells were isolated from normal donors and polyclonally activated using plate-bound anti-CD3 and soluble anti-CD28. The conditioned T cell supernatants caused toxicity to cultured human fetal neurons, which could be blocked by immunodepleting the supernatants of granzyme B (GrB). Recombinant GrB also caused toxicity in neurons by caspase-dependent pathways but no toxicity was seen in astrocytes. The neurotoxicity was independent of perforin and could not be blocked by mannose-6-phosphate. However, GrB-induced neurotoxicity was sensitive to pertussis toxin, implicating the stimulation of Gialpha protein-coupled receptors. GrB caused a decrease in cAMP levels but only modest increases in intracellular calcium. The effect on intracellular calcium could be markedly potentiated by stromal-derived factor 1alpha. GrB-induced neurotoxicity could also be blocked by vitamin E and a neuroimmunophilin ligand. In conclusion, GrB may be an important mediator of neuronal injury in T cell-mediated neuroinflammatory disorders.

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    • "In contrast, murine astrocytes quickly respond to degranulation (release of lytic enzymes) by cytotoxic CD8 + T cells [21]. Cell death of human neurons has been observed upon the addition of granzyme B [22], another lytic enzyme than perforin. Moreover, cytotoxic CD8 + T cells can selectively attack neuronal neurites supporting the notion that axonal damage observed in MS lesions could be mediated by these cells [23]. "
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    • "For example, the extent of axonal damage is directly related to the numbers of infiltrated T cells in multiple sclerosis plaques (Kuhlmann et al., 2002). In vitro studies have also shown that activated T cells can induce direct neuronal damage, through both cell contact-dependent (Giuliani et al., 2003) and – independent pathways(Wang et al., 2006). In the present study, we observed that patients with multiple sclerosis had higher levels of GrB compared to controls in their CSF. "
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    • "COLLATERAL NEURONAL APOPTOSIS IN CNS INFLAMMATION GLIA ent with previous reports showing the (relative) resistance of astrocytes against cell death by purified perforin (Wang et al., 2006; Zeine et al., 2001), granzyme B (Wang et al., 2006), and FasL (Becher et al., 1998; Lee et al., 2000) in vitro. "
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