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Hue, S. et al. A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity 21, 367-377

Equipe Avenir INSERM, Hôpital Necker-Enfants Malades, 75015 Paris, France.
Immunity (Impact Factor: 19.75). 10/2004; 21(3):367-77. DOI: 10.1016/j.immuni.2004.06.018
Source: PubMed

ABSTRACT MICA molecules interact with the NKG2D-activating receptor on human NK and CD8 T cells. We investigated the participation of the MICA/NKG2D pathway in the destruction of intestinal epithelium by intraepithelial T lymphocytes (IEL) in Celiac disease and its premalignant complication, refractory sprue. We show that MICA is strongly expressed at epithelial cell surface in patients with active disease and is induced by gliadin or its p31-49 derived peptide upon in vitro challenge, an effect relayed by IL-15. This triggers direct activation and costimulation of IEL through engagement of NKG2D, leading to an innate-like cytotoxicity toward epithelial targets and enhanced TCR-dependent CD8 T cell-mediated adaptive response. Villous atrophy in Celiac disease might thus be ascribed to an IEL-mediated damage to enterocytes involving NKG2D/MICA interaction after gliadin-induced expression of MICA on gut epithelium. This supports a key role for MIC/NKG2D in the activation of intraepithelial immunity in response to danger.

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    • "Soluble MIC concentrations were measured in the plasma using a sandwich enzymelinked immunoabsorbent assay as previously described [37]. The detection threshold of recombinant soluble MICA protein , used as standard in each experiment, was 0.1 ng/mL and plasma levels higher than 0.3 ng/mL were considered as positive. "
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    • "T cells (Molberg et al. 1998; van de Wal et al. 1998a, b; Vader et al. 2002; Arentz- Hansen et al. 2000, 2002; Tollefsen et al. 2006; Camarca et al. 2009). It has also been shown that innate immune response to gliadin peptides from Pro/Gln poor regions of gliadin can lead to epithelial cell death (Maiuri et al. 2003; Meresse et al. 2004; Hue et al. 2004). Gliadin-derived peptides are thus capable of inducing adverse immune reactions in genetically susceptible individuals. "
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    • "The interaction of NK receptors with their ligands leads to the death of intestinal epithelial cells and releases IFN-γ and cytolytic proteins (perforin, granzymes, etc.), resulting in observable tissue damage. IL-15 has been shown to upregulate both CD94/NKG2C and NKG2D NK receptors in IELs of active patients, boosting their ability to lyse enterocytes [15] [24]. "
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