Because ligand binding unconditionally triggers NKG2D without counterbalance by a known antagonist, its dysregulation together with anomalous expression of MIC in local tissue sites may promote autoreactive T cell stimulation. Indeed, recent evidence indicates that MIC-NKG2D may play important roles in the pathogenesis of several autoimmune diseases. In rheumatoid arthritis (RA), the severity of autoimmune and inflammatory joint disease correlates with large numbers of CD4+CD28- T cells, which are scarce in healthy individuals. Large proportions of these T cells aberrantly express NKG2D, which is absent from almost all normal CD4 T cells. NKG2D is induced by TNF-a and IL-15, which are present in RA synovia and RA patient sera. RA synoviocytes aberrantly express MIC, presumably because of pannus invasion, and thus stimulate autologous CD4+CD28-T cell cytokine production and proliferation (Groh et al. 2003). As with cancer patients, RA serum contains substantial amounts of soluble MIC, which fails to downmodulate NKG2D because of the opposing activity of TNF-a and IL-15. Thus, by causing autoreactive T cell stimulation, MIC-NKG2D may promote the self-perpetuating pathology in RA (Groh et al. 2003). CD4+CD28- T cells are also expanded in other autoimmune diseases and chronic inflammatory conditions, including multiple sclerosis, Wegener granulomatosis, ankylosing spondylitis, atherosclerotic coronary artery disease, and inflammatory bowel disease, suggesting the possibility of an involvement of MIC-NKG2D. In active celiac disease, upregulation of MIC on enterocytes by gliadin or its p31-49 peptide triggers NKG2D-dependent activation of IEL, resulting in cytotoxicity against epithelial targets and enhanced TCR-dependent CD8 T cell responses (Hue et al. 2004; Meresse et al. 2004). IL-15-mediated induction of NKG2D and resultant TCR-independent T cell activation may also contribute to villous atrophy (Meresse et al. 2004).
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