Yasuhiro Kizu

Possible Involvement of EBV-Mediated α-Fodrin Cleavage for Organ-Specific Autoantigen in Sjogren’s Syndrome

A cleavage product of α-fodrin may be an important organ-specific autoantigen in the pathogenesis of Sjogren’s syndrome (SS), but the mechanisms of α-fodrin cleavage remain unclear. Since EBV has been implicated in the pathogenesis of SS, we determined whether EBV activation could induce the SS-specific 120-kDa autoantigen α-fodrin. ZEBRA mRNA expression, a marker for activation of the lytic cycle of EBV, was found in the salivary gland tissues from SS patients, but not in those from control individuals. ZEBRA-expressing lymphoid cells were also found in the SS glands in double-stained immunohistochemistry. Furthermore, a significant link between production of Abs against 120-kDa α-fodrin and reactivated EBV Ag was found in sera from patients with SS, but not in those from control individuals. EBV-activated lymphoid cells showed specific α-fodrin cleavage to the expected 120-kDa fragments in vitro. Pretreatment with caspase inhibitors inhibited cleavage of α-fodrin. Thus, an increase in apoptotic protease activities induced by EBV reactivation may be involved in the progression of α-fodrin proteolysis in the development of SS.

Possible Role of Nitric Oxide in Radiation-Induced Salivary Gland Dysfunction

Abstract Takeda, I., Kizu, Y., Okamoto, Y., Saito, I. and Yamane, G. Possible Role of Nitric Oxide in Radiation-Induced Salivary Gland Dysfunction. Radiat. Res. 159, 465–470 (2002). In this study, we developed a murine model of xerostomia to elucidate the mechanism of radiation-induced salivary gland dysfunction and determined the levels of nitric oxide (NO) in the salivary glands to assess its involvement in the salivary dysfunction induced by radiation. In addition, an inhibitor of NO synthesis was administered to the model in vivo, and its effect on saliva secretion was investigated. Salivary gland irradiation at a dose of 15 Gy caused a significant decrease in secretion compared to unirradiated salivary glands. There were no marked differences between the irradiated mice and unirradiated mice in water or food consumption or in body weight changes. The NO levels in the cultured salivary gland epithelial cells were increased by treatment with a combination of interferon γ (Ifng), interleukin β (Il1b), and tumor necrosis factor α (Tnfa). Irradiation increased the NO level in the salivary gland tissue. The presence of NG-monomethyl-l-arginine acetate (l-NMMA), an inhibitor of NO synthesis, caused a decrease in the NO level in cultured salivary gland tissues after irradiation. Administration of l-NMMA to irradiated mice improved saliva secretion. These results suggest that excessive production of NO induced by radiation is involved in the formation of radiation-induced xerostomia. The finding that administration of an inhibitor of NO synthesis ameliorated the dysfunction of irradiated salivary glands indicates that NO plays a role as a mediator of the dry mouth symptoms that occur after irradiation.

Activation of Epstein–Barr virus by saliva from Sjogren's syndrome patients

The aim of this study was to examine the mechanism of Epstein–Barr virus (EBV) activation by soluble factors from the inflamed salivary glands of patients with Sjogrens syndrome (SS). Saliva from SS patients was used to examine the regulation of EBV activation by an inflammatory salivary microenvironment. Transient transfection of the EBV‐negative salivary gland cell line (HSY) with BZLF1, a trans‐activating EBV gene promoter‐fusion construct (Zp‐luc), was used in this study. The results showed that under conditions where the BZLF1 promoter is activated by potent stimuli, SS saliva (from eight of 12 patients) exerts a significant effect on expression of the luciferase gene. A specific inhibitor of protein kinase C did not affect the SS saliva‐induced Zp‐luc activity, whereas treatment with inhibitors of calmodulin, calcineurin and IP3, dose‐dependently decreased this induction. Transforming growth factor β1 (TGF‐β1), which is known to be expressed in SS salivary glands, dose‐dependently induced Zp‐luc activity. Hence, these results demonstrate the activation of EBV by SS saliva and suggest that EBV activation at the inflammatory site may occur in the presence of TGF‐β1 via triggering of the mitogen‐activated protein kinase (MAPK) kinase signalling pathway.

Biomechanical three-dimensional finite-element analysis of maxillary prostheses with implants. Design of number and position of implants for maxillary prostheses after hemimaxillectomy.

The present study analyzed stress distributions in craniofacial structures around implant-supported maxillary prostheses. Using post-hemimaxillectomy computed tomography (CT) of a patient, the authors constructed a three-dimensional (3D) solid model using Digital Imaging and Communications in Medicine data (DICOM data) for maxillofacial and cranial bones. The effects of different prosthesis designs on stress distributions in craniofacial bones and osseous tissues around the implants were biomechanically investigated using 3D finite-element analysis. Maxillary prostheses were designed with 2 implants in the zygoma on the affected side and 2-3 implants in the maxillary alveolar bone on the unaffected side, without using a cantilever. Zygomatic implants provided suitable stress dispersal to the zygomatic and craniofacial bones on the affected side. This information is useful for designing maxillary prostheses.