| Co-Investigator(Kenkyū-buntansha) |
MIGITA Kiyoshi Nagasaki Medical Center, Research Center, Director Clinical, 臨床研究センター, 免疫研究部部長 (60264214)
NAMAMURA Tatsufumi Nagasaki University, Graduate School of Biomedical Sciences, Assistant Professor, 大学院・医歯薬学総合研究所, 助教授 (00198219)
KUMAGAI Shunichi Kobe University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (00153346)
|
|---|
| Budget Amount *help |
¥10,100,000 (Direct Cost: ¥10,100,000)
Fiscal Year 2003: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2002: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2001: ¥4,000,000 (Direct Cost: ¥4,000,000)
|
|---|
| Research Abstract |
HTLV-I has been identified as a causative agent which initiates and/or perpetuates the process of Sjogren's syndrome (SS). A high seroprevalence of HTLV-I infection has been determined in SS patients in the HTLV I-endemic area of Nagasaki, Japan. Many patients with HTLV-I-associated myelopathy (HAM/TSP) have been complicated with SS. The present study was undertaken to clarify the involvement of HTLV-I infection on the development or perpetuation of SS. At first, we analyzed promoter region polymorphisms of the IL-10 gene. Our results suggest that the presence of the ATA haplotype of the IL-10 gene are associated with an increased susceptibility to primary SS. Moreover, IL-10 gene promoter region polymorphism affects the age at onset of SS, and the amounts of serum IgG. However, there is no association between the presence of anti-HTLV-I antibodies and IL-10 gene polymorphism. Next, two-color analysis by flow cytometry revealed a significantly high percentage of IL-12Rβl^+ cells in CD4
… More
^+T lymphocytes in HAM/TSP patients compared to the control. These results suggest Th1 immune activation in patients with HAM/TSP, which leads to chronic inflammation in the tissues, mediated by dysregulation of the IL-12/IL-12R. Furthermore, the sLe^<x+>+ cell population, which has features of activated Th1 cells with up-regulated expression of E-selectin and P-selectin ligands mediated by HTLV I infection, is increased in peripheral blood CD4^+T lymphocytes in HAM/TSP patients. These findings suggest their involvement in transmigration of T lymphocytes from peripheral blood into tissues. In addition, our results indicate that peripheral blood CD4^+T lymphocytes of HAM/TSP patients are resistant to apoptosis triggered through mitochondrial death pathway through up-regulations of expression of anti-apoptotic protein, Bcl-xL. We used HTLV-I tax transfectants to show that tax-mediated induction of Bcl-xL expression can protect cells from apoptotic stimuli in a mitochondria-dependent fashion. Compared with tax-negative JPX-9 cells, Bcl-xL expression was clearly augmented in tax-positive JPX-9 cells. These cells were resistant to both receptor-mediated apoptosis and chemical induced apoptosis. Theses results suggest that tax-mediated Bcl-xL expression inhibit apoptosis of activated T lymphocytes in HTLV-I-seropositive subjects, which consequently promotes the onset of autoimmune disorders such as SS. Finally, we demonstrated the expression of TLR-2, TLR-3 and TLR4 on the acinal and ductal cells, and infiltrated mononuclear cells from minor salivary glands of SS. When a human salivary glands (HSG) cell line were stimulated by peptidoglycan, poly I : C, or LPS, HSG cell line augmented the expression of CD54 and production of IL-6, through the phosphorylation of MAP kinase. From the above findings, the development and/or perpetuation of SS might be implicated with HTLV-I infection and the susceptibility genes. Less
|
