Analysis of suscebility genes and pathogenesis of HTLV-I-associated Sjogren's syndrome

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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