| Budget Amount *help |
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1994: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1993: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Research Abstract |
Autoimmune diseases occur in a genetically susceptible patient after tiggering events including bacterial and viral infections, environmental insults, drugs or hormons.
There is accumulating evidence that human T cell lymphotropic virus type-I (HTLV-I) infection contributes to the development of various inflammatory disorders. To elucidate the relation between the infection and Sjogren's syndrome (SjS), seroepidemiological and virological studies were conducted on patients with this syndrome. The HTLV-I seroprevalence rate among the patients with SjS was significantly higher than that among blood donors. Titers of serum antibodies in the HTLV-I seropositive patients with SjS were similar to those among patients with HTLV-I-associated myelopathy/tropical spatic paraparesis (HAM/TSP) and significantly higher than those among healthy carriers. IgM antibodies to HTLV-I were commonly detected in the sera of patients with SjS.Salivary IgA antibodies to HTLV-I were common among seropositive pa
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tients with SjS,which might be due to increased viral activity in the salivary glands. Those antibodies were barely detectable in HAM/TSP patients or healthy carriers.
HTLV-IcDNA (gag, pol, Tax, LTR) was detected in salivary glands from patients with SjS by PCR.HTLV-I could infect the synovial cells and vascular endothelial cells, resulting the active production of cytokines such as granulocyte/macrophage colony-stimulating factor, granulocyte colony-stimulating factor and interleukin 6. We presented that transient cotrasfection with the Tax-expression plasmid activated the transcription from the human IL-6 promotor in COS 1 cells. This finding directly indicates the potential of Tax for transactivating the human IL-6 gene. The analysis of a series of deletions of the IL-6 promoter suggested that the region (-105/-47) containing a NFkB site was crucial for the Tax responsivessess. From the above data, inflammaotry cytokines such as IL-6 produced through Tax-mediated transactivation is likely to play an important role in triggering and exacerbating SjS.
SjS patients with anti-HTLV-I antibodies had increased prevalence of rucurrent fever, myositis and complication with HAM/TSP and uveitis as compared with SjS patients without these antibodies. Furthermore, we reported that interferon-alpha (IFN-alpha) was effective clinically in treating polyarthritis patients who were seropositive for anti-HTLV-I antibodies.
Finally, we show that the fusion of HTLV-I-infected cells and target cells contribute to syncytium formation, and that a syncytium formation assay would be a model of HTLV-I transmission in vitro. Dextran sulfate, heparin, and anti-adhesion molecule antibodies including anti-CD18 and anti-CD50 (ICAM-3) monoclonal antibodies blocked HTLV-I-induced syncytium formation.
In summary, our prosent results strongly suggest that HTLV-I is involved in the pathogenesis of the SjS. Less
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