- Professor Takemi Otsuki, M.D., Ph.D.
Main Areas and Themes of Research
Investigation of mechanisms involved in immunological effects of silica or silicates including asbestos
Silicosis patients suffer not only from respiratory disorders but also from autoimmune diseases. In an effort to delineate the mechanisms involved in the dysregulation of autoimmunity found in silicosis patients, we have been focusing on Fas and Fas-related molecules in the Fas-mediated apoptotic pathway since Fas is one of the most important molecules regulating autoimmunity in T cells. Our findings showed that silicosis patients exhibited elevated serum soluble Fas levels, increased relative expression of soluble fas and dcr3 genes in peripheral blood mononuclear cells, other highly detectable variant messages of the fas transcript, relatively decreased expression of several physiological inhibitors (survivin and toso), and a dominancy of lower membrane Fas expressers in lymphocytes, which transcribe soluble fas dominantly, when compared with healthy donors. These findings are consistent with immunological factors such as serum immunoglobulin G levels and the titer of anti-nuclear autoantibodies. In addition, anti-caspase 8 autoantibody and anti-Fas autoantibody were detected in the serum of silicosis patients, and a functional assay showed that anti-Fas antibody stimulated Fas-mediated apoptosis. We hypothesize that there are two subpopulations of silicosis lymphocytes. One represents a long-term survival fraction and includes a self-recognizing fraction showing lower levels of membrane Fas and inhibition of Fas/Fas ligand binding in the extracellular spaces. The other subpopulation represents a fraction that exhibits apoptosis caused by silica/silicates, recruiting from bone marrow, shows higher levels of membrane Fas, and is sensitive to anti-Fas autoantibody. Further investigations should be performed to confirm the effects of silica/silicates on the human immune system.
Asbestos (e.g. chrysotile, crocidolite and amosite) is known to cause malignant lung cancer or mesothelioma. The International agency for Research on Cancer (IARC) categorizes both asbestos and crystalline silica as group I carcinogens. According to the IARC classification, asbestos affects alveolar epithelial and mesothelial cells. Many studies have investigated asbestos-induced apoptosis in these cells. In these experiments, cells underwent apoptosis following relatively high-level, short-term exposure to asbestos via the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) with activation of the mitochondrial apoptotic pathway. Thus, it has been considered that during low-level, long-term exposure to asbestos in the human body, alveolar epithelial and mesothelial cells can escape these apoptotic pathways due to genetic changes and undergo malignant transformation. We have also found that asbestos polyclonally activated CD4-positive T cells and caused activation-induced cell death. In addition, peripheral blood mononuclear cells (PBMCs) from healthy individuals exposed to asbestos in culture underwent apoptosis. However, many patients with asbestosis have had chronic, occupational and recurrent exposure to silicates. Therefore, there seems to be a need to develop an in vitro experimental model of chronic exposure to analyze the immunobiological effects of silicates during long-term exposure.
Effects of silica/asbestos on the function of human immune competent cells such as regulatory T, NKT and NK cells
We are using digital procedures for reporting and testing.