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MINIREVIEW

Alterations of Fas and Fas-Related Molecules in Patients with Silicosis

Takemi Otsuki^*,1, Yoshie Miura^*, Yasumitsu Nishimura^*, Fuminori Hyodoh^*, Akiko Takata^*, Masayasu Kusaka, Hironobu Katsuyama, Masafumi Tomita, Ayako Ueki^|| and Takumi Kishimoto^¶

^* Departments of Hygiene, Public Health and Medical Toxicology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Japan; Kusaka Hospital, 1122 Nishikatagami, Bizen, Japan; ^|| Department of Medical Welfare and Environmental Design, School of Medical Welfare, Kawasaki University of Medical Welfare, 288 Matsushima, Kurashik, Japan; and ^¶ Okayama Rousai Hospital, 1-10-25 Chikkou Midorimachi, Okayama, Japan

To whom requests for reprints should be addressed at ¹ Department of Hygiene, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 7010192, Japan. E-mail: takemi{at}med.kawasaki-m.ac.jp

Persons with silicosis have not only respiratory disorders but also autoimmune diseases. To clarify the mechanisms involved in the dysregulation of autoimmunity found in patients with silicosis, we have been focusing on Fas and Fas-related molecules in the Fas-mediated apoptotic pathway, because Fas is one of the most important molecules regulating auto-immunity involving T cells. Our findings showed that patients with silicosis exhibited elevated serum soluble Fas levels, an increased relative expression of the soluble fas and dcr3 genes in peripheral blood mononuclear cells, high levels of other variant messages of the fas transcript, relatively decreased expression of genes encoding several physiological inhibitors (such as survivin and toso), and dominancy of lower-membrane Fas expressers in lymphocytes, which transcribe soluble fas dominantly, compared with soluble fas transcription in healthy donors. These findings are consistent with known features regarding immunological factors, such as serum immunogulobulin G levels and the titer of anti-nuclear autoantibodies in silicosis. In addition, anti-caspase 8 autoantibody and anti-Fas autoantibody were detected in serum specimens from patients with silicosis, and a functional assay showed that anti-Fas antibody stimulated Fas-mediated apoptosis. We hypothesize that there are two subpopulations of silicosis lymphocytes. One is a long-term surviving fraction that includes self-recognizing clones showing lower levels of membrane Fas and inhibition of Fas/Fas ligand binding in extracellular spaces. The other subpopulation exhibits apoptosis caused by silica and silicates, is recruited from bone marrow, shows higher levels of membrane Fas, and is sensitive to anti-Fas autoantibody. Further investigation should be performed to confirm the effects of silica and silicates on the human immune system.

Key Words: silicosis • Fas • autoimmunity • apoptosis