KAWAKAMI Yasuhiko Kawasaki Med.Sch.Medical School, Research Associate, 医学部, 助手 (10234030)
TOMOKUNI Akiko Kawasaki Med.Sch.Medical School, Research Associate, 医学部, 助手 (30278957)
UEKI Ayako Kawasaki Med.Sch.Medical School, Professor, 医学部, 教授 (10069031)
|Budget Amount *help
¥3,000,000 (Direct Cost : ¥3,000,000)
Fiscal Year 1998 : ¥1,300,000 (Direct Cost : ¥1,300,000)
Fiscal Year 1997 : ¥1,700,000 (Direct Cost : ¥1,700,000)
We have been studying the immunodysregulation and acquisition of autoimmunity induced by silica compounds and have observed following findings ; i) increase of relative expression of soluble Fas as compared with membrane Fas message in peripheral blood mononuclear cells (PBMC) from silicosis cases (SIL), ii) No difference of total Fas or Fas ligand expression between SIL and healthy volunteers (HV), iii) elevation of serum soluble Fas in SIL, iv) No difference of membrane Fas on the surface of peripheral blood lymphocytes (PBL), v) NO difference of serum soluble Fas ligand, v) induction of apoptosis of PBMC cultured with silica compound, chrysotile B, vi) inhibition of this apoptosos by addition of antibodies for Fas/Fas ligand pathway, and anti-caspase 8 neutralizing antibody, vii) upregulatlon of Fas, Fas ligand, caspase, 1, 3, and 8 genes during apoptosis induced by silica, viii) stronger inducibility of apoptosis by silica than man-made mineral fibers, ix) detection of alternatively spliced variant messages in PBMC from SIL.
These findings indicate that lymphocytes which are resistant to the silica-induced apoptosis will appear during exposure of silica compounds occupationally and chronically, although healthy lymphocytes easily enter the Fas-mediated apoptosis pathway and die after activation due to silica exposure. These resistant clones may include subpopulation of self-reccgnizing clones and they may produce soluble Fas which may antagonize with membrane Fas to bind with Fas ligand and make self-recognize clones to survive longer. These clones may possess an important role to acquire autoimmunity in cases with silicosis.