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

Abstract

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.

Rheumatoid pneumoconiosis (Caplan's syndrome)

“…The radiological features consist in multiple well-defined round opacities, measured between 0.5 and 5 cm in diameter, distributed throughout both lung fields but predominantly at the periphery [8]. The association between long exposure to silica, pneumoconiosis and RA is proved [9]. In the study of Calvert GM et al [10], the link between crystalline silica exposure and RA is well demonstrated.…”

Keynote lecture in the 13th Japanese Society of Immunotoxicology (JSIT 2006)

“…Consequently, it is speculated that there is a particular fraction of CD4+ T lymphocytes in SILs that expresses weak levels of membrane Fas, secretes higher levels of soluble Fas, DcR3, and spliced variants, and is resistant to anti-Fas autoantibody-induced apoptosis, as shown in Fig. 1 and previous reports (30,43,44). Because the patients with a weaker MFI of membrane Fas have a higher titer of anti-nuclear antigens (ANA), as reported previously (30), selfrecognizing clones in SILs may be included in this fraction, because these clones may survive longer and show resistance to apoptosis.…”

“…1 and preliminarily reported previously (30,43,44). The findings of the levels of factors in extracellular spaces, such as soluble Fas, DcR3, and products from various alternatively spliced fas variants indicate that apoptosis mediated by membrane Fas seems to interfere with these molecules and Fas-mediated apoptosis is reduced.…”

“…III) Although the percentage of Fas-positive lymphocytes (membrane Fas expression) did not differ between SILs and HDs, the mean fluorescence intensity (MFI) of membrane Fas was lower in SILs than in HDs. In addition, the weakermembrane Fas expressers among lymphocytes were identified to be weaker-fas message expressers (26,30).…”

Silica-Associated Systemic Lupus Erythematosus in an Elderly Man

“…They developed a syndrome that is serologically and pathologically similar to human SLE. In humans, the serum levels of soluble Fas (sFas), the most typical alternatively spliced variant of wild-type fas genes, are higher in silicosis and SLE patients (17,18 (17). (20,21 (22,24,25 Fig.…”