Soluble Fas mRNA is dominantly expressed in cases with silicosis

Abstract

SUMMARYAlthough it is well known that cases with silicosis exhibit various immunological abnormalities, the mechanisms involved in the occurrence of immuno-dysfunction or dysregulation induced by silica compounds have not yet been determined. Fas is a well-known cell surface molecule that is involved in the apoptosis pathway that belongs to the tumour necrosis factor-receptor family. Soluble Fas (sFas) is produced as an alternatively spliced product of the Fas gene and protects cells from apoptosis due to antagonization of the binding between membrane form of the Fas gene (mFas) and the Fas ligand. To determine the role of the Fas/Fas ligand system in silicainduced immunological abnormalities, we investigated Fas and Fas-ligand message expression levels using the multiplex reverse transcription-polymerase chain reaction (RT-PCR) method with peripheral blood mononuclear cells from silicosis cases with no clinical symptoms of autoimmune diseases. Although the relative expression levels of the Fas or Fas-ligand genes were not remarkably altered in these cases, we observed the sFas message was dominantly expressed compared with mFas expression. These results suggest that self-recognizing clones in cases with silicosis survive for decades, escaping the exclusion mechanisms induced by apoptosis. Then they cause the appearance of autoantibodies and the acquisition of autoimmune diseases sequentially.

Evidence for the role of environmental agents in the initiation or progression of autoimmune conditions.

“…Acquired humoral immunity (48), upregulation of soluble Fas (49), increased macrophage sensitivity to lipopolysaccharides (50), and reduced antigen presentation (50) have all been demonstrated. Observations on soluble Fas are particularly interesting given the recent findings that Fas and Fas ligand may be critically involved in the pathogenesis of Hashimoto's thyroiditis (51).…”

“…In the thyroid and under select cytokine conditions, cells may express both Fas ligand and membrane Fas, leading to locally induced (fratricidal) apoptosis, so dysregulation of this mechanism would similarly have implications in autoimmunity (51). Soluble Fas, which is an alternatively spliced product of the Fas gene, antagonizes the binding between membrane Fas and the Fas ligand; elevated levels could inhibit apoptosis of selfrecognizing clones, precipitating autoimmune responses at a later stage (49).…”

Detection of anti-topoisomerase I autoantibody in patients with silicosis

“…We found that dysregulation of the Fas-mediated apoptotic pathway might play an important role in the pathogenesis of the immunological abnormalities found in silicosis patients 7,8,[17][18][19] . Therefore, it is suggested that the genesis of anti-topo I autoantibodies is associated with the abnormalities of apoptosis-related molecules in silicosis patients.…”

“…Details of materials and methods for B (i), (iii), (iv) and (v) and B (vi) were previously reported by Tomokuni et al 7,17) and Otsuki et al 8) , respectively.…”

“…We investigated the mechanisms involved in the immunological disturbances found in silicosis, focusing on the Fas-mediated apoptotic pathway, because abnormalities in Fas and related molecules have been reported in human idiopathic autoimmune diseases such as SLE and rheumatoid arthritis [4][5][6] . We found that serum soluble Fas (sFas) levels were elevated in silicosis patients with no clinical symptoms of autoimmune disease 7) , and that the sFas message was dominantly expressed in peripheral blood mononuclear cells (PBMC) derived from these patients 8) . Based on these investigations, we concluded that dysregulation of the Fas-mediated apoptotic pathway may play an important role in the pathogenesis of the immunological abnormalities found in patients with silicosis.…”