Dysregulation of autoimmunity caused by silica exposure: Fas-mediated apoptosis in T lymphocytes derived from silicosis patients

Hiroaki Hayashi, Yasumitsu Nishimura, Fuminori Hyodo, Megumi Maeda, Naoko Kumagai, Yoshie Miura, Masayasu Kusaka, Kozo Uragam, Takemi Otsuki

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Abstract

Silicosis patients suffer not only from respiratory disorders, but also from autoimmune diseases. To clarify 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 because Fas is one of the most important molecules regulating autoimmunity in T cells. Our findings have shown that in comparison to healthy donors, silicosis patients exhibit elevated serum soluble Fas levels, an increased relative expression of the soluble fas and dcr3 genes in peripheral blood mononuclear cells, other highly detectable variant messages of the fas transcript, a 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. 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 serum from 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 is a long-term survival fraction including a self-recognizing fraction showing lower levels of membrane Fas and inhibition of Fas/Fas ligand binding in the extracellular spaces. The other is a fraction exhibiting apoptosis caused by silica/silicates, recruitment from bone marrow, higher levels of membrane Fas, and sensitivity to anti-Fas autoantibody. Further investigations should be performed to confirm the effects of silica/silicates on the human immune system. In addition, results concerning whether serum soluble interleukin-2 receptor and soluble CD40 ligand levels should be considered immunological markers in silicosis patients are discussed. Furthermore, based on our previous reports showing in vitro activation of peripheral T cells by silica and reduced function of the CD4+CD25+ fraction in which FoxP3+ regulatory T cells (Treg) are located, the reconstitution of the CD4+CD25+ fraction in silicosis patients (SILs) was analyzed. Since T cells in peripheral CD4+CD25+ as well as CD4+CD25- fractions from SILs showed higher expression of pd-1 (marker gene for T-cell activation) compared to that of healthy donors (HDs), chronic T-cell activation is thought to have occurred in SILs. In addition, surface Fas expression of Treg was higher in SILs than HDs. The ex vivo experiments using freshly isolated peripheral blood mononuclear cells (PBMCs) from SILs and HDs cultured with or without silica showed loss of Treg by Fas-mediated apoptosis and an increase of activated CD25+ T cells in PBMCs from SILs as well as HDs. Although T cells in SILs are thought to have been exposed to low-dose silica for a long time, their effector T cells (Teff) and Treg still possess the capacity to be activated by silica. These activations of both Teff and Treg cause re-constitution of the peripheral Treg fraction, loss of Treg and contamination of activated Teff, resulting in a reduction of the size and function of Treg. These results might contribute to an elucidation of the development of autoimmune diseases found in silicosis patients.

Original languageEnglish
Title of host publicationAutoimmune Disorders: Symptoms, Diagnosis and Treatment
PublisherNova Science Publishers, Inc.
Pages293-302
Number of pages10
ISBN (Print)9781617615528
Publication statusPublished - Jan 2011

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    Hayashi, H., Nishimura, Y., Hyodo, F., Maeda, M., Kumagai, N., Miura, Y., Kusaka, M., Uragam, K., & Otsuki, T. (2011). Dysregulation of autoimmunity caused by silica exposure: Fas-mediated apoptosis in T lymphocytes derived from silicosis patients. In Autoimmune Disorders: Symptoms, Diagnosis and Treatment (pp. 293-302). Nova Science Publishers, Inc..