Expression of the T Cell Receptor Vβ Repertoire in a Human T Cell Resistant to Asbestos-Induced Apoptosis and Peripheral Blood T Cells from Patients with Silica and Asbestos-Related Diseases

Abstract

To explore the effects of asbestos and silica on the human immune system, an experimental model of lowdose and long-term exposure was established using a human UTLV-l-immortalized polyclonal T cell line, MT-2 (MT-20rg). MT-2 cells were continuously exposed to asbestos at a concentration (10 ug/ml) which does not induce complete cell death during short-term exposure. After acquiring resistance to CD-induced apoptosis (designated MT-2Rst), an immunological comparison was made between the MT-20rg and MT2Rst lines in terms of T cell receptor-VO (TcR-VO) expression. MT-2Rst cells showed excess expression of various TcR-VO, although TcR-VO-overpresenting cells were characterized as undergoing apoptosis due to first contact with CD. Patients with asbestos-related diseases (AJ{D), such as asbestosis and malignant mesothelioma, were compared with silicosis (SIL) patients as a disease control and with healthy donors (UD). SIL and ARD not only differed in their causative materials, silica and asbestos as mineral silicates, but also in terms of complications; autoimmune disorders in SIL and tumors in ARD. ARD patients showed a restricted overpresentation ofTcR-VO without clonal expansion, whereas SIL patients revealed significant overpresentation of TcR-VO 7.2. These experimental and clinical analyses indicate the superantigenic and dysregulation of autoimmunity-inducing effects of asbestos and silica, respectively.Asbestos (e.g. chrysotile, crocidolite and amosite) is known to cause malignant lung cancer or mesothelioma. The International Agency for Research on Cancer (IARC) categorizes both asbestos and crystalline silica as group I carcinogens (1). According to the IARC classification, asbestos affects alveolar epithelial and mesothelial cells. There have been many studies concerning asbestosinduced apoptosis in these cells. Experimentally, these cells have undergone apoptosis on a relatively high-level, short-term exposure to asbestos via the production of ROS and RNS with activation of the mitochondrial apoptotic pathway (2-4). Thus, it has been considered that during low-level and long-term exposure to asbestos in the human body, alveolar epithelial and mesothelial cells escape from

Dysregulation of the immune system caused by silica and asbestos

“…Parts of these findings were confirmed using clinical samples derived from patients with pleural plaque, for whom there was evidence of past asbestos exposure or malignant mesothelioma. For instance, plasma levels of IL-10 and TGF-β and gene expression of bcl-2 in peripheral CD4 + T-lymphocytes were seen to be elevated in samples from SPs compared to samples from HDs, results that were in accordance with those suggested by the results seen with the chronically-exposed MT-2 cells Nishimura et al, 2006;Maeda et al, 2008;Otsuki et al, 2009;see Figure 3). …”

“…Additionally, screening for sensitivity to chrysotile asbestos revealed that the MT-2 cells and a few Epstein-Barr virus-immortalized B-lymphoblastoid cell lines were relatively more sensitive to cell death in comparison to other T-and B-lymphocyte tumor-derived lines. As it has been suggested that effects on T-lymphocytes may be more important than those on B-lymphocytes (regarding alteration of tumor immunity), this was another key reason the MT-2 cells were chosen for use in our in vitro experiments Nishimura et al, 2006;Maeda et al, 2008;Otsuki et al, 2009). …”

Immunological alterations found in mesothelioma patients and supporting experimental evidence

“…This overexpression was also observed when TCRVb expression in MT-2Org and MT-2Rst cell lines was compared, revealing that MT-2Rst cells overexpressed various TcRVbs. Although TcRVb-overexpressing MT-2Org cells underwent apoptosis due to their first contact with chrysotile, MT-2Rst cells showed no significant changes when they again came in contact with chrysotile [29]. These findings may be interpreted as follows: the overexpression of various TcRVbs may be the result of contact between cells and chrysotile, an asbestos fiber, during the acquisition of resistance to chrysotile-induced apoptosis caused by long-term and low-dose exposure to chrysotile [29].…”

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

“…ARDs showed a limited overexpression of TcRVβ without clonal expansion, whereas SILs showed a significant overexpression of TcRVβ 7.2. These experimental and clinical analyses indicate the superantigenic and dysregulation of the autoimmunity-inducing effects of asbestos and silica, respectively (71).…”