Immunological Risks Caused by Fibrous and Particulate Substances

The immunological risks caused by fibrous and particulate substances, especially the effects caused by asbestos fibers and silica particles, are discussed in this chapter. Patients with silicosis often suffer from autoimmune diseases, such as rheumatoid arthritis, systemic sclerosis, and antineutrophil cytoplasmic antibody–related vasculitis. Silica particles, SiO2, may influence directly various immune cells resulting in the production of many autoantibodies and imbalance between responder and regulatory T cells. The core chemical content of asbestos fibers is Si and O, although the physical feature is different. Considering the complications in asbestos-exposed patients, malignant tumors, such as lung cancer and malignant mesothelioma, are the most important. To think about these situations, asbestos fibers may cause the reduction of antitumor immunity. The experimental findings and measurements of various immunological parameters in silicosis patients, as well as asbestos-exposed population, such as patients with pleural plaque and mesothelioma, are demonstrated and discussed in this chapter

Enhanced expression of nicotinamide nucleotide transhydrogenase (NNT) and its role in a human T cell line continuously exposed to asbestos

The effects of asbestos fibers on human immune cells have not been well documented. We have developed a continuously exposed cell line model using the human T-lymphotropic virus 1 (HTLV-1)-immortalized human T cell line MT-2. Sublines continuously exposed to chrysotile (CH) or crocidolite (CR) showed acquired resistance to asbestos-induced apoptosis following transient and high-dose re-exposure with fibers. These sublines in addition to other immune cells such as natural killer cells or cytotoxic T lymphocytes exposed to asbestos showed a reduction in anti-tumor immunity. In this study, the expression of genes and molecules related to antioxidative stress was examined. Furthermore, complexes related to oxidative phosphorylation were investigated since the production of reactive oxygen species (ROS) is important when considering the effects of asbestos in carcinogenesis and the mechanisms involved in resistance to asbestos-induced apoptosis. In sublines continuously exposed to CH or CR, the expression of thioredoxin decreased. Interestingly, nicotinamide nucleotide transhydrogenase (NNT) expression was markedly enhanced. Thus, knockdown of NNT was then performed. Although the knockdown clones did not show any changes in proliferation or occurrence of apoptosis, these clones showed recovery of ROS production with returning NADPH/NADP+ ratio that increased with decreased production of ROS in continuously exposed sublines. These results indicated that NNT is a key factor in preventing ROS-induced cytotoxicity in T cells continuously exposed to asbestos. Considering that these sublines showed a reduction in anti-tumor immunity, modification of NNT may contribute to recovery of the anti-tumor effects in asbestos-exposed T cells

Induction of IL-17 production from human peripheral blood CD4+ cells by asbestos exposure

We have previously reported that chronic, recurrent and low-dose exposure to asbestos fibers causes a reduction in antitumor immunity. Investigation of natural killer (NK) cells using an in vitro cell line model and comprising in vitro activation using freshly isolated NK cells co-cultured with chrysotile fibers, as well as NK cells derived from asbestos-exposed patients with pleural plaque (PP) or malignant mesothelioma (MM), revealed decreased expression of NK cell activating receptors such as NKG2D, 2B4 and NKp46. An in vitro differentiation and clonal expansion model for CD8+ cytotoxic T lymphocytes (CTLs) showed reduced cytotoxicity with decreased levels of cytotoxic molecules such as granzyme B and perforin, as well as suppressed proliferation of CTLs. Additionally, analysis of T helper cells showed that surface CXCR3, chemokine receptor, and the productive potential of interferon (IFN)γ were reduced following asbestos exposure in an in vitro cell line model and in peripheral CD4+ cells of asbestos-exposed patients. Moreover, experiments revealed that asbestos exposure enhanced regulatory T cell (Treg) function. This study also focused on CXCR3 expression and the Th-17 cell fraction. Following activation with T-cell receptor and co-culture with various concentrations of chrysotile fibers using freshly isolated CD4+ surface CXCR3 positive and negative fractions, the intracellular expression of CXCR3, IFNγ and IL-17 remained unchanged when co-cultured with chrysotile. However, subsequent re-stimulation with phorbol 12-myristate 13-acetate (PMA) and ionomycin resulted in enhanced IL-17 production and expression, particularly in CD4+ surface CXCR3 positive cells. These results indicated that the balance and polarization between Treg and Th-17 fractions play an important role with respect to the immunological effects of asbestos and the associated reduction in antitumor immunity

Induction of IL-17 production from human peripheral blood CD4+ cells by asbestos exposure

We have previously reported that chronic, recurrent and low-dose exposure to asbestos fibers causes a reduction in antitumor immunity. Investigation of natural killer (NK) cells using an in vitro cell line model and comprising in vitro activation using freshly isolated NK cells co-cultured with chrysotile fibers, as well as NK cells derived from asbestos-exposed patients with pleural plaque (PP) or malignant mesothelioma (MM), revealed decreased expression of NK cell activating receptors such as NKG2D, 2B4 and NKp46. An in vitro differentiation and clonal expansion model for CD8+ cytotoxic T lymphocytes (CTLs) showed reduced cytotoxicity with decreased levels of cytotoxic molecules such as granzyme B and perforin, as well as suppressed proliferation of CTLs. Additionally, analysis of T helper cells showed that surface CXCR3, chemokine receptor, and the productive potential of interferon (IFN)γ were reduced following asbestos exposure in an in vitro cell line model and in peripheral CD4+ cells of asbestos-exposed patients. Moreover, experiments revealed that asbestos exposure enhanced regulatory T cell (Treg) function. This study also focused on CXCR3 expression and the Th-17 cell fraction. Following activation with T-cell receptor and co-culture with various concentrations of chrysotile fibers using freshly isolated CD4+ surface CXCR3 positive and negative fractions, the intracellular expression of CXCR3, IFNγ and IL-17 remained unchanged when co-cultured with chrysotile. However, subsequent re-stimulation with phorbol 12-myristate 13-acetate (PMA) and ionomycin resulted in enhanced IL-17 production and expression, particularly in CD4+ surface CXCR3 positive cells. These results indicated that the balance and polarization between Treg and Th-17 fractions play an important role with respect to the immunological effects of asbestos and the associated reduction in antitumor immunity

Asbestos-Induced Cellular and Molecular Alteration of Immunocompetent Cells and Their Relationship with Chronic Inflammation and Carcinogenesis

Asbestos causes lung fibrosis known as asbestosis as well as cancers such as malignant mesothelioma and lung cancer. Asbestos is a mineral silicate containing iron, magnesium, and calcium with a core of SiO2. The immunological effect of silica, SiO2, involves the dysregulation of autoimmunity because of the complications of autoimmune diseases found in silicosis. Asbestos can therefore cause alteration of immunocompetent cells to result in a decline of tumor immunity. Additionally, due to its physical characteristics, asbestos fibers remain in the lung, regional lymph nodes, and the pleural cavity, particularly at the opening sites of lymphatic vessels. Asbestos can induce chronic inflammation in these areas due to the production of reactive oxygen/nitrogen species. As a consequence, immunocompetent cells can have their cellular and molecular features altered by chronic and recurrent encounters with asbestos fibers, and there may be modification by the surrounding inflammation, all of which eventually lead to decreased tumor immunity. In this paper, the brief results of our investigation regarding reduction of tumor immunity of immunocompetent cells exposed to asbestos in vitro are discussed, as are our findings concerned with an investigation of chronic inflammation and analyses of peripheral blood samples derived from patients with pleural plaque and mesothelioma that have been exposed to asbestos

Investigating methods regarding diagnostic and prognostic biomarkers for malignant mesothelioma

Malignant mesothelioma (MM) is a pleural malignant tumor that results predominantly from exposure to asbestos and has a poor prognosis. After a brief review of the epidemiology, etiology, and clinical status of MM, we detail methods being used to search for diagnostic and prognostic biomarkers for MM, particularly approaches involving the use of blood samples. The soluble mesothelin-related protein (SMRP), mesothelin/ERC and osteopontin are typical biomarkers for MM. In addition to these biomarkers, fibulin-3 has recently been introduced as a biomarker for MM. Furthermore, several molecules have been reported as useful biomarkers. In addition to an introduction outlining newer approaches such as those of proteomics, we hope to summarize the recent status of biomarkers for MM in this review

Silica and mineral silicates causing autoimmune diseases

There are many environmental, occupational and medical substances that cause dysregulation of autoimmunity. Among these substances, the effects and causative mechanisms of silica particles and asbestos fibers are discussed in this review. Many epidemiological studies have shown a significant association between silica exposure and the occurrence of autoimmune diseases such as rheumatoid arthritis (RA), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and anti-neutrophil cytoplasm antibody (ANCA)-related vasculitis. Although the importance of NALP3 inflammasome as the initial immune reaction against silica particles has been recognized, the processes that form the various autoimmune diseases in silica-exposed patients remain unclear. Silica can activate various immune cells and cause an unbalance of regulatory T cells, responder T cells and T helper 17 cells, which might be key factors in understanding the silica-induced autoimmune alteration. In contrast, asbestos exposure shows a smaller association with autoimmune diseases. However, interesting findings have been reported regarding anti-endothelial and mesothelial cell antibodies detected in asbestos-exposed patients. Further investigations may contribute to elucidation of the mechanisms involved in environmental factor-induced modification of autoimmunity

Biological effects of refractory ceramic fiber

Refractory ceramic fibers (RCFs) are one of the many man-made mineral fibers (MMMFs) / synthetic vitreous fibers (SVFs) used as alternative products to asbestos fibers. The Japanese Ministry of Health, Labour and Welfare began to regulate the manufacturing and handling of RCFs under specific chemical disorder prevention rules to reduce the risks of exposure to RCFs since November 1st, 2015. In fact, the International Agency for Research on Cancer (IARC) categorized RCFs as group 2B, being possibly carcinogenic to humans, according to results obtained from animal experiments. Thus, given the biological effects of RCFs previously reported in the literature, it is necessary to consider further monitoring in addition to the development of measures to prevent adverse health effects caused by exposure to RFCs. In this review, a summary of the biological effects of refractory ceramic fibers (RCFs) is presented and discussed with respect to toxicity, animal models and epidemiological studies, and a comparison is made with asbestos exposure to outline and clarify the current status pertaining to the biological effects of RCFs

Immunological Changes in Mesothelioma Patients and Their Experimental Detection

It is common knowledge that asbestos exposure causes asbestos-related diseases such as asbestosis, lung cancer and malignant mesothelioma (MM) not only in people who have handled asbestos in the work environment, but also in residents living near factories that handle asbestos. These facts have been an enormous medical and social problem in Japan since the summer of 2005. We focused on the immunological effects of asbestos and silica on the human immune system. In this brief review, we present immunological changes in patients with MM and outline their experimental detection. For example, there is over-expression of bcl-2 in CD4+ peripheral T-cells, high plasma concentrations of interleukin (IL)-10 and transforming growth factor (TGF)-ß, and multiple over-representation of T cell receptor (TcR)-Vß in peripheral CD3+ T-cells found in MM patients. We also detail an experimental long-term exposure T-cell model. Analysis of the immunological effects of asbestos may help our understanding of the biological effects of asbestos

Accelerated cell cycle progression of human regulatory T cell-like cell line caused by continuous exposure to asbestos fibers

Asbestos exposure causes malignant tumors such as lung cancer and malignant mesothelioma. Based on our hypothesis in which continuous exposure to asbestos of immune cells cause reduction of antitumor immunity, the decrease of natural killer cell killing activity with reduction of NKp46 activating receptor expression, inhibition of cytotoxic T cell clonal expansion, reduced CXCR3 chemokine receptor expression and production of interferon-γ production in CD4+ T cells were reported using cell line models, freshly isolated peripheral blood immune cells from health donors as well as asbestos exposed patients such as pleural plaque and mesothelioma. In addition to these findings, regulatory T cells (Treg) showed enhanced function through cell-cell contact and increased secretion of typical soluble factors, interleukin (IL)-10 and transforming growth factor (TGF)-β, in a cell line model using the MT-2 human polyclonal T cells and its sublines exposed continuously to asbestos fibers. Since these sublines showed a remarkable reduction of FoxO1 transcription factor, which regulates various cell cycle regulators in asbestos-exposed sublines, the cell cycle progression in these sublines was examined and compared with that of the original MT-2 cells. Results showed that cyclin D1 expression was markedly enhanced, and various cyclin-dependent kinase-inhibitors were reduced with increased S phases in the sublines. Furthermore, the increase of cyclin D1 expression was regulated by FoxO1. The overall findings indicate that antitumor immunity in asbestos-exposed individuals may be reduced in Treg through changes in the function and volume of Treg