In this chapter, cellular and molecular approaches to clarify the immunological effects of asbestos are described, and all findings indicate that a reduction of tumor immunity is caused by asbestos exposure and is involved in asbestos-induced cancers. In addition to confirming the well-known biological effects of asbestos, these investigations provide a basis for the development of a novel procedure for the early detection of previous asbestos exposure, mesothelioma and the chemoprevention of asbestos-related cancers.
Schematic representation of immunological risks caused by exposure to silica particles and asbestos fibers. The immunological risks induced crucial complications, such as autoimmune diseases, in silicosis patients, as well as malignant tumors, such as lung cancer and malignant mesothelioma, in asbestos-exposed populations.
In this chapter, the immunological effects on various immune cells caused by silica particles and asbestos fibers as investigated in our laboratory will be presented and discussed with respect to the detection of immunological risks of particulate and fibrous environmental factors [ 11 — 16 ].
These summarized findings may be helpful in the development of future risk management strategies, including cases related to newly developed fibrous and particulate matter, such as nanoparticles and nanotubes. These findings were established by in vitro assays using peripheral blood mononuclear cells PBMC derived from HD cultured with silica particles as well as freshly isolated immune cells derived from SIL. Additionally, various autoantibodies aAbs were detected from SIL [ 11 — 14 ]. All SIL showed no symptoms related to autoimmune diseases or cancers.
First, the risk of dysregulated autoimmunity assessed by the detection of particular aAbs will be discussed. As a result, a minimum of four and a maximum of ten epitopes were found, and several amino acid residues involved in binding Fas ligand, such as C66, R87, L90 E93, and H, were identified [ 61 ]. The association of anticaspase 8 aAb with HLA types was examined.
Furthermore, epitope mapping showed that a minimum of four and a maximum of thirteen polypeptides seemed to be involved. Among these, two important catalytic cysteine residues were found, cysteine Cys and Cys, located in the unique pentapeptide motif QACQG [ 62 ]. Moreover, although the titer index of anti-CENP-B autoantibody formed the same factor with anti-Scl autoantibody, the Ig G value, and age of SIL, the property of other factors extracted indicated that anti-Scl antibody was positively related with the Ig A value, while the converse was true for anti-CENP-B from the results of factor analysis.
Taken together, various aAbs found in SIL have indicated that dysregulation of autoimmunity was caused by chronic and recurrent exposure to silica particles that remained in lung and related lymph nodes of various human cells, especially B cells. Although it can be mentioned that repeated and continuous screening of aAbs as well as the initial screening of HLA types seems to be necessary among workers in contact with silica-related substances for the detection of dysregulation of autoimmunity, the use of genotyping, such as determining HLA types, is not permitted during employee selection procedures.
Biological Effects of Fibrous and Particulate Substances
However, a consideration of particular occupational health risks together with individual sensitivities is required in an effort to prevent occupational health hazards and associated future hardships. Hence all of these translation products are secreted into the extracellular space and bind with Fas ligand, thereby protecting cells against membrane Fas-mediated apoptosis [ 70 ].
Furthermore, the expression of the protective molecule decoy receptor 3 DcR3 , which acts against the Trail molecule and similarly induces apoptosis via a Trail receptor and the same intracellular signaling molecules for apoptosis, such as caspase 8 and 10 [ 71 , 72 ], was higher in SIL PBMC compared with HD [ 73 ].
Further studies revealed that this fraction may include Treg cells [ 13 , 14 ]. Thus, a decrease in the number of Treg cells by apoptosis and an increase in the number of responder T cells caused by silica exposure may be the cellular biological mechanisms at work in SIL, which consequently impart susceptibility to autoimmune diseases in SIL. Furthermore, when PBMC from HD were cultured with silica particles in vitro, Treg cell numbers were selectively reduced by apoptosis and the population of responder T cells was enhanced [ 77 ].
Moreover, there is evidence showing chronic activation of responder T cells. Taken together, SIL possess a risk of developing dysregulation of autoimmunity. Of course, asbestos fibers possess carcinogenic-related activities, such as oxygen stress caused by iron in the asbestos fibers, frustrated macrophages incapable of phagocytosing asbestos fibers, chromosome tangling, and the absorption of other carcinogenic substances inhaled in the lung, such as materials from tobacco smoke and other air pollutants [ 34 — 36 ].
However, given the long latency period that precedes the onset of MM following initial exposure to asbestos, it was considered that asbestos fibers cause alterations in antitumor immunity by recurrent and chronic encounters with various immune cells at the lung and related lymph nodes.
Among these receptors, NKp46 was thought to be an important marker for impaired function of NK cells exposed to asbestos. Moreover, reduced cytotoxicity in NK cells exposed to asbestos was accompanied with reduced phosphorylation of extracellularly regulated kinases ERK 1 and 2 and reduced degranulation of perforin and granzyme B, which are the killing small molecules secreted from NK cells [ 82 , 83 ]. Other types of cytokilling immune cells, CTLs, are also involved and have their functional and cellular properties altered by asbestos exposure.
These findings indicated that asbestos exposure caused dysfunction of CTLs, while specific cell functions differed depending on disease status, for example, PP patients do not carry any malignant tumors, whereas MM patients suffer from mesothelioma.
However, the impact of asbestos fibers on CTLs is considered to involve a reduction of tumor immunity, as we showed in NK cells mentioned above [ 84 , 85 ]. Asbestos fibers are also known to modify Th1 cells. We developed continuously exposed sublines using a cell line model. The cDNA microarray data were examined of the original cell line, which has had no contact with asbestos fibers, and six independently established sublines, which were continuously exposed to asbestos fibers for more than 8 months using an asbestos concentration that did not induce apoptosis in more than half of the cells by transient exposure.
Taken together, one of the immunological risks resulting from asbestos exposure concerns a reduction of Th1-type T cell—derived antitumor immunity. Treg cells are important in antitumor immunity. If the function and number of Treg cells are enhanced, immune cells responding to tumor antigen show suppressed function, which causes a reduction of antitumor immunity [ 75 , 76 ]. Overproduction of IL is regulated by the Src-family receptor and is used by the IL receptor via autocrine mechanisms, which then causes activation of the signal transducer and activator of transcription 3 STAT 3 and upregulation of antiapoptotic molecule Bcl-2 located downstream of STAT3 [ 88 ].
Continuously exposed sublines acquire resistance to apoptosis induced via transient exposure to asbestos [ 88 ]. Taken together, exposure to asbestos results in enhanced Treg function, which is manifested by a reduction of antitumor immunity [ 11 , 12 , 15 , 16 , 80 , 81 ]. These findings are considerable and the risks associated with asbestos exposure may be used as early detection markers for the occurrence of asbestos-induced malignancies. Additionally, the ability to mitigate the observed reduction of antitumor immunity through the use of chemopreventive substances derived from foods or plants may be an important strategy in the treatment of high-risk groups exposed to asbestos, such as residents who have a history of living near factories handling asbestos and workers in the building demolition and rubble processing fields.
Risks associated with exposure to fibers, such as asbestos, and particulates, such as silica, were discussed based on our experimental findings and analyzed using cell lines, freshly isolated peripheral immune cells from HD, as well as patients exposed to silica particles, exposed to asbestos fibers, and patients with silicosis, PP, and MM. The immunological risks manifested in different directions, in that silica caused dysregulation of autoimmunity, whereas asbestos induced a reduction of antitumor immunity.
Both cellular and molecular alterations contributed to the complications of silica exposure, the occurrence of autoimmune diseases and asbestos exposure, and the development of malignant tumors. These risks may be detected using findings described in this chapter, and early detection of these risks may assist workers, as well as other exposed populations, in avoiding further exposure and therefore prevent the onset of various pathological states caused by exposure to fibrous and particulate substances. Recently, although exposure to silica and asbestos has been reduced through the improvement of work-related environments as well as banning the use of asbestos, new substances, such as nanomaterials, which are widely used in the industrial fields, are now feared to cause health risks.
It should be reiterated that risks, and particularly immunological ones which hitherto have not received a great deal of attention, caused by classical types of particulate and fibrous substances, such as silica and asbestos, require continued and greater consideration in an effort to further prevent the health impairment caused by environmental substances. F: This cross does not three-dimensional. We see our best to do this from falling, but the ability may suppress slain moved, detects already be initially, or is project to Crypt.
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Biological Effects of Fibrous and Particulate Substances | Takemi Otsuki | Springer
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Induction of altered mRNA expression profiles caused by fibrous and granular dust
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