Skip to main content
Download PDF
  • Minireview Article
  • Published:

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

—Pathophysiological Development and Immunotoxicology: what we have found from research related to silica and silicate such as asbestos—

Environmental Health and Preventive Medicine volume 12, pages 153–160 (2007)Cite this article

Abstract

Silica and silicates may disturb immune functions such as autoimmunity and tumor immunity, because people who are exposed to the materials sometimes develop autoimmune and malignant diseases, respectively. Although silica-induced disorders of autoimmunity have been explained as adjuvant-type effects of silica, more precise analyses are needed and should reflect the recent progress in immunomolecular findings. A brief summary of our investigations related to the immunological effects of silica/asbestos is presented. Recent advances in immunomolecular studies led to detailed analyses of the immunological effects of asbestos and silica. Both affect immuno-competent cells and these effects may be associated with the pathophysiological development of complications in silicosis and asbestos-exposed patients such as the occurrence of autoimmune disorders and malignant tumors, respectively. In addition, immunological analyses may lead to the development of new clinical tools for the modification of the pathophysiological aspects of diseases such as the regulation of autoimmunity or tumor immunity using cell-mediated therapies, various cytokines, and molecule-targeting therapies. In particular, as the incidence of asbestos-related malignancies is increasing and such malignancies have been a medical and social problem since the summer in 2005 in Japan, efforts should be focused on developing a cure for these diseases to eliminate the nation wide anxiety about these malignancies.

References

  1. Bartunkova J, Tesar V, Sediva A. Diagnostic and pathogenetic role of antineutrophil cytoplasmic autoantibodies. Clin Immunol. 2003; 106: 73–82.

    Article  PubMed  CAS  Google Scholar 

  2. Steenland K, Goldsmith DF. Silica exposure and autoimmune diseases. Am J Ind Med. 1995; 28: 603–608.

    Article  PubMed  CAS  Google Scholar 

  3. Uber CL, McReynolds RA. Immunotoxicology of silica. Crit Rev Toxicol. 1982; 10: 303–319.

    Article  PubMed  CAS  Google Scholar 

  4. Caplan A. Rheumatoid pneumoconiosis syndrome. Med Lav. 1965; 56: 494–499.

    PubMed  CAS  Google Scholar 

  5. Caplan A. Contribution to discussion on rheumatoid pneumoconiosis. Grundfragen Silikoseforsch. 1963; 6: 345–349.

    PubMed  CAS  Google Scholar 

  6. Lamvik J. Rheumatoid pneumoconiosis. A case of Caplan’s syndrome in a chalk-mine worker. Acta Pathol Microbiol Scand. 1963; 57: 169–174.

    PubMed  CAS  Google Scholar 

  7. Mayes MD. Epidemiologic studies of environmental agents and systemic autoimmune diseases. Environ Health Perspect. 1999; 107S5: 743–748.

    Article  Google Scholar 

  8. Brown SL, Langone JJ, Brinton LA. Silicone breast implants and autoimmune disease. J Am Med Womens Assoc. 1998; 53: 21–24, 40.

    PubMed  CAS  Google Scholar 

  9. Reyes H, Ojo-Amaize EA, Peter JB. Silicates, silicones and autoimmunity. Isr J Med Sci. 1997; 33: 239–242.

    PubMed  CAS  Google Scholar 

  10. Jenkins ME, Friedman HI, von Recum AF. Breast implants: facts, controversy, and speculations for future research. J Invest Surg. 1996; 9: 1–12.

    Article  PubMed  CAS  Google Scholar 

  11. Gilson JC. Health hazards of asbestos. Recent studies on its biological effects. Trans Soc Occup Med. 1966; 16: 62–74.

    Article  PubMed  CAS  Google Scholar 

  12. Rom WN, Palmer PE. The spectrum of asbestos-related diseases. West J Med. 1974; 121: 10–21.

    PubMed  CAS  Google Scholar 

  13. Dodson RF, Hammar SP. Asbestos: Risk Assessment, Epidemiology, and Health Effects. Boca Raton, FL: CRC Press Taylor & Francis Group; 2006.

    Google Scholar 

  14. Roccli VL, Oury TD, Sporn TA. Asebstos-associated Diseases. 2nd ed. New York, U.S.A.: Springer; 2004.

    Google Scholar 

  15. Nagata S. Fas and Fas ligand: a death factor and its receptor. Adv Immunol. 1994; 57: 129–144.

    Article  PubMed  CAS  Google Scholar 

  16. Nagata S, Suda T. Fas and Fas ligand: lpr and gld mutations. Immunol Today. 1995; 16: 39–43.

    Article  PubMed  CAS  Google Scholar 

  17. Ferguson TA, Griffith TS. A vision of cell death. Fas ligand and immune privilege 10 years later. Immunol Rev. 2006; 213: 228–238.

    Article  PubMed  CAS  Google Scholar 

  18. Kim KS. Multifunctional role of Fas-associated death domain protein in apoptosis. J Biochem Mol Biol. 2002; 35: 1–6.

    PubMed  CAS  Google Scholar 

  19. Peng SL. Fas (CD95)-related apoptosis and rheumatoid arthritis. Rheumatology (Oxford). 2006; 45: 26–30.

    Article  CAS  Google Scholar 

  20. Pinkoski MJ, Green DR. Fas ligand, death gene. Cell Death Differ. 1996; 6: 1174–1181.

    Article  CAS  Google Scholar 

  21. Owen-Schaub L, Chan H, Cusack JC, Roth J, Hill LL. Fas and Fas ligand interactions in malignant disease. Int J Oncol. 2000; 17: 5–12.

    PubMed  CAS  Google Scholar 

  22. Bettinardi A, Brugnoni D, Quiros-Roldan E, Malagoli A, La Grutta S, Correra A, et al. Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: a molecular and immunological analysis. Blood. 1997; 89: 902–909.

    PubMed  CAS  Google Scholar 

  23. Hasunuma T, Kayagaki N, Asahara H, Motokawa S, Kobata T, Yagita H, et al. Accumulation of soluble Fas in inflamed joints of patients with rheumatoid arthritis. Arthritis Rheum. 1997; 40: 80–86.

    Article  PubMed  CAS  Google Scholar 

  24. Tokano Y, Miyake S, Kayagaki N, Nozawa K, Morimoto S, Azuma M, et al. Soluble Fas molecule in the serum of patients with systemic lupus erythematosus. J Clin Immunol. 1996; 16: 261–265.

    Article  PubMed  CAS  Google Scholar 

  25. Cheng J, Zhou T, Liu C, Shapiro JP, Brauer MJ, Kiefer MC, et al. Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science. 1994; 263: 1759–1762.

    Article  PubMed  CAS  Google Scholar 

  26. Tomokuni A, Aikoh T, Matsuki T, Isozaki Y, Otsuki T, Kita S, et al. Elevated soluble Fas/APO-1 (CD95) levels in silicosis patients without clinical symptoms of autoimmune diseases or malignant tumors. Clin Exp Immunol 1997; 110: 303–309.

    PubMed  CAS  Google Scholar 

  27. Tomokuni A, Otsuki T, Isozaki Y, Kita S, Ueki H, Kusaka M, et al. Serum levels of soluble Fas ligand in patients with silicosis. Clin Exp Immunol. 1999; 118: 441–444.

    Article  PubMed  CAS  Google Scholar 

  28. Tanaka M, Suda T, Haze K, Nakamura N, Sato K, Kimura F, et al. Fas ligand in human serum. Nat Med. 1996; 2: 317–322.

    Article  PubMed  CAS  Google Scholar 

  29. Kayagaki N, Kawasaki A, Ebata T, Ohmoto H, Ikeda S, Inoue S, et al. Metalloproteinase-mediated release of human Fas ligand. J Exp Med. 1995; 182: 1777–1783.

    Article  PubMed  CAS  Google Scholar 

  30. Otsuki T, Miura Y, Nishimura Y, Hyodoh F, Takata A, Kusaka M, et al. Alterations of Fas and Fas-related molecules in patients with silicosis. Exp Biol Med (Maywood). 2006; 231: 522–533.

    CAS  Google Scholar 

  31. Otsuki T, Sakaguchi H, Tomokuni A, Aikoh T, Matsuki T, Kawakami Y, et al. Soluble Fas mRNA is dominantly expressed in cases with silicosis. Immunology. 1998; 94: 258–262.

    Article  PubMed  CAS  Google Scholar 

  32. Otsuki T, Tomokuni A, Sakaguchi H, Aikoh T, Matsuki T, Isozaki Y, et al. Over-expression of the decoy receptor 3 (DcR3) gene in peripheral blood mononuclear cells (PBMC) derived from silicosis patients. Clin Exp Immunol. 2000; 119: 323–327.

    Article  PubMed  CAS  Google Scholar 

  33. Otsuki T, Tomokuni A, Sakaguchi H, Hyodoh F, Kusaka M, Ueki A. Reduced expression of the inhibitory genes for Fasmediated apoptosis in silicosis patients. J Occup Health. 2000; 42: 163–168.

    Article  CAS  Google Scholar 

  34. Guo Z-Q, Otsuki T, Shimizu T, Tachiyama S, Sakaguchi H, Isozaki Y, et al. Reduced expression of survivin gene in PBMC from silicosis patients. Kwasaki Med J. 2001; 27: 75–81.

    CAS  Google Scholar 

  35. Bai C, Connolly B, Metzker ML, Hilliard CA, Liu X, Sandig V, et al. Overexpression of M68/DcR3 in human gastrointestinal tract tumors independent of gene amplification and its location in a four-gene cluster. Proc Natl Acad Sci U S A. 2000; 97: 1230–1235.

    Article  PubMed  CAS  Google Scholar 

  36. Pitti RM, Marsters SA, Lawrence DA, Roy M, Kischkel FC, Dowd P, et al. Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature. 1998; 396: 699–703.

    Article  PubMed  CAS  Google Scholar 

  37. Otsuki T, Sakaguchi H, Tomokuni A, Aikoh T, Matsuki T, Isozaki Y, et al. Detection of alternatively spliced variant messages of Fas gene and mutational screening of Fas and Fas ligand coding regions in peripheral blood mononuclear cells derived from silicosis patients. Immunol Lett. 2000; 72: 137–143.

    Article  PubMed  CAS  Google Scholar 

  38. Takata-Tomokuni A, Ueki A, Shiwa M, Isozaki Y, Hatayama T, Katsuyama H, et al. Detection, epitope-mapping, and function of anti-Fas autoantibody in patients with silicosis. Immunology. 2005; 116: 21–29.

    Article  PubMed  CAS  Google Scholar 

  39. Ueki A, Isozaki Y, Tomokuni A, Hatayama T, Ueki H, Kusaka M, et al. Intramolecular epitope spreading among anti-caspase-8 autoantibodies in patients with silicosis, systemic sclerosis and systemic lupus erythematosus, as well as in healthy individuals. Clin Exp Immunol. 2002; 129: 556–561.

    Article  PubMed  CAS  Google Scholar 

  40. Ueki A, Isozaki Y, Kusaka M. Anti-caspase-8 autoantibody response in silicosis patients is associated with HLA-DRB1, DQB1 and DPB1 alleles J Occup Health. 2005; 47: 61–67.

    Article  PubMed  CAS  Google Scholar 

  41. Wu P, Hyodoh F, Hatayama T, Sakaguchi H, Hatada S, Miura Y, et al. Induction of CD69 antigen expression in peripheral blood mononuclear cells on exposure to silica, but not by asbestos/chrysotile-A. Immunol Lett. 2005; 98: 145–152.

    Article  PubMed  CAS  Google Scholar 

  42. Wu P, Miura Y, Hyodoh F, Nishimura Y, Hatayama T, Hatada S, et al. Reduced function of CD4+25+ regulatory T cell fraction in silicosis patients. Int J Immunopathol Pharmacol. 2006; 19: 357–368.

    PubMed  CAS  Google Scholar 

  43. Otsuki T, Takata A, Hyodoh F, Ueki A, Matsuo Y, Kusaka M. Dysregulation of Fas-mediated apoptotic pathway in silicosis patients. Rec Res Develop Immunol. 2002; 4: 703–713.

    CAS  Google Scholar 

  44. Otsuki T, Takata A, Hyodoh F, Ueki A. Review of regulation for the Fas-mediated apoptotic pathway in silicosis patients. Kawasaki Med J. 2003; 29: 33–43.

    CAS  Google Scholar 

  45. Takahashi T, Sakaguchi S. The role of regulatory T cells in controlling immunologic self-tolerance. Int Rev Cytol. 2003; 225: 1–32.

    Article  PubMed  CAS  Google Scholar 

  46. Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M, et al. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells. their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev. 2001; 182: 18–32.

    Article  PubMed  CAS  Google Scholar 

  47. Sakaguchi S. Animal models of autoimmunity and their relevance to human diseases. Curr Opin Immunol. 2000; 12: 684–690.

    Article  PubMed  CAS  Google Scholar 

  48. Sakaguchi S, Toda M, Asano M, Itoh M, Morse SS, Sakaguchi N. T cell-mediated maintenance of natural self-tolerance: its breakdown as a possible cause of various autoimmune diseases. J Autoimmun. 1996; 9: 211–220.

    Article  PubMed  CAS  Google Scholar 

  49. Venet F, Pachot A, Debard AL, Bohe J, Bienvenu J, Lepape A, et al. Human CD4+CD25+ regulatory T lymphocytes inhibit lipopolysaccharide-induced monocyte survival through a Fas/Fas ligand-dependent mechanism. J Immunol. 2006; 177: 6540–6547.

    PubMed  CAS  Google Scholar 

  50. Fritzsching B, Oberle N, Pauly E, Geffers R, Buer J, Poschl J, et al., Naive regulatory T cells: a novel subpopulation defined by resistance toward CD95L-mediated cell death. Blood. 2006; 108: 3371–3378.

    Article  PubMed  CAS  Google Scholar 

  51. Yuan Z, Taatjes DJ, Mossman BT, Heintz NH. The duration of nuclear extracellular signal-regulated kinase 1 and 2 signaling during cell cycle reentry distinguishes proliferation from apoptosis in response to asbestos. Cancer Res. 2004; 64: 6530–6536.

    Article  PubMed  CAS  Google Scholar 

  52. Shukla A, Stern M, Lounsbury KM, Flanders T, Mossman BT. Asbestos-induced apoptosis is protein kinase C delta-dependent. Am J Respir Cell Mol Biol. 2003; 29: 198–205.

    Article  PubMed  CAS  Google Scholar 

  53. Cummins AB, Palmer C, Mossman BT, Taatjes DJ. Persistent localization of activated extracellular signal-regulated kinases (ERK1/2) is epithelial cell-specific in an inhalation model of asbestosis. Am J Pathol. 2003; 162: 713–720.

    PubMed  CAS  Google Scholar 

  54. Puhakka A, Ollikainen T, Soini Y, Kahlos K, Saily M, Koistinen P, et al. Modulation of DNA single-strand breaks by intracellular glutathione in human lung cells exposed to asbestos fibers. Mutat Res. 2002; 514: 7–17.

    PubMed  CAS  Google Scholar 

  55. Ollikainen T, Puhakka A, Kahlos K, Linnainmaa K, Kinnula VL. Modulation of cell and DNA damage by poly(ADP)ribose polymerase in lung cells exposed to H2O2 or asbestos fibres. Mutat Res. 2000; 470: 77–84.

    PubMed  CAS  Google Scholar 

  56. Adamson IY. Early mesothelial cell proliferation after asbestos exposure:in vivo andin vitro studies. Environ Health Perspect. 1997; 105S5: 1205–1208.

    Article  Google Scholar 

  57. BeruBe KA, Quinlan TR, Moulton G, Hemenway D, O’Shaughnessy P, Vacek P, et al. Comparative proliferative and histopathologic changes in rat lungs after inhalation of chrysotile or crocidolite asbestos. Toxicol Appl Pharmacol. 1996; 137: 67–74.

    Article  PubMed  CAS  Google Scholar 

  58. Kamp DW, Graceffa P, Pryor WA, Weitzman SA. The role of free radicals in asbestos-induced diseases. Free Radic Biol Med. 1992; 12: 293–315.

    Article  PubMed  CAS  Google Scholar 

  59. Rom WN, Travis WD, Brody AR. Cellular and molecular basis of the asbestos-related diseases. Am Rev Respir Dis. 1991; 143: 408–422.

    PubMed  CAS  Google Scholar 

  60. Haura EB, Zheng Z, Song L, Cantor A, Bepler G. Activated epidermal growth factor receptor-Stat-3 signaling promotes tumor survivalin vivo in non-small cell lung cancer. Clin Cancer Res. 2005; 11: 8288–8294.

    Article  PubMed  CAS  Google Scholar 

  61. Song L, Turkson J, Karras JG, Jove R, Haura EB. Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells. Oncogene. 2003; 22: 4150–4165.

    Article  PubMed  CAS  Google Scholar 

  62. Vega MI, Huerta-Yepez S, Jazirehi AR, Garban H, Bonavida B. Rituximab (chimeric anti-CD20) sensitizes B-NHL cell lines to Fas-induced apoptosis. Oncogene. 2005; 24: 8114–8127.

    PubMed  CAS  Google Scholar 

  63. Vega MI, Huerta-Yepaz S, Garban H, Jazirehi A, Emmanouilides C, Bonavida B. Rituximab inhibits p38 MAPK activity in 2F7 B NHL and decreases IL-10 transcription: pivotal role of p38 MAPK in drug resistance. Oncogene. 2004; 23: 3530–3540.

    Article  PubMed  CAS  Google Scholar 

  64. Whitson BA, Kratzke RA. Molecular pathways in malignant pleural mesothelioma. Cancer Lett. 2006; 239: 183–189.

    Article  PubMed  CAS  Google Scholar 

  65. Carbone M, Kratzke RA, Testa JR. The pathogenesis of mesothelioma. Semin Oncol. 2002; 29: 2–17.

    Article  PubMed  CAS  Google Scholar 

  66. Robinson BW, Musk AW, Lake RA. Malignant mesothelioma. Lancet. 2005; 366: 397–408.

    Article  PubMed  CAS  Google Scholar 

  67. Aikoh T, Tomokuni A, Matsuki T, Hyodoh F, Ueki H, Otsuki T, et al. Activation-induced cell death in human peripheral blood lymhpocytes after stimulation with silicatein vitro. Int J Oncol. 1998; 12: 1355–1359.

    PubMed  CAS  Google Scholar 

  68. Ma Z, Otsuki T, Tomokuni A, Aikoh T, Matsuki T, Sakaguchi H, et al. Man-made mineral fibers induce apoptosis of human peripheral blood mononuclear cells similar to chrysotile B. Int J Mol Med. 1999; 4: 633–637.

    PubMed  CAS  Google Scholar 

  69. Hyodoh F, Takata-Tomokuni A, Miura Y, Sakaguchi H, Hatayama T, Hatada S, et al. Inhibitory effects of anti-oxidants on apoptosis of a human polyclonal T cell line, MT-2, induced by an asbestos, chrysotile-A. Scand J Immunol. 2005; 61: 442–448.

    Article  PubMed  CAS  Google Scholar 

  70. Miura Y, Nishimura Y, Katsuyama H, Maeda M, Hayashi H, Dong M, et al. Involvement of IL-10 and Bcl-2 in resistance against an asbestos-induced apoptosis of T cells. Apoptosis. 2006; 11: 1825–1835.

    Article  PubMed  CAS  Google Scholar 

  71. Nishimura Y, Miura Y, Maeda M, Hayashi H, Dong M, Katsuyama H, et al. 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. Int J Immunopathol Pharmacol. 2006; 19: 795–805.

    PubMed  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Yoshie Miura

    Present address: Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, Nebraska, USA

Authors and Affiliations

  1. Department of Hygiene, Kawasaki Medical School, 577 Matsushima, 701-0192, Kurashiki, Japan

    Takemi Otsuki, Yoshie Miura, Megumi Maeda, Hiroaki Hayashi, Shuko Murakami, Maolong Dong & Yasumitsu Nishimura

  2. Department of Plastic Surgery, Kawasaki Medical School, Japan

    Maolong Dong

Authors
  1. Takemi Otsuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoshie Miura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Megumi Maeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroaki Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shuko Murakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maolong Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yasumitsu Nishimura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takemi Otsuki.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Otsuki, T., Miura, Y., Maeda, M. et al. Keynote lecture in the 13th Japanese Society of Immunotoxicology (JSIT 2006). Environ Health Prev Med 12, 153–160 (2007). https://doi.org/10.1007/BF02897984

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02897984

Key words

Environmental Health and Preventive Medicine

ISSN: 1347-4715

Contact us