Cellular & Molecular Immunology 261
Immunological Effects of Silica and Asbestos
Takemi Otsuki1, 8, Megumi Maeda1, Shuko Murakami1, Hiroaki Hayashi1, Yoshie Miura1, 2,
Masayasu Kusaka3, Takashi Nakano4, Kazuya Fukuoka4, Takumi Kishimoto5, Fuminori Hyodoh6,
Ayako Ueki7 and Yasumitsu Nishimura1
Silicosis patients (SILs) and patients who have been exposed to asbestos develop not only respiratory diseases but
also certain immunological disorders. In particular, SIL sometimes complicates autoimmune diseases such as
systemic scleroderma, rheumatoid arthritis (known as Caplan syndrome), and systemic lupus erythematoses. In
addition, malignant complications such as lung cancer and malignant mesothelioma often occurr in patients
exposed to asbestos, and may be involved in the reduction of tumor immunity. 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
of 2005 in Japan, efforts should be focused on developing a cure for these diseases to eliminate nationwide anxiety.
Cellular & Molecular Immunology. 2007;4(4):261-268.
Key Words: silica, asbestos, immunology, Fas, regulatory T cell, apoptosis
Silicosis patients (SILs) develop respiratory fibrosis and
impaired their pulmonary function. In addition, silica is
known as one of the strongest environmental substances
causing autoimmunity dysfunction (1-3). SILs often develop
immunological complications such as rheumatic arthritis
(known as Caplan syndrome (4-6)), systemic sclerosis (SSc),
and systemic lupus erythematoses (SLE). The effects of silica
Volume 4 Number 4 August 2007
on autoimmunity have also been assumed as patients who
have undergone plastic surgery with implants containing
silicone ([SiO2-O-]n) show frequent complications of
autoimmune disorders (7-9). These accumulated findings
clearly indicate that crystalline silica causes dysregulation
and/or disturbance of the human immune system, particularly
Regarding asbestos, which is categorized as a silicate
(mineralogical complexes containing metals, such as iron and
magnesium) including chrysotile, crocidolite, and amosite,
patients exposed to asbestos also develop pulmonary fibrosis
1Department of Hygiene, Kawasaki Medical School, Matsushima 577,
Kurashiki 7010192, Japan;
2Eppley Institute for Cancer Research, University of Nebraska Medical
Center, Omaha, Nebraska 68198, USA;
3Department of Internal Medicine, Kusaka Hospital, 1122 Nishikatagami,
Bizen 7050021, Japan;
4Department of Respiratory Medicine, Hyogo Medical College of Medicine,
1-1 Mukogawa-cho, Nishinomiya, Hyogo 6638131, Japan;
Received Jun 2, 2007. Accepted Jul 19, 2007.
Copyright © 2007 by The Chinese Society of Immunology
5Okayama Rosai Hospital, 1-10-25 Chikkou-midori-machi, Okayama
6Department of Rehabilitation, Faculty of Health Sciences and Technology,
Kawasaki University of Medical Welfare, 288 Matsushima, Kurashiki
7Department of Nursing, Kawasaki College of Allied Health Professions,
316 Matsushima, Kurashiki 7010194, Japan;
8Corresponding to: Dr. Takemi Otsuki, Department of Hygiene, Kawasaki
Medical School, 577 Matsushima, Kurashiki 7010192, Japan. Tel: +81-86-
462-1111, Fax: +81-86-464-1125, E-mail: email@example.com
262 Immunological Effects of Silica and Asbestos
Volume 4 Number 4 August 2007
known as asbestosis, mesothelial plaque, and malignant
diseases such as lung cancer and mesothelioma (10-13).
Some of these malignancies may be considered a result of a
decline in tumor immunity owing to exposure of immuno-
competent cells to asbestos.
Silica and silicates may disturb immune functions such as
autoimmunity and tumor immunity. In this article, a brief
summary of our investigations related to the immunological
effects of silica/asbestos is presented. Details of each subject
can be found in the references cited.
Immunological effects of chrysotile and asbestos
The International Agency for Research on Cancer (IARC)
categorizes both asbestos and crystalline silica as group I
carcinogens, because it is well known that asbestos (e.g.,
chrysotile, crocidolite, and amosite) causes malignant lung
cancer or mesothelioma (10-13). According to the IARC
classification, asbestos affects alveolar epithelial and
mesothelial cells. There have been many studies of
asbestos-induced apoptosis of these cells (14-22). In
comparison with most other solid tumors, mutation of the
p53 gene is rare. Instead of the alteration of p53, loss of
p16INK4a expression has been detected in most mesotheliomas
and cell lines. In addition, p14ARF, a p53 regulator, is
simultaneously deleted (23-25).
conditions, these cells undergo apoptosis upon high-level,
short-term exposure to asbestos as a result of the production
of reactive oxygen species (ROS) and reactive nitrogen
species (RNS) via activation of the mitochondrial apoptotic
pathway. Furthermore, several non-small-cell lung cancer
cell lines constitutively contain the active signal transducer
and activator of transcription 3 (STAT3) (26, 27). Moreover,
inhibition of tumor-derived interleukin (IL)-10 and IL-10
receptor (IL-10R) interaction by an autocrine/paracrine loop
results in a decrease in the expression level of constitutively
active STAT3 and the subsequent inhibition of Bcl-2
￭Resistance to asbestos-induced apoptosis
￭Activation of multiple TCR-Vβrepertoires
resembled superantigen exposure
Mitochondria Bcl-2 Bax
Multiple, but not clonal
overexpression of TCR-Vβ
Figure 1. Experimental findings of immunological effects of chrysotile, a form of asbestos, induced by short-term and high-dose
exposure (left panel) or long-term and low-dose exposure using MT-2, an HTLV-1 immortalized human polyclonal T cell line.
Cellular & Molecular Immunology 263
Volume 4 Number 4 August 2007
transcription and expression (28, 29). Thus, it has been
considered that during low-level, long-term exposure to
asbestos, alveolar epithelial and mesothelial cells escape
from the apoptotic pathway due to genetic changes and
undergo malignant transformation. Although nuclear factor-κ
B (NF-κB) was shown to be involved in the transcriptional
activity of anti-apoptotic genes such as bcl-2, the role of
NK-κB in the carcinogenesis of mesothelioma has not been
well investigated. Advancement in genetic analyses related to
the oncogenesis of mesothelioma may lead to the discovery
of newer target genes for molecular therapy.
We have mainly focused on the immunological effects of
chrysotile. Asbestos, chrysotile, polyclonally activated CD4+
T cells and caused activation-induced cell death (30, 31).
PBMCs from HD exposed to asbestos in culture underwent
apoptosis; however, many patients with asbestosis have had
chronic occupational or other recurrent exposure to silicates.
Therefore, there seems to be a need to develop an in vitro
experimental model of chronic exposure to analyze the
immunobiological effects of silicates during long-term
For this purpose, we employed a human T-cell leukemia
virus type-1 (HTLV-1)-immortalized human polyclonal T cell
line, MT-2, for the development of an in vitro model. Upon
short-term, high-level exposure to chrysotile, MT-2 cells
underwent apoptosis with the production of ROS via the
activation of the mitochondrial apoptotic pathway with the
phosphorylation of p38 mitogen-activated protein kinase
(MAPK) and c-Jun N-terminal kinase (JNK) signaling
molecules, resulting in a shift of the Bax-dominant Bax/Bcl-2
balance, the release of cytochrome-c from mitochondria into
cytosol, and the activation of caspases 9 and 3, as shown on
the left side of Figure 1 and as previously reported (32).
Next, we established a chrysotile-B (CB)-induced apoptosis-
resistant subline of MT-2 (MT-2Rst), and characterized the
cell biological differences between the original MT-2 cell line
(MT-2Org) and MT-2Rst. The MT-2Rst cells were
characterized by (i) an enhanced expression of bcl-2,
restoring apoptosis sensitivity with a decrease in the bcl-2
expression level by siRNA, (ii) excessive IL-10 secretion and
expression, and (iii) the activation of STAT3 inhibited by
pyrimidine (PP2), a specific inhibitor of Src family kinases.
These findings suggest that contact between cells and
asbestos may affect the human immune system and trigger a
cascade of biological events, such as the activation of Src
family kinases, enhancement of IL-10 expression, STAT3
activation, and Bcl-2 overexpression, as shown on the right
side of Figure 1 and as previously reported (33). This
speculation was partially confirmed by the detection of
higher bcl-2 expression levels in CD4+ peripheral blood T
cells from patients with malignant mesothelioma than in
those from patients with asbestosis or from HDs (33).
In addition, if asbestos possesses the superantigenic
potential against T cells, a certain number of the T cell
receptor Vβ (TCR Vβ) repertoire may be overexpressed
without evidence of clonal expansion, as observed on T cells
exposed to superantigens such as staphylococcal enterotoxin
B (SEB). Therefore, the expression levels of TCR Vβ on
MT-2Org and MT-2Rst were compared. In addition, 23 types
of TCR Vβ expression were examined on CD3+ peripheral
blood T cells. As a result, MT-2Rst cells overexpressed
various TCR Vβ (34). Although TCR Vβ-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 CB. The over-
expression of various TCR Vβ may be the result of contact
between cells and CB, asbestos fiber, during the acquisition
of resistance to CB-induced apoptosis caused by long-term
and low-dose exposure to CB. To support this interpretation,
patients with asbestos-related diseases (ARDs), such as
asbestosis and malignant mesothelioma, were compared with
SILs as a disease control and with HDs. ARDs showed
limited overexpression of TCR Vβ without clonal expansion,
whereas SILs showed significant overexpression of TCR Vβ
7.2. These experimental and clinical analyses indicate
superantigenic and dysregulation of the autoimmunity-
inducing effects of asbestos and silica, respectively (34).
There are still many issues concerning the immunological
effects of asbestos, particularly from the viewpoint of tumor
immunity. NK cells may also be affected by exposure to
asbestos, and Treg, which regulate autoreactions including
tumor immunity, may change their function following their
exposure to asbestos. In addition, the characterization of
immunocompetent cells may be modified not only by
asbestos fibers in vivo, but also by malignant tumor cells
such as mesothelioma cells; however, most of these changes
have not been clarified yet. Thus, future investigations should
be carried out, and the discovery of biological tools to
improve the prognosis of patients with asbestos-related
malignancies is anticipated.
Detection of autoantibodies, alterations of Fas-
related molecules and CD4+CD25+ regulatory T
cell fraction in SILs
To clarify the status of autoimmunity abnormalities found in
SILs, efforts have been made to detect autoantibodies in
serum derived from SILs, and autoantibodies against
topoisomerase I (35-37), desmoglein (38), caspase-8 (39) and
Fas (40) were detected. In particular, the last two
autoantibodies may be of interest because the target
molecules, i.e., caspase-8 and Fas, have a key role during
apoptosis processing in lymphocytes. The functional assay of
antibodies against Fas showed that the autoantibody induces
Fas-mediated apoptosis of membrane-Fas-expressing cells
Fas (CD95), which is mainly expressed on the cell
membrane of lymphocytes, usually exists as membrane
type-Fas and forms a trimer after binding with the Fas ligand.
The signal-transducing death-domain located in the intra-
cellular domain of Fas then recruits Fas-associating death-
domain-containing protein (FADD) and procaspase 8 to form
the active death-inducing signaling complex (DISC).
Thereafter, activated caspase-8 triggers a caspase cascade
264 Immunological Effects of Silica and Asbestos
Volume 4 Number 4 August 2007
involving the activation of CAD/CPAN/DFF40 by removing
its inhibitor, ICAD/DFF45, DNA fragmentation, and finally
The most typical alternatively spliced variant of the
wild-type fas gene transcript is soluble fas. As this variant
transcript lacks 63 bp of the transmembrane domain, its
product (soluble Fas) is secreted from cells to suppress
membrane Fas-mediated apoptosis by blocking the binding
between membrane Fas and the Fas ligand in the
extracellular region (46, 47). If there is a high level of soluble
Fas in the extracellular region, lymphocytes in these regions
may avoid apoptosis and survive longer. Indeed, there have
been several studies showing elevated levels of serum-
soluble Fas in patients with autoimmune diseases (48-51);
therefore, we compared cellular and molecular changes in the
levels of Fas and Fas-related molecules between SILs and
healthy donors (HDs):
The level of serum-soluble Fas was higher in SILs than
HDs (52). The level of serum-soluble Fas ligand did not
differ between SILs and HDs (53). Although the Fas ligand is
usually localized in the membrane of natural killer (NK) cells,
activated T cells, and cytotoxic T cells, it is sometimes
cleaved by matrix-metalloproteinase-like enzymes and
secreted into extracellular spaces (54, 55). Although the
percentage of Fas-positive lymphocytes (membrane Fas
expression) did not differ between SILs and HDs, the mean
fluorescence intensity (MFI) of membrane Fas was lower in
SILs than in HDs. In addition, weaker membrane Fas
expressers among lymphocytes were identified to be weaker
fas message expressers (52, 56). The relative gene expression
ratio of wild-type and soluble fas and various genes related to
Fas-mediated apoptosis, such as decoy receptor 3 (dcr3), the
apoptosis-accelerating genes caspase-8, -3, and -9 and cpan
(cad), and the intracellular apoptosis-inhibitory genes xiap,
Reduced apoptotic signals
(including self-recognizing clones)
Fraction repeating apoptosis caused by silica
and recruitment from bone marrow
Other variant messages
of Fas transcript
Figure 2. Schematic presentation of the activation mechanisms of autoimmunity found in silicosis patients focusing on the alterations
of Fas and Fas-related molecules, and attenuated function of the CD4+CD25+ T cell fraction.
Cellular & Molecular Immunology 265
Volume 4 Number 4 August 2007
survivin, dff45 (icad), toso, i-flice, and sentrin, in peripheral
blood mononuclear cells (PBMCs) was analyzed (57-60).
DcR3 was initially discovered as a protein secreted from lung
and colon cancer cells that prevents the Fas ligand from
targeting them, and is also expressed on cytotoxic T cells and
natural killer cells (61, 62). Thus, DcR3 functions similarly
to soluble Fas, namely, it inhibits membrane Fas-mediated
apoptosis. The findings were as follows, (i) soluble fas
mRNA is predominantly expressed in PBMCs from SILs, but
not from HDs (57), (ii) the dcr3 gene expression level is
higher in PBMCs from SILs than from HDs (59) and these
may induce the inhibition of Fas and Fas ligand binding
similar to the cases with a higher level of soluble Fas
molecules and (iii) the gene expression levels of intracellular
inhibitors of Fas-mediated apoptosis such as i-flice, sentrin,
survivin, and icad were lower in SILs than in HDs (59, 60).
Alternatively spliced variants of fas and mutational screening
for fas and fas ligand genes were then detected (63).
Although significant mutations in fas and fas ligand coding
sequences were not detected, many alternatively spliced
variants were found and analysis of amino-acid translation
from detected variants showed that all of these as well as the
Experimental high-dose and
Production of ROS & RNS
Activation of mitochondrial
Alveolar epithelial cells
Pleural mesothelial cells
Chronic and recurrent long-term exposure
and long-term exposure
blood T cells
Acquisition of apoptosis
•IL-10: overproduction, Bcl-2
•Multiple activation of TcR-Vb
repertoire like super-antigen
Reduction of activation signal?
Reduction of tumor immunity
blood T cells
Dysregulation of Fas molecule
Substituted by chronically
activated T cells
Accumulation of DNA
Escape from apoptosis
Induction of early
Figure 3. Summary of immunological effects of silica/asbestos.
266 Immunological Effects of Silica and Asbestos
Volume 4 Number 4 August 2007
typical soluble fas, possess the binding site of the Fas ligand,
but lack the transmembrane domain and death domain. These
findings indicate that all these variants may inhibit the
binding between membrane Fas and the Fas ligand, similar to
soluble Fas and DcR3 molecules (63).
In vitro exposure of T cells derived from HD to silica
causes slow but precise activation of these cells, as indicated
by the expression of CD69, a typical early marker of T cell
The percentage of the peripheral blood CD4+CD25+
fraction, which includes CD4+CD25+FoxP3+ regulatory T
cells (Treg) suppressing excess autoreaction, in the scarce
self-recognizing T cell fraction in peripheral blood, was
slightly lower in SILs as determined in terms of
age-predicted values calculated from the analysis of HD. In
addition, the function of this fraction in SILs was less
significant than in HDs, as determined by alloreactive mixed
lymphocyte reaction (MLR) analysis (65).
From these findings, a hypothesis for activated
autoimmunity in SILs has been proposed, as shown in Figure
2 and preliminarily reported previously (56, 66). The findings
of the levels of factors in extracellular spaces, such as soluble
Fas, DcR3, and products from various alternatively spliced
fas variants, indicate that apoptosis mediated by membrane
Fas seems to interfere with these molecules and Fas-mediated
apoptosis is reduced. However, since there was a reduced
expression of intracellular molecules for anti-Fas-mediated
apoptosis such as i-flice, sentrin, and survivin gene products
in SILs compared with those in HDs, it seemed likely that
Fas-mediated apoptosis is enhanced in lymphocytes derived
from SILs. In addition, the anti-Fas autoantibody found in
serum from SILs may contribute to the enhanced apoptosis of
lymphocytes, because of the Fas-stimulating function of this
antibody. As compared with HDs, in which the apoptosis of
lymphocytes is assumed to be neither enhanced nor reduced,
it seems that the two fractions of lymphocytes would
respectively show enhanced and reduced Fas-mediated
apoptosis in SILs.
Thus, there are two populations of CD4+ lymphocytes,
the stronger expresser of membrane Fas and the weaker
expresser of Fas, in SILs. Weaker expressers may have
developed owing to excessive transcription of the
alternatively spliced fas gene and other variant messages;
therefore, these cells may be resistant to the functional
anti-Fas autoantibody, because membrane Fas is relatively
scarce. Consequently, it is speculated that there is a particular
fraction of CD4+ T lymphocytes in SILs that expresses weak
levels of membrane Fas, secretes higher levels of soluble Fas,
DcR3, and spliced variants, and is resistant to anti-Fas
autoantibody-induced apoptosis, as shown in Figure 2 and
previous reports (56, 66). As patients with a weaker MFI of
membrane Fas have a higher titer of anti-nuclear antigens
(ANA), as reported previously (56), self-recognizing clones
in SILs may be included in this fraction, because these clones
may survive longer and show resistance to apoptosis.
It is possible that Fas-mediated apoptosis occurs to a
certain degree in lymphocytes of SILs, because of the
observed decrease in the levels of intracellular inhibitors of
Fas-mediated apoptosis. This may be explained by the
presence of a different fraction of lymphocytes in SILs,
which are strongly positive for membrane Fas, sensitive to
the anti-Fas autoantibody, and undergo apoptosis; however,
this fraction may be recruited from bone marrow after
reaching the final stage of cell death. This recruited fraction
would not have encountered silica and would be sensitive to
silica/silicate-induced apoptosis. As a result, cells in this
fraction would be continuously undergoing renewal and
apoptosis (56, 66).
In addition, the attenuated function of the CD4+CD25+
fraction of T cells also activated autoimmunity (67-70). This
attenuation may be caused by substitution of the CD4+CD25+
fraction by chronically activated T cells due to their chronic
and recurrent exposure to silica, as shown by our in vitro
findings of the slower activation of T cells by silica (64).
However, it is necessary to clarify why silica exposure
leads to a higher frequency of alternative splicing of fas (or
other) gene(s), whether weaker expressers of membrane Fas
among lymphocytes survive for a significantly long time and
include self-recognizing clones, and how silica exposure
causes a decrease in CD4+CD25+FoxP3+ Treg. Recently, the
relationship between the expression level of membrane Fas
and Treg function has been noted and investigated (71, 72).
This may also be interesting to clarify the mechanisms
underlying the dysregulation of autoimmunity caused by
A summary of the findings described in this article is shown
in Figure 3. 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 discovery of new
clinical tools to modify the pathophysiological aspects of
diseases such as the regulation of autoimmunity or tumor
immunity using cell-mediated therapies, various cytokines
and molecule-targeting therapies. As the incidence of
asbestos-related malignancies is increasing and such
malignancies have been a medical and social problem since
the summer of 2005 in Japan, efforts should be focused on
developing a cure for these diseases to eliminate nationwide
The authors thank former members of the Department of
Hygiene, Kawasaki Medical School, Drs. Akiko Takata, Ping
Wu, Zhongqiu Guo, Zhongjie Ma, Maolong Dong and
Yasuhiko Kawakami for help with experiments, and Ms.
Tamayo Hatayama, Minako Kato, Naomi Miyahara, Misao
Kuroki, Keiko Kimura, Tomoko Sueishi, Yoshiko Yamashita,
Cellular & Molecular Immunology 267
Volume 4 Number 4 August 2007
Satomi Hatada, Yumika Isozaki and Haruko Sakaguchi for
The data obtained in the Department of Hygiene,
Kawasaki Medical School and published by the authors were
supported by Special Coordination Funds for Promoting
Science and Technology (H18-1-3-3-1), JSPS KAKENHI
(17790375, 18390186, 19689153, 19790431 and 19790411),
Kawasaki Medical School Project Grants (16-212, 16-401N,
17-210S, 7-404M, 17-611O, 18-209T, 18-403 and 18-601), a
Sumitomo Foundation Grant (053027), and a Yasuda
Memorial Foundation Grant (H18).
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