REVIEW

CURRENT
OPINION Silicosis and autoimmunity
Suni Lee a, Hiroaki Hayashi b, Hidenori Mastuzaki a, Naoko Kumagai-Takei a,
and Takemi Otsuki a

Purpose of review
Of the various environmental, occupational, and medical substances that cause dysregulation of
autoimmunity, the effects and causative mechanisms of silica particles and asbestos fibers are discussed in
this review.
Recent findings
With respect to silica, many epidemiological studies have shown a significant association between silica
exposure and the occurrence of autoimmune diseases. Although the importance of the NACHT, LRR and
PYD domains-containing protein 3 (NALP3) inflammasome as the initial immune reaction against silica
particles has been identified, the mechanisms involved that lead to various autoimmune diseases in patients
exposed to silica remain largely unknown. Silica can activate various immune cells and investigation of the
associated imbalance of regulatory T cells, responder T cells as well as Th17 cells might be key in
furthering our understanding of silica-induced autoimmune alterations. On the other hand, asbestos
exposure shows less association with autoimmune diseases. However, interesting findings pertaining to the
detection of antiendothelial and mesothelial cell antibodies in asbestos-exposed patients have been
reported.
Summary
Taken together, further investigations may contribute in delineating the mechanisms involved in
environmental factor-induced modification of autoimmunity.
Keywords
asbestos, autoantibody, autoimmune, fas, regulatory T cell, responder T cell, silica

INTRODUCTION reported. Additionally, specific autoantibody pro-

We have been investigating the immunological
effects of occupational and environmental substan-
ces such as silica particles and asbestos fibers [1–7].
With this view in mind, the reduction of antitumor
immunity was evaluated in cluster of differentiation
(CD4þ) T helper cells [8,9], natural killer cells [10,11],
and CD8þ cytotoxic T lymphocytes [12,13]. More-
over, regulatory T cell (Treg) function was found to be
enhanced following experimental exposure to asbes-
tos. On the other hand, Treg function and cell num-
bers were reduced in silicosis patients or people
exposed continuously to silica particles. The former
details (asbestos-induced reduction of antitumor
immunity) have been summarized in our previous
publications and reviews [1–7]. The latter findings
are described in this review.
Taken together, the phenomena comprising
excess activation and reduced function in immuno-
toxicity caused by occupational and environmental
substances require careful consideration. In this
review, the disorders of autoimmunity found
in silicosis patients is mainly summarized and
duction caused by asbestos fibers is also described
and compared with silica-induced dysregulation
of autoimmunity.
EPIDEMIOLOGICAL STUDIES OF
COMPLICATED AUTOIMMUNE DISEASES
IN SILICOSIS PATIENTS
As is well known, Caplan syndrome was initially
described in 1953 by Caplan [14]. This condition
represents a complication of rheumatoid arthritis
(RA) in pneumoconiosis. The initial report did not
define the causative agent of pneumoconiosis as
a
Department of Hygiene and bDepartment of Dermatology, Kawasaki
Medical School, Kurashiki, Okayama, Japan
Correspondence to Takemi Otsuki, MD, PhD, Department of Hygiene,
Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-
0192, Japan. Tel: +81 86 462 1111; fax: +81 86 464 1125;
e-mail: takemi@med.kawasaki-m.ac.jp
Curr Opin Allergy Clin Immunol 2017, 17:78–84
DOI:10.1097/ACI.0000000000000350

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Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.


KEY POINTS
 Epidemiological studies regarding relationship between
silicosis and autoimmune diseases, the detection of
various autoantibodies found in silicosis patients, and
cellular and molecular investigations indicate that
exposure to silica induces susceptibility to autoimmune
disorders with an imbalance of responder T cells and
regulatory T cells.
 Specific autoantibodies which may be related with
asbestos-induced lung fibrosis are found in patients
exposed to asbestos.
silica, and other materials such as coal and asbestos
were referred to. However, subsequent investi-
gations showed that this syndrome was most com-
monly associated with exposure to silica [15–20].
Additionally, Erasmus syndrome, a complication of
progressive systemic sclerosis (SSc), was first
reported in 1957 [21]. That report was based on
Witwatersrand gold miners who apparently showed
a higher prevalence of complications associated
with these two diseases.
Many epidemiological reports including meta-
analyses have highlighted the association between
silica exposure (silicosis) and various autoimmune
diseases including RA and SSc. The relative risk of RA
was shown to be more than three times higher in the
silica-exposed population compared with nonex-
posed populations [22–26]. Additionally, the com-
plication of SSc was also higher in silica-exposed
individuals [25,26]. In terms of other autoimmune
diseases, the risk of systemic lupus erythematosus
(SLE) was also shown to be greater in silica-exposed
populations [25,27–29]. Recently, various reports
regarding antineutrophil cytoplasmic antibody
(ANCA)-related vasculitis in silica-exposed individ-
uals have been reported [30–40].
It seems that silica exposure causes mainly
generalized autoimmune diseases, and compli-
cations did not comprise organ-specific disturb-
ances of autoimmunity, although there were
&& && &
specific case reports [41 ,42 ,43 ]. This may be
attributable to the interplay of autoimmune diseases
with certain individual factors such as human leu-
kocyte antigen (HLA)-typing, specific single-nucleo-
tide polymorphisms, or other genetic or epigenetic
alterations. Further investigations are required to
identify genetic or epigenetic changes found in
silicosis complicated with various autoimmune dis-
eases in an effort to further our understanding of the
causative mechanisms responsible for the dysregu-
lation of autoimmunity, and to assist in the preven-
tion of these diseases.
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Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Silicosis and autoimmunity Lee et al.
MECHANISTIC INVESTIGATIONS
Inflammasomes are very important when consider-
ing the mechanisms underlying silica-induced dis-
eases [44–48]. Various foreign danger signals
induced by silica particles, asbestos fibers, bacteria
and their toxins, as well as other internal signals
(crystalline derived from uric acid, cholesterol, and
others) are recognized by antigen-presenting cells
(APC), and leads to the activation of inflammasomes
as an initial step in the processing of these danger
signals to protect the human body. Inflammasomes
are large multimolecular complexes composed of
caspase-1, apoptosis-associated speck-like protein
containing caspase recruitment domain, and
NACHT, LRR and PYD domains-containing proteins
(NALPs) (a type of nucleotide-binding oligomeriza-
tion domain-like receptor). These induce the
secretion of mature IL-1b and IL-18 as proinflam-
matory cytokines from APC [49–53]. Activation of
inflammasomes in the pulmonary region where the
inhaled danger signals such as silica particles and
asbestos fibers are invading the body is important
for the formation of lung fibrosis such as silicosis
and asbestosis, two typical forms of pneumoconiosis
[54–56]. However, general alteration of the immune
system caused by long-term exposure to particulate
and fibrous materials, and the development of auto-
immune disorders, may require additional cellular
and molecular responses.
There are many factors that appear to be involved
in the development of autoimmune disorders found
in the human immune system, such as the inter-
action between APC and T cells, B cells receiving
instructions for antibody and cytokine production
by T cells, and the polarization of Treg and Th17 to
promote reactivity to self-antigens and others [57–
66]. Regarding cytokine networks, IL-1b and IL-18 are
produced from APC [49–53]. IL-1a is also secreted
from monocyte–macrophage and APC and allows
expanded Th1 cells to produce IFN-g. Thereafter,
IFN-g stimulates various transcription factors such
as interferon regulatory factor 1 to activate immune
reactions. Additionally, nuclear factor-kB is import-
ant in the activation of T and B cells to facilitate
reaction with various self-antigens. However,
detailed investigations regarding interaction
between various immune cells and silica particles
located lung tissues and related lymph nodes are
required to obtain cellular and molecular mechan-
isms in silica-induced changes in immune tolerance.
DETECTED AUTOANTIBODIES IN
SILICOSIS
As mentioned above, RA, SSc, SLE, and ANCA-
related vasculitis are well known complications in
www.co-allergy.com 79
Occupational disease
silicosis patients. Therefore, autoantibodies such as
antinuclear antibodies, anti-Scl-70, anticentromere
antibody, as well as ANCA, are frequently found in
silicosis patients, even though these patients did not
show significant symptoms of related autoimmune
diseases. It could be said that silicosis patients
represent a preliminary state of autoimmunity
disorder.
The relationship between individual genetic fac-
tors such as HLA and the appearance of specific
autoantibody anti-Scl-70 were investigated in our
laboratories [67–69]. This work revealed that the
allelic frequency of HLA-DQB10402 was signifi-
cantly higher in anti Scl-70 antibody-positive
patients than in negative patients or healthy con-
trols. This allele (DQB10402) may play an import-
ant role with respect to Japanese silicosis patients
[67–69]. Additionally, we detected anti-Fas/CD95
[70], anticaspase 8 [71,72], and antidesmoglein
[73] autoantibodies in silicosis patients. Regarding
anticaspase 8 autoantibody, the frequencies of HLA-
DRB10406 were significantly higher in antibody-
positive patients than in control individuals. In
these cases, the importance of HLA types was again
found with respect to the occurrence of auto-
immune disorders in silicosis patients. Furthermore,
anti-Fas autoantibody was found to be functional,
indicating induced Fas-mediated apoptosis in Fas-
expressing cells, and especially lymphocytes. This
may contribute to the imbalance of Treg and res-
ponder T helper/CD4þ cells found in silicosis per-
ipheral blood, as Treg expression of the CD95/Fas
molecule is more dominant than that of CD4þ
responder cells. When anti-Fas autoantibody is
generated in silicosis patients, Treg may be lost by
Fas-mediated apoptosis, and this imbalance may
lead to the development of autoimmune diseases.
The role of autoantibodies found in silicosis
patients may be important when considering the
occurrence of various autoimmune diseases compli-
cating silicosis.
CHRONIC ACTIVATION OF IMMUNE CELLS
CAUSED BY SILICA EXPOSURE
The chronic activated status of CD4þ responder T
cells and Treg were reported from our previous
investigations. As a result of chronic activation,
responder T cells possessed CD69 surface molecules
[74], program cell death-1 expression [75], pro-
duction of the soluble form of the CD95/Fas mol-
ecule [76–79], excess message of decoy receptor 3
[80], and increased secretion of soluble IL-2 receptor
[81]. The presence of most of these activated mol-
ecules indicated that responder T cells encountering
silica particles at the pulmonary lesions and related
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lymph nodes frequently and recurrently were
directed toward long-term survival, avoiding Fas-
mediated apoptosis, and included self-antigen rec-
ognizing clones. In contrast, Treg was also chroni-
cally activated by encounters with silica particles. As
a result, Treg altered CD95/Fas surface expression to
a greater extent than usual. Thereafter, Treg might
be lost earlier in silicosis. Taken together, the imbal-
ance of responder T cells (increase) and Treg
(decrease) occurred in silicosis, and this might lead
to a state whereby silicosis patients are susceptible
to autoimmune disease under basic immune con-
ditions [82–84].
Although we have not investigated the altera-
tion of Th17 cells caused by silica exposure, it has
been reported that Th17 can regulate silica-induced
lung inflammation, in addition to fibrosis, through
&&
an IL-1b-dependent mechanism [85–89,90 ]. Our
preliminary data regarding serum cytokines in sili-
cosis patients analyzed by factor analysis indicated
that serum IL-6 was included in the same factor with
the antinuclear antibodies titer and ANCA levels.
Considering the importance of IL-6 in facilitating T
helper cell polarization to Th17 cells in micro and
cytokine environments, silicosis patients may pos-
sess a Th17-prone cytokine condition as an immune
state, and this may also lead toward the loss of
&&
Treg [85–89,90 ]. These scenarios may provide
additional contributions toward the occurrence of
autoimmune diseases in silicosis patients.
ADDITIONAL REMARK: ASBESTOS AND
AUTOANTIBODY
As mentioned in the introduction, our previous
investigations indicated that asbestos exposure
caused a reduction of antitumor immunity. One
natural killer cell activating receptor, NKp46, was
reduced in an experimental cell line model, and ex-
vivo expanded natural killer cells freshly isolated
from healthy volunteers, in addition to peripheral
blood natural killer cells from asbestos-exposed
patients in cases of pleural plaque and malignant
mesothelioma [10,11]. The differentiation and clo-
nal expansion of CD8þ cytotoxic T lymphocytes
from freshly isolated CD8þ T cells from peripheral
blood of healthy volunteers analyzed by the mixed
lymphocyte reaction were reduced when asbestos
fibers (chrysotile) were added in the mixed lympho-
cyte reaction [12,13]. Additionally, expression of the
chemokine motif chemokine receptor 3 (CXCR3),
being important in antitumor immunity to mobilize
antitumor T cells near tumor cells in CD4þ cells, was
reduced by asbestos exposure in a cell line model,
ex-vivo exposure using freshly isolated peripheral
CD4RR cells from healthy volunteers, as well as
Volume 17  Number 2  April 2017
 Silicosis and autoimmunity Lee et al.

FIGURE 1. Schematic presentation outlining the biological effects of silica and asbestos. Both silica particles and asbestos
fibers are identified as danger signals by inflammasome. However, subsequent alterations of immune cells are different. As
shown in left side of figure, silica-exposed patients often complicate with various autoimmune diseases as well as appearance
of various autoantibodies. The suspected cellular and molecular mechanisms underlying are chronic activation of responder
and regulatory T cells caused by silica particles. Responder T cell is surviving longer and is avoiding from cell death and
regulatory T cell is proceeding to cell death. As a result, imbalance of these two T cell types causes occurrence of autoimmune
diseases. On the other hand, as shown in right side of figure, asbestos exposure causes cancers. In addition with this, some
reports shows asbestos exposure induce autoantibodies against endothelial and mesothelial cells. These autoantibodies may
relate with occurrence of pulmonary fibrosis caused by asbestos exposure. ANA, antinuclear antibodies; ANCA,
antineutrophil cytoplasmic antibody; PD-1, program cell death-1; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus;
SSc systemic sclerosis; Th, T helper.

asbestos-exposed patients in cases of pleural plaque
and malignant mesothelioma [8,9]. Moreover,
experimental exposure of asbestos to Treg-like cells
(MT-2 cell line) resulted in enhancement of Treg
function, in addition to the excess production
of two typical soluble factors of Treg, IL-10 and
TGF-b [91,92]. Additionally, our preliminary data
indicated that our asbestos-exposed Treg model
(MT-2 cell line) showed enhancement of cell cycle
progression. Thus, asbestos induced an increase in
the quality and quantity of Treg, indicating a
reduction of antitumor immunity. However, as
mentioned above, silica particles caused a decrease
in Treg. Thus, from the viewpoint of Treg being

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Occupational disease
located at the center of various immune reactions,
silica and asbestos may exert their influence in
opposite directions.
Some interesting investigations have been
reported that show autoantibody production with
asbestos exposure. Several reports indicated that
asbestos exposure induced the production of certain
specific autoantibodies such as antiendothelial cell
antibody, antifibroblast antibody, and antimesothe-
&&
lial antibody [93 ,94–97]. Some antibodies were
found in a mouse model, and in a humans compris-
ing a ‘Libby Amphibole (LA)’-exposed population.
Libby amphibole comprises a mixture of amphibole
fibers that contain contaminated vermiculite and is
mined at Libby, Montana, USA. The researchers
considered that these antibodies may play a role
in the formation of lung and pleural fibrosis caused
by asbestos exposure. In any case, it is clear that
asbestos exposure may produce specific autoanti-
&&
bodies [93 ,94–97]. Thus, further investigations
are required to delineate the mechanisms involved
in the asbestos and silica-induced production of
autoantibodies, and the roles played in the patho-
logical progression of lung and pleural fibrosis, in
addition to the occurrence of cancer and auto-
&&
immune disorders [93 ,94–97].
CONCLUSION
As shown in Fig. 1, silica and asbestos exposure cause
lung fibrosis known as pneumoconiosis. In addition
to fibrosis, silica-exposed patients often show com-
plications of various autoimmune diseases. On the
other hand, the most important and critical com-
plication associated with asbestos-exposed patients
is cancer, and specifically the occurrence of lung
cancer and malignant mesothelioma. As summar-
ized in the figure, silica exposure induces the pro-
duction of various autoantibodies. Furthermore, the
cellular and molecular modifications of responder T
cells and Treg caused by silica exposure indicate that
silica-exposed patients are made prone to auto-
immune diseases such as RA, SSc, SLE, and ANCA-
related vasculitis. On the other hand, the dysregu-
lation of autoimmunity in asbestos-exposed popu-
lation remains poorly understood. It would be
certain that asbestos exposure would lead to the
production of specific autoantibodies. However,
whether these autoantibodies influence the onset
of lung fibrosis and/or complications of auto-
immune disorders can be determined by future epi-
demiological and experimental investigations.
The relationship between occupational and
environmental exposure to particulate and fibrous
substances and immunotoxicity is very complicated
and not easy to understand. Further studies
82 www.co-allergy.com
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
concerning silica and asbestos-induced immuno-
toxicity should assist in our understanding of the
biological effects of these occupational materials,
and contribute toward the development of preven-
tive measures and procedures to stem the occur-
rence of diseases caused by particulate and fibrous
substances.
Acknowledgements
The authors thank former colleagues in the Department
of Hygiene, Kawasaki Medical School, namely, Prof.
Ayako Ueki, Drs. Fuminori Hyodoh, Akiko Takata-
Tomokuni, Yasuhiko Kawakami, Takaaki Aikoh, Shuko
Murakami, Yoshie Miura and Megumi Maeda. In
addition, present colleagues, Drs. Kei Yoshitome and
Yasumitsu Nishimura for their advisory assistances.
We also appreciate the technical assistance of Ms. Har-
uko Sakaguchi, Naomi Miyahara, Minako Katoh,
Yumika Isozaki, Shoko Yamamoto, Miho Ikeda and
Tamayo Hatayama. We express special thanks to Drs.
Masayasu Kusaka and Kozo Urakami for coordinating
the collection of clinical samples.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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Autoimmune Dis 2014; 2014:782045.
Volume 17  Number 2  April 2017