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Annals of Mens Health and Wellness
Review Article *Corresponding author
Otsuki T, Department of Hygiene, Kawasaki Medical

Alteration of Immune Cells in School, 577 Mastushima, Kurashiki, 701-0192, Japan, Tel:
81864621111; Email:

Silicosis: Roles in Development

Submitted: 01 February 2017
Accepted: 14 March 2017
Published: 16 March 2017

of Autoimmunity and Lung Copyright

© 2017 Otsuki et al.

Fibrosis OPEN ACCESS

Keywords
Hidenori Matsuzaki1, Hiroaki Hayashi2, Suni Lee1, Naoko • Silicosis
Kumagai-Takei1, Shoko Yamamoto1, Miho Ikeda1, Tamayo • Autoimmunity
• Regulatory T cell
Hatayama1, Kei Yoshitome1, Yasumitsu Nishimura1, and Takemi • Th17
Otsuki1*
1
Department of Hygiene, Kawasaki Medical School, Japan
2
Department of Dermatology, Kawasaki Medical School, Japan

Abstract
In addition to lung fibrosis, silicosis (SIL) patients often suffer from complicated autoimmune disorders such as rheumatoid arthritis, systemic sclerosis and
anti-neutrophil cytoplasmic antigen-related vasculitis/nephritis. Thus, chronic and recurrent exposure to silica particles located in the lung and lymph nodes
can result in alterations in the function of immune cells, which can lead to the dysregulation of autoimmunity in addition to the development of lung fibrosis.
Regarding B cells which produce various antibodies, in SIL many autoantibodies are often detected in autoimmune diseases, and specifically autoantibodies
against apoptosis-related molecules. Responder T helper (rTh) cells which respond to foreign and auto-antigens have been reported to survive longer and have
apoptosis inhibited. Additionally, regulatory T (Treg) cells seem to proceed to early apoptosis. This imbalance between rTh and Treg cells may make SIL patients
prone to autoimmune disorders. Although the role of dendritic cells (DCs) including alveolar macrophages and T helper 17 (Th17) cells in the dysregulation of
immune tolerance in SIL remains poorly understood, these cells play a role in pulmonary inflammation and the development of fibrosis via specific receptor and
signaling molecules. Further studies are required to delineate the roles of DCs and Th17 cells in the disturbance of autoimmunity found in SIL, and investigation
of the immunological alterations that lead to autoimmune dysregulation may assist in the recognition, prevention, and treatment of complicated autoimmune
diseases found in SIL.

ABBREVIATIONS and is caused by chronic and recurrent occupational exposure

SIL: Silicosis; DC: Dendritic Cell; AM: Alveolar Macrophage;
RA: Rheumatoid Arthritis; SLE: Systemic Lupus Erythematosus;
Ssc: Systemic Sclerosis; ANCA: Anti-Neutrophil Cytoplasmic
Antibody; rTH: Responder T Helper Cell; Treg: Regulatory T
Cell; CD: Cluster Of Differentiation; Foxp3: Forkhead Box P3;
Th17: T Helper 17 Cell; Ig: Immunoglobulin; ANA: Anti-Nuclear
Antibody; HV: Healthy Volunteer; APC: Antigen-Presenting Cell;
PBMC: Peripheral Blood Mononuclear Cell; PD-1: Programmed
Cell Death-1; Sil-2R: Soluble IL-2 Receptor; Sfas: Soluble Fas; PR:
Profusion Rate; FEV1.0: Percentage Of Forced Expiratory Volume
In 1 Second; FVC: Forced Vital Capacity; V25/H: PFR At 25%
FVC/Height V25/H; %VC: Percent Volume Capacity; Dcr3: Decoy
Receptor 3; NALP: NACHT, LRR and PYD Domains-Containing
Protein; MARCO: Macrophage Receptor With Collagenous
Structure; ROS: Reactive Oxygen Species; TNFRSF9:Tumor
Necrosis Factor Receptor Superfamily Member 9; Myd88: Myeloid
Differentiation Primary Response Gene 88; Nfκb: Nuclear Factor-
Κb
INTRODUCTION
Silicosis (SIL) represents a typical form of pneumoconiosis
to silica particles [1-3]. Inhaled silica particles are recognized as
foreign bodies and a danger signal by dendritic cells (DCs) and
alveolar macrophages (AMs) in the pulmonary region, which
leads to chronic inflammation and the development of fibrosis by
various functional alterations in DCs as well as other immune cells
such as T helper cells [4-6]. Although clinical subtypes of SIL are
divided as acute, subacute and chronic, simple SIL is characterized
by the presence of small nodules found in the upper and middle
lobes of the lung [1-3]. These nodules sometimes develop to
more than 1 cm in diameter. The inhaled silica particles remain
in the lung and related lymph nodes. Thus, circulating immune
cells may recurrently encounter these particles and are caused
various alterations.
Pulmonary complications such as lung tuberculosis,
chronic bronchitis and airflow limitation, non-tuberculosis
mycobacterium infection, fungal lung infection, compensatory
emphysema, pneumothorax and lung cancer are well known [7-
10]. As a result of these complications, SIL patients suffer from
shortness of breath, coughs, fever, and cyanosis. In addition
to these pulmonary complications, SIL often reveals various
symptoms of autoimmune diseases [4,11,12]. Complicated

Cite this article: Matsuzaki H, Hayashi H, Lee S, Kumagai-Takei N, Yamamoto S (2017) Alteration of Immune Cells in Silicosis: Roles in Development of Auto-
immunity and Lung Fibrosis. Ann Mens Health Wellness 1(1): 1002.

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rheumatoid arthritis (RA) is well-known and referred to as
Caplan’s syndrome [13-15]. Many epidemiological studies have
been reported regarding complicated autoimmune diseases
found in SIL, such as systemic lupus erythematosus (SLE)
[16-18], systemic sclerosis (SSc) [19-21], and anti-neutrophil
cytoplasmic antibody (ANCA)-related vasculitis/nephritis [23-
25]. Although the causative mechanism responsible for the silica-
induced dysregulation of autoimmunity was thought to involve
an adjuvant effect of silica particles to present relatively small
molecules as self-antigens for antigen-presenting cells (APCs)
[26,27], recent investigations have revealed direct effects of silica
particles on immune cells such as responder T helper (rTh) and
regulatory T (Treg) cells, defined as CD (cluster of differentiation)
4 and CD25 positive with forkhead box P3 (FoxP3; a transcription
factor) positive [28-30].
In this review, the pathophysiological alteration of the
immune status found in SIL and causative mechanisms involved in
the development of disorders of autoimmunity are summarized,
as well as the relations of immune cells such as DC and T helper
17 (Th17) cells in the development of pulmonary inflammations
and fibrosis.
B CELLS
B cells produce various antibodies (immunoglobulins:
Igs). Although the direct cellular and molecular alterations
of B cells caused by direct exposure to silica particles remain
to be delineated, it is supposed that the detection of various
autoantibodies present in SIL is an important clue when
considering alterations of humoral immunity in SIL.
Many epidemiological studies have identified the presence of
general and specific autoantibodies such as anti-nuclear antibody
(ANA), anti-Scl-70 (antibody for topoisomerase I) and anti-
CENP-B (antibody for centromere protein B) antibodies specific
for SSc and ANCA in SIL [31-33].
Regarding autoantibodies for SSc, anti-Scl-70 was detected
in Japanese SIL patients who did not reveal any symptoms
of autoimmune diseases with higher frequencies compared
with healthy volunteers (HV) [34-36]. Regarding anti-Scl-70
autoantibody specificity, the allelic frequency of HLA-DQB1*0402
was investigated and results showed a significantly higher
frequency in anti-Scl-70-positive SIL (28.6%) than in anti-Scl-70-
negative SIL or HV. Additionally, HLA-DQB1*0301, DQB1*0601
and DPB1*1801 alleles were more frequently detected in
positive SIL than in SIL without anti-Scl-70 or in HV (although no
significant difference was observed) [34-36]. In addition to anti-
Scl-70 antibody, anti-CENP-B autoantibody is also recognized as
specific to SSc. Although anti-CENP-B is clinically more common
in the limited form than in the diffuse form, and anti-Scl70 is
more common in the diffuse form [37,38], the detection of these
antibodies in SIL is important. Investigation of the relationship
between anti-CENP-B titers and other immunological parameters
such as cytokines, apoptosis-related molecules, immunoglobulins
and molecules related to the T cell activation may provide a better
understanding of immunological modifications in SIL.
For example, the titer index (Log10) of anti-CENP-B
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autoantibody in SIL was higher than that in HV from the Japanese
population, and that of SSc was higher than those of HV and SIL
patients [39]. This titer index was positively correlated with
an assumed immune status of 1 for HV, 2 for SIL, and 3 for SSc.
The correlation study of the titer indices of anti-CENP-B and
Scl-70 autoantibodies showed a significant positive correlation.
Although the titer index of the anti-CENP-B autoantibody showed
no significant correlation with other parameters examined, the
titer index of the anti-Scl-70 autoantibody showed a significant
positive correlation with the ANA titer index and serum IgA.
Additionally, although factor analysis revealed that the titer
index of the anti-CENP-B autoantibody formed the same factor
with the anti-Scl-70 autoantibody, IgG value and age in SIL cases,
another extracted factor indicated that the IgA value and anti-
Scl-70 antibody were positively related, although anti-CENP-B
showed the opposite pattern in the results from the factor
analysis. These findings indicated that the titer index of anti-
CENP-B autoantibody may be a biomarker of dysregulation in SIL
cases [39].
ANCA positivity in SIL has been reported in many case
reports and epidemiological studies [23-25]. Although the
pathophysiological role of ANCA positivity has not been
extensively investigated, monitoring the high frequency of ANCA-
positive SIL may be important in SIL [23-25].
Other particular auto-antibodies have been reported in
Japanese cases of SIL. The anti-desmoglein autoantibody was
found and this antibody is specific to pemphigus, an autoimmune
bullous disease. Thirteen-percent of SIL cases were found to
be positive by immunofluorescence. Additionally, use of ELISA
showed that 11% of cases were positive against the desmoglein 1
antigen, two SIL cases against the desmoglein 3 antigen, and two
SIL cases against both desmoglein 1 and desmoglein 3 [40]. This
report indicated that dermatological follow-up may be important
in the treatment of SIL.
Regarding molecules related to cell apoptosis, anti-Fas and
anti-caspase-8 auto antibodies were found in SIL [41-43]. Fas,
known as CD95, is a key molecule involved in cellular apoptosis,
especially in immune cells. Approximately one-fourth of Japanese
SIL cases were positive for anti-Fas. Interestingly, this anti-
Fas was functional, in that it could induce cellular apoptosis.
The sera of the highest titer of anti-Fas in SIL caused cellular
growth inhibition due to apoptosis in the Fas-presenting human
myeloma cell line KMS-12-PE derived from pleural effusion of a
Japanese myeloma patient. However, it did not induce growth
inhibition in the KMS-12-BM cell line, a sister cell line of KMS-12-
PE, derived from bone marrow myeloma cells obtained from the
same patient, but did show the presence of scant Fas molecules
on the cell surface [41,44]. This investigation suggested that
certain immune cells prone to Fas-mediated apoptosis readily
proceed to apoptosis and that the cellular function of these cells
may be lost in anti-Fas-positive SIL. This may be related to the
dysregulation of autoimmunity in SIL.
The anti-caspase-8 autoantibody is also of interest since
caspase-8 is closely related to Fas-mediated apoptosis [42,43].
Although functional analyses were not performed with this
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autoantibody, it was detectable in SIL, SSc and SLE patients

[42,43]. Using epitope mapping and employing 12 amino acid
polypeptides with the SPOTs system, a minimum of four epitopes
and a maximum of 13 were found, which implied that epitope
spreading was in progress. The study showed that two important
catalytic cysteine residues were included within the epitopes,
comprising active-site cysteine Cys287, and Cys360 located in
the unique penta-peptide motif QACQG. These analyses may
provide a better clue to the relationship between altered cellular
and molecular mechanisms of apoptosis in lymphocytes and
irregular immune tolerances in SIL [42,43].
Taken together, B cells in SIL produce various auto-antibodies
that may result from cellular signals derived from rTh as shown
in Figure (1), DC and APC cells, in addition to certain alterations
of antigen recognition in B cells.
RESPONDER T HELPER (RTH) CELLS
Silica particles chronically activate rTh and Treg cells.
Regarding rTh cells, CD69 expression, the earliest marker for
T cell activation, was induced under in vitro culture conditions
when peripheral blood mononuclear cells (PBMCs) were cultured
with silica particles [45]. Additionally, the molecule programmed
cell death-1 (PD-1) was highly expressed in CD4+ T cells derived
from SIL patients, but not from HV [46]. Since these surface
markers are considered to be T cell activation markers, silica
exposure caused chronic activation of circulating rTh cells in SIL.
Moreover, soluble IL-2 receptor (sIL-2R) in the serum of SIL
patients tended to be higher than in HV, and increased gradually
in the order HV to SIL to SSc [47]. A correlation assay, multiple
regression stepwise and factor analyses using sIL-2R levels and
various immunological parameters including percentage of
CD4+CD25+ and CD8+CD25+ cells in PBMCs, serum IgG, serum
soluble Fas (sFas), serum IL-2, titer of ANA, titers of anti-Scl-70
and CENP-B autoantibodies as well as respiratory and exposure
parameters including age, exposure years, profusion rate (PR;
according to the ILO pneumoconiosis radiological classification,
2011 revised guidelines, 1 to 4), subjective dyspnea (numbered 1
(slight) to 4 (severe), according to the Hugh-Jones classification),
the percentage of forced expiratory volume in 1 second (FEV1.0),
peak flow rate (PFR) at 25% forced vital capacity (FVC)/Height
(v25/H), and percent volume capacity (%VC) were all performed.
As a result, it was found that the level of sIL-2R was not related
to respiratory parameters, and was positively correlated with
ANA, anti-Scl-70 and anti-CENP-B titers. The stepwise regression
test showed that sIL-2R was significantly regulated by IgG and
tended to be regulated by anti-CENP-B. Moreover, from the
factor analysis, sIL-2R was extracted with various immunological
parameters including IgG, sFas, CD4+CD25+ cell percentage,
and anti-CENP-B. Taken together, sIL-2R levels in SIL indicated
immunological disturbance without any manifestations of
autoimmune symptoms, and suggested the presence of
chronically activated T cells in SIL [47].
Although foreign- and/or self-antigen-stimulated T cells
proceed to apoptosis in a process referred to as activation-
induced cell death, this is usually mediated by Fas/CD95. sFas is
Figure 1 The effects of silica particles on human B cells. Although direct effects
were not analyzed well, at least B cells yield various autoantibodies under
stimulation from responder T cells.
secreted from cells and binds with Fas-ligand at the extracellular
area which interferes with the binding between Fas ligand and
Fas located on the cell surface [48]. In fact, serum levels of sFas
were higher in SIL patients compared with HV, and a similar case
was found with SLE [48]. Additionally, mRNA analysis showed
that expression of the sFas transcript was higher in PBMCs
derived from SIL patients compared with HV [49]. In addition
to the sFas transcript, higher levels of other Fas alternatively
spliced variants, which have lost the transmembrane domain
but maintain the Fas ligand binding domain similar to sFas and
were assumed to act in a similar way as sFas in preventing Fas-
mediated apoptosis in T cells, were detected in PBMCs derived
from SIL patients compared with HV [50].
Moreover, decoy receptor 3 (DcR3) is known to possess
functionality that resembles that of sFas with respect to Trail-
induced apoptosis. As reported, DcR3 mRNA expression in
PBMCs derived from SIL patients was higher compared with HV
[51]. Taken together, rTh cells in SIL are supposed to be activated
chronically and survive for longer periods by the inhibition
of Fas-mediated apoptosis as shown in Figure (2). These cell
populations would include self-antigen recognizing clones.
REGULATORY T (TREG) CELLS
Treg cells are well-known as the regulator subpopulation of
T helper cells, and enable rTh cells to cease stimulation-induced
proliferation physiologically. The decrease and/or reduced
function of Treg cells may induce autoimmune diseases or
allergic conditions since rTh cells stimulated by self or foreign
antibodies are not quite activated. In contrast, increased and/
or enhanced Treg cell activity may result in cancer development
and proliferation since T cells attacking cancer cells may be over-
suppressed by Treg cells [52-54].
From this viewpoint, the Treg, CD4+CD25+ cell fraction, in

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DENDRITIC CELLS (DCS) IN THE PULMONARY

REGION
DCs, alveolar macrophages (AMs), are the first responders
following the inhalation of foreign substances including silica
particles. Once DCs recognize foreign bodies, NACHT, LRR and
PYD domains-containing protein (NALP)-3 inflammasome
is activated to produce IL-1β due to lysosomal damage and
cathepsin B [56,57]. Although the roles of DCs with respect
to forthcoming disorders of autoimmunity in SIL are not well
understood, the alterations in DCs related to the development
of lung inflammation have been documented in detail. One
of the key molecules involved in the development of silica-
induced pulmonary inflammation is the macrophage receptor
with collagenous structure (MARCO), which is the predominant
scavenger receptor for the recognition and binding of silica
particles [58-61]. The role of MRCO seemed to prevent silica-
induced inflammation [58-61]. Mice null for MARCO showed

Figure 2 The effects of silica particles on human responder T cells. Responder

T cells exposed chronically and recurrently to silica particles are chronically
activated and expressed PD-1 and CD69, and produce soluble IL-2R as activation
markers. In addition, various molecules such as soluble Fas, DcR3, and other
Fas-alternative spliced variants are produced from responder T cells to inhibit
Fas-mediated apoptosis. Thereafter, these responder T cells including self-
recognizing clones survive longer with chronically activated status, subsequently
cause autoimmune diseases.

the peripheral blood of SIL patients was examined with respect

to Treg function and compared with HV [55]. As a result, this
fraction from SIL patients showed reduced Treg function
compared with HV [55]. Consequently, it had to be considered
that rTh cells obtained from SIL patients are chronically activated
by exposure to silica particles as described above and that
activated rTh cells possess the CD25 molecule, unlike the case
with resting T cells. Taken together, the CD4+CD25 fraction in
cases of SIL included true Treg cells and chronically activated
rTh cells, and as a result Treg function was reduced in this
fraction [46]. In addition to these findings, when Treg cells are
chronically activated, Fas is over-expressed on the surface, which
facilitates earlier apoptosis [46]. In fact, expression of cell surface
Fas was higher in peripheral blood Treg cells derived from SIL
patients compared with HV. Furthermore, when PBMCs from HV
were cultured with silica particles, Treg cell expression of CD4,
CD25 and intranuclear FoxP3 gradually decreased, although the
CD25-expressing cell percentage remained unchanged. These
results indicated that the presence of silica particles lead to Treg
cell apoptosis by Fas-mediated apoptosis, and also result in the
activation of rTh cells [46].
These findings regarding rTh and Treg cells suggested that
Figure 3 In addition with effects of silica particles on responder T cells shown
the balance between rTh and Treg cells in SIL is disturbed, where in Figure 2, these particles modify and chronically activate the regulatory T cells.
levels of the former increase as shown in Figure (3), and the latter As the results, regulatory T cells express excess Fas molecule resulting early
decrease. This imbalance may provide the framework for the apoptotic loss. Thereafter, the imbalance of responder and regulatory T cells
onset of autoimmune disorders. occur to trigger to be prone to autoimmune diseases.

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a greater degree of lung inflammation, increased activation of

inflammasome as revealed by the release of IL-1β, increased
release of cathepsin B, and excessive activation of caspase-1.
Additionally, silica is capable of inducing the production of
reactive oxygen species (ROS) on the particle surface as well as
cells responding to silica such as AMs. These cellular alterations
are causative for pulmonary inflammation. Moreover, activated
AMs proceed to apoptosis, and thereafter phagocytized proteins
and nucleotides may be released [58-61]. These proteins and
nucleotides may be recognized as auto-antigens by rTh cells.
Of course, rTh cells are also stimulated by activated AMs as
well as silica particles as described above. Taken together, AM
activation may also function as one of the triggers involved in the
dysregulation of autoimmunity.
TH17 CELLS
The Th17 subpopulation of helper T cells is known to be
important in the development of autoimmune disorders. Both
the decrease in Treg cells resulting from the suppression of its
inhibitory function and enhancement of the effectiveness of
Th17 cells and/or increase in Th17 cell numbers are considered
to make the human body prone to autoimmune disorders.
Additionally, the polarization of Treg or Th17 cells is regulated
by immunological circumstances surrounding T helper cells. For
example, Treg cells mainly differentiate via transforming growth
factor (TGF)-β, however, Th17 cells can be promoted by TGF-β
and IL-6 with IL-23 as the expansion and survival factor [63-66].
Thus, if the cytokine-based circumstances change, the balance of
Treg and Th17 cells is also modified and the human body may
become prone to autoimmune disorders. With this in mind,
the direct effects of silica particles on Th17 cell polarization
and Treg cell differentiation should be investigated for a better Figure 4 Although the roles of Th17 cells and DCs for occurrence of
autoimmune diseases are not well studies, at least these cells are important for
understanding of silica-induced dysregulation of autoimmunity.
forming lung impairment caused by silica particles, forming fibrosis.
Several reports have detailed the role of Th17 cells in silica-
induced lung fibrosis. These reports have indicated that IL- this review. All of the alterations that lead to the development
1β and IL-17 enhance fibrosis [67,68]. Additionally, 4-1BB/ of lung fibrosis as well as autoimmune diseases in SIL are also
CD137 (tumor necrosis factor receptor superfamily member 9; shown. Experimental results obtained by examining the effects of
TNFRSF9), which is induced by lymphocyte activation and plays exposing various immune cells to silica particles have indicated
a role as an immune checkpoint molecule in a co-stimulatory that silica-exposed patients possess altered immune functions
manner, also stimulated the development of silica-induced and are prone to lung fibrosis and autoimmune disorders. These
lung fibrosis [69]. In contrast, myeloid differentiation primary findings may be utilized as clinical markers for follow-up SIL in
response gene 88 (MyD88), which is an adaptor protein and terms of immunological modifications. It seems that not all SIL
plays an important role in the signals of toll-like receptor (TLR), patients develop pulmonary pathologies and immunological
nucleotide-binding oligomerization domain receptor (NLR) abnormalities. Approximately one-fifth to one-fourth of SIL
and IL-1R superfamily to the downstream activation of nuclear patients might reveal a better immunological status with
factor-κB (NFκB), blocked fibrosis formation [70]. The Wnt the development of pulmonary fibrosis [72]. The opposite
signaling pathway and β-catenin also inhibited the progression pattern, comprising very slow progression of lung fibrosis with
of fibrosis. These findings were derived from animal models in accelerated immunological deterioration, was also reported for a
addition to the blocking of certain molecules by antibodies, and similar subpopulation [72].
the use of specific inhibitors or comparisons between knock-out
and wild-type mice [71]. Thus, future investigations will need to Taken together, in addition to considering the management
focus on the relations of these key molecules in terms of their of SIL patients, these findings may assist in our understanding
involvement in human SIL.The roles of DCs and Th17 in forming of the pathophysiological changes involved in various general
lung fibrosis are show in Figure (4). autoimmune diseases.

CONCLUSION ACKNOWLEDGEMENTS
Figure (1) shows the summarized findings described in The authors thank former colleagues from the Department

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Figure 5 Schematic summary of the alterations of various immune cells in
silica-exposed patients with respect to the development of lung inflammation
and fibrosis, as well as autoimmune disorders.
of Hygiene, Kawasaki Medical School, Kurashiki, Japan, Professor
Ayako Ueki, Drs. Yasuhiko Kawakami, Fuminori Hyodoh, and
Akiko takata-Tomokuni, Yoshie Miura, Shuko Murakami, Ping
Wu, Ying Chen and Megumi Maeda.
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Cite this article

Matsuzaki H, Hayashi H, Lee S, Kumagai-Takei N, Yamamoto S (2017) Alteration of Immune Cells in Silicosis: Roles in Development of Autoimmunity and Lung
Fibrosis. Ann Mens Health Wellness 1(1): 1002.

Ann Mens Health Wellness 1(1): 1002 (2017)

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