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Interstitial lung disease in scleroderma. Immune complexes in sera and bronchoalveolar lavage fluid

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525
INTERSTITIAL LUNG DISEASE IN SCLERODERMA
Immune Complexes in Sera and Bronchoalveolar Lavage Fluid
RICHARD M. SILVER, JOHN F. METCALF. and E. CARWILE LEROY
Interstitial lung disease is a common feature of
sderoderma (systemic sclerosis), and it may be a major
determinant of morbidity and mortality. Analysis of
bronchoalveolar lavage fluid from patients with
sderoderma has shown evidence of inflammation in the
lower respiratory tract of many patients. We have
analyzed sera and bronchoalveolar lavage fluid from
scleroderma patients for the presence of immune complexes, which may play a role in the inflammatory
process. Using a solid-phase Clq enzyme-linked immunosorbent assay, we detected immune complexes in
the sera of 6 of 23 patients (26%) and in none of 32
controls (P< 0.01). All 6 patients with serum immune
complexes had inflammatory cells in bronchoalveolar
lavage fluid, and the presence of serum immune complexes correlated with the percentage of neutrophils in
lavage fluid (P < 0.02). Immune complexes were detected in lavage fluid of ll of 21 patients (52%) compared with 1 of 7 normal controls (14%). Subjects
having immune complexes in lavage fluid had a lower
forced vital capacity than did those without lavage fluid
immune complexes (P < 0.05). The levels of immune
Presented in part at the 49th Annual Meeting of the American liheumatism Association, Anaheim, CA, June 1985.
From the Division of Rheumatology and Immunology and
the Division of Pulmonary and Critical Care Medicine, Department
of Medicine, Medical University of South Carolina, Charleston.
Supported in part by the National Institutes of Health
(grants RR-1070 and AM-30431), the RGK Foundation, and the
United Scleroderma Foundation.
Richard M. Silver, MD; John F. Metcalf, MD; E. Carwile
LeRoy, MD.
Address reprint requests to Richard M. Silver, MD, Division of Rheumatology and Immunology, Clinical Sciences Building,
Room 912, 171 Ashley Avenue, Charleston, SC 29425.
Submitted for publication June 25, 1985; accepted in revised form September 23, 1985.
Arthritis and Rheumatism, Vol. 29, No. 4 (April 1986)
complexes in bronchoalveolar lavage fluid exceeded
those in serum by a mean of 45-fold, suggesting either
local formation or selective deposition of immune complexes in the lower respiratory tract of some scleroderma patients.
Interstitial lung disease occurs frequently in
scleroderma (systemic sclerosis), with demonstrable
pathologic changes in over 80% of postmortem cases
and with clinical pulmonary involvement in 60% of
cases (1,2). Although it has long been believed to be a
bland, fibrotic process, the histologic features of
scleroderma lung disease are indistinguishable from
those of idiopathic pulmonary fibrosis (IPF), a condition in which inflammation is believed to precede
fibrosis (3). The recent application of 67gallium lung
scans and the development of the technique of bronchoalveolar lavage (BAL)for obtaining cells and proteins from the lower respiratory tract have permitted
demonstration of evidence of ongoing inflammation in
the lungs of a significant proportion of scleroderma
patients (4-10). The presence of inflammatory cells
(neutrophils, eosinophils, and occasionally lymphocytes), as well as the presence of potential mediators
of inflammation (such as IgG and collagenase) in
scleroderma lavage fluid, give an appearance similar to
that of IPF. Since immune complexes have been
demonstrated in serum and lavage fluid from patients
with IPF (11-13), and are believed to play a role in its
pathogenesis (14), and since several studies have demonstrated serum immune complexes in a variable
percentage of scleroderma patients (15-21), we analyzed scleroderma lavage fluid for Clq binding activity. Correlations between BAL cellular composition
and findings of pulmonary function tests were sought.
5 26
SILVER ET AL
Table 1. Clinical characteristics of scleroderma patients who were studied by bronchoalveolar lavage*
Patient
Extrapulmonary organ involvement
Disease
duration EsoAgelsex (years) phagus Cardiac Renal Muscle Sjogren’s FVC
Pulmonary involvement
FEV I
FVC TLC
2
3
4
5
52lF
21lM
361F
30lM
48lF
55
46
35
54
15
83
91
86
97
80
6
1
8
9
321F
32lF
48lM
49lM
78
52
81
37
10
I1
12
13
14
23lF
35lM
43lF
44lM
40lM
64lM
42lF
58IM
37lM
30lF
531F
291F
1
15
16
17
18
19
20
21
22
23
24
35lF
5OlF
54lM
3
Mean e SD 41 ? 2.2 4.5 k 0.8
+
+
18/23
5/24
4/24
-
-
8124
1/24
50
RV
CXR Concomitant
DLco pattern drug therapy
51
45
63
ND
ND
52
14
47
81
17
22
ND
34
82
87
88
88
81
85
50
83
103
50
96
48
I03
32
61
57
34
51
68
98
95
104
85
12
83
21
49
59
94
17
95
82
82
67
93
59
88
I00
87
94
38
51
69
89
87
41
87
52
79
19
55
91
ND
79
59
60
..
41
105
82
82
80
34
53
76
47
14
68
82
66
96
73
102
11
71
ND
ND
Diffuse
Diffuse
Diffuse
Diffuse
Basilar
30
74
81
70
53
19
58
67
ND
55
95
63 c 4 85 c 2 61 c 4 72 2 4 60
45
92
54
2
Prednisone
-
D-penicillamine
Normal Prednisone
Diffuse
Basilar
Basilar D-penicillamine,
prednisone
Basilar
Normal
Normal
Basilar
Normal
Basilar
Normal
Basilar
Normal Colchicine
Diffuse Prednisone
Basilar
Normal D-penicillamine
Diffuse
Basilar
Normal
51
91
-
5
-
or total
* PVC = forced vital capacity; FEV, = forced expiratory volume in 1 second; TLC = total lung capacity; RV = residual volume; DLco = lung
di$us#ing capacity for carbon monoxide; CXR = chest radiograph; ND = not determined. Pulmonary involvement values are % observed.
PATIENTS AND METHODS
Patients. Twenty-four patients with scleroderma
(systemic sclerosis) who were participating in a prospective
study of interstitial lung disease were evaluated. The sole
criteria for selection were fulfillment of the American Rheumatism Association (ARA) preliminary criteria for the classification of systemic sclerosis (22) and a willingness to
participate in the study. The clinical characteristics of the
patients studied are outlined in Table 1. As shown in Table 1,
the SI udy population included patients who had normal lung
volumes, diffusing capacities, andlor chest radiographic results. Sixteen patients had diffuse skin involvement and 8
had limited skin involvement. Seven normal individuals
were entered into the study as controls (mean age 4 SD, 27
8 years). Patients or controls who had a recent history of
cigarette smoking, lower respiratory tract infection, or a
his tory of chronic bronchitis were excluded from the study.
Eight of the 24 patients had a remote smoking history (i.e.,
they had smoked in the past, but stopped) (patients I , 3 , 9,
11, 13, 14, 15, and 17; Table 1). These patients had test
results similar to those in patients with no prior smoking
*
history, except for a 1-second forced expiratory volume/
forced vital capacity <70% of predicted in 2 former smokers.
After informed consent was obtained, all subjects were
admitted to the General Clinical Research Center, where the
following studies were performed: history-taking and physical examination, chest radiographs, pulmonary function
tests, and bronchoscopy with bronchoalveolar lavage.
During the latter part of the study, patients with clinically
obvious pulmonary hypertension were excluded. Some patients may have had subclinical or mild pulmonary
hypertension.
Methods. Standard spirometric measurements of
lung volume, flow indices, and diffusing capacity were
performed on each subject. Bronchoalveolar lavage was
performed as previously described (6). Briefly, local anesthesia of the upper respiratory tract was obtained with
topical lidocaine spray (2%), after which a fiberoptic
bronchoscope (Olympus Corp. of America, New Hyde Park,
NY) was wedged in a subsegment of the right middle lobe.
Lavage was performed by instillation and immediate withdrawal by syringe of 5 60-ml volumes of sterile 0.9% sodium
chloride solution, all at 1 site. The recovered lavage fluid was
LUNG DISEASE IN SCLERODERMA
527
Table 2. Composition of bronchoalveolar lavage (BAL) fluid from patients with scleroderma
BAL cell differential
Total cells Alveolar
recovered macro- LymphoNeutro.
( ~ 1 0 ~ ) phages
cytes
phils
Patient
-
73
9.0
28.5
91
12.0
72
89
34.0
9.0
96
14.6
63
94
24.5
30.8
87
15.0
96
24.0
77
16.0
96
96
18.0
90
24.7
99
11.3
1.9
98
4.0
98
93
19.0
53.8
98
20.2
80
97
8.9
16.0
94
17.4
88
81
18.8
99
95.0
21.9f 3.9 89.4 ? 2.0 3.0
1
I
;!
3
4
ti
ti
7
8
9
10
1 1I
1:!
13
14
Iti
10
1-7
18
19
20
2 1I
2:!
23
24
Mean
f
9
1
3
3
4
3
0
Eosinophils
14
6
25
7
0
34
4
9
1
4
2
0
1
0
0
2
3
0
8
3
1
3
6
0
2
1
0
2
0
0
0
9
1
1
1
5
0
0
2
4
0
0
0
1
3
1
0
0
2
2
19
1
0
1
1
2
5
10
17
0
1
1
1
0
1
f 0.8 5.9 t 1.8 1.6 2
BAL protein analysis*
IgG
Albumin
IC
Serum protein analysis*
IgG
Albumin
1C
ND
ND
33
31
33
40
31
26
25
29
19
36
25
52
32
74
56
66
32
ND
ND
ND
28
ND
<I5
< 15
17
<I5
16
17
32
<15
<I5
<15
<15
16
< 15
66
4
<15
6/23 (26%)
9
0/32 (0%)
0.23
3.60
<30
ND
ND
ND
ND
ND
ND
0.40
40
9
0.36
0.64
30
13
0.57
0.79
35
9
1.90
55
0.57
9
0.84
3.13
<30
17
0.84
1S O
<30
15
3.30
33
0.39
65
11.50
3.45
80
18
6.20
2.90
85
19
0.31
3.38
35
17
17
0.79
35
2.53
0.43
<30
21
3.00
1.46
4.00
<30
20
0.40
4.00
<30
19
2.48
ND
<30
18
4.49
5.90
40
30
ND
ND
ND
8
0.90
0.96
<30
9
2.01
6.80
<30
20
0.40
0.48
ND
56
1.30
1.70
<30
13
6.20
3.10
35
23
0.4 2.11 2 0.62 2.59 2 0.39 11/21 (52%) 18.3 ? 2.2
39
2
1.5 0.47
48
?
<I 5
<I5
<15
<I5
< l5
<15
<I5
<15
15
SEM
Control
mean
SEM
-
*
17.2 +- 6.6 95.1 2 4.3 3.6
f
3.0 0.6
f 0.8
0.7
?
?
0.11 0.92
?
0.13
1/7 (14%)
9.9
?
2.0
* IgG and albumin expressed as mg/ml; BAL IgG, albumin, and immune complexes (IC) determined on concentrated lavage fluid (see Patients
and Methods); immune complexes expressed as pghl aggregated human gamma globulin equivalents. ND = not determined.
paoled, filtered through sterile gauze, and added to an equal
volume of Hanks’ balanced salt solution (HBSS; Gibco,
Grand Island, NY). The fluid was centrifuged at 50013 for 15
minui.es at room temperature. The cell pellet was resuspended in HBSS and cytocentrifuge smears were prepared and
stained with Wright’s stain and with a nonspecific esterase
stain. Slides were examined by light microscopy, and 400
cells from each sample were scored as alveolar macrophages, lymphocytes, neutrophils, or eosinophils. Normal
values were established from lavage fluid samples from
normal control subjects. These consisted of 95.1 k 4.3%
(mean 4 SD) alveolar macrophages, 3.6 ? 3.0% lymphocytes, 0.6 k 0.8% neutrophils, and 0.7 1.5% eosinophils.
Abnormal values were defined as those values >2 SD
above the mean values in normal control subjects. The
individual values for each of the 24 patients studied are
given in Table 2.
Cell-free supernate was concentrated to a final volume of 1.0 ml, using vacuum filtration with a molecular
filtration membrane (Immersible Cx-10 Filter Units, 10,000
nmwl; Millipore Corp., Bedford, MA). Albumin and IgG
were quantitated in concentrated lavage fluids from 21
*
patients and from all 7 controls by radial immunodiffusion in
agar (Meloy Laboratories, Springfield, VA). The same technique was used to quantitate albumin and IgG present in
setum samples from 23 patients and all 7 controls, obtained
immediately prior to BAL and maintained at -70°C prior to
use. Patient values are given in Table 2.
Immune complex assay. The presence of immune
complexes in concentrated bronchoalveolar lavage samples
and serum samples was detected by a solid-phase Clq
enzyme-linked immunosorbent assay (23). In brief, BAL
samples and serum samples were diluted with 0.02M phosphate buffered saline containing 0.01M EDTA (PBS-EDTA)
and incubated at 37°C for 1 hour to redissolve a n y cryoprecipitated protein. Aliquots of 100 pl were added to flatbottom microtiter wells (Costar, Cambridge, MA) which had
been coated with C l q (Center for Blood Research, Boston,
MA), 100 pg/ml in high salt (0.64M NaC1) PBS-EDTA, and
to wells which had been coated with buffer only. Following
a 1-hour incubation at 3TC, the wells were washed with
PBS-EDTA. Alkaline phosphatase-labeled, affinity-purified
anti-human IgG (Kirkegaard and Perry, Gaithersburg, MD),
100 pl diluted 1:1,200 in PBS-EDTA containing I% bovine
SILVER ET AL
528
Table 3. Relationship between scleroderma serum immune
complexes (IC) and bronchoalveolar lavage (BAL) fluid cell
differential
-
Serum
BAL cell differential
Abnormal*
Normal
-
1c+
IC -
6t
0
4
13
* Increased neutrophils, eosinophils, or lymphocytes as defined in
Patients and Methods.
t P 0.01, positive IC and abnormal BAL cell differential, using
chi-square with Yates’ correction.
:<
serum albumin, was added to each well and incubated at
37°C for 90 minutes. The wells were washed and pnitrophenylphosphate substrate (250 pl) (Sigma, St. Louis,
MO) was added to each well. These were incubated ih the
dark for 30 minutes at room temperature. NaOH (0.75M)
was added to stop the reaction.
Absorbance at 405 nm was recorded by a Titertek
Multiskan photometer (Flow Laboratories, McLean, VA).
b c h sample was assayed in duplicate. For each assay, a
standard curve was prepared by subtracting the blanks
(wells coated with buffer alone) and plotting the absorbance
at 405 nm on the linear scale versus cancentrations of
aggregated human gamma globulin (AHGG) (Sigma) on
semilog graph paper. The standard curve for calculating
serum immune complexes was generated by serial dilutions
of AHGG in normal human serum, with the sensitivity of the
assay being 15 pg/ml AHGG equivalents. Control serum
specimens obtained from 32 healthy volunteers all yielded
values below the sensitivity of the assay. Ninety-five percent
of sera from normal controls yielded values <10 pdml
AHCiG equivalents. For detection of immune complexes in
bronchoalveolar lavage fluid, the standard curve was generated by diluting AHGG in normal human lavage fluid, with a
sensitivity of 30 pdml AHGG equivalents. Patient values are
given in Table 2.
Statistical comparisons. The associations between
serum or BAL fluid immune complexes and tests of pulmonary function, BAL cell composition, chest radiographs, and
IgG levels were analyzed by nonparametric statistical tests
using the BMDP3S statistical software program converted
for use on Prime computers (24).
RESULTS
Analysis of serum immune complexes. Using a
solid-phase C 1q enzyme-linked immunosorbent assay,
immune complexes were detected in the sera of 6 of 23
patients (26%) and 0 of 32 controls ( P < 0.01). The 6
patiemts with detectable serum immune complexes had
values which ranged from 15 pg/ml to 32 pg/ml AHGG
equivalents (Table 2). All 6 patients with serum immune complexes on the day of bronchoalvedar lavage
had an abnormal cellular composition to their BAL
fluid; 5 of 6 patients had increased neutrophils (1 1.4 t
5.7%; mean k SEM) and 1 of 6 had increased lymphocytes (17%) (Table 3). The 1 patient with increased
BAL lymphocytes had Sjogren’s syndrome; this patient had normal pulmonary function test results, but
had basilar fibrosis seen on chest radiograph. Although
4 patients without serum immune complexes had increased neutrophils in their bronchoalveolar lavage
fluid, there was a statistically significant correlation
between the presence of serum immune complexes
and the percentage of neutrophils in BAL fluid (P <
0.02). Serum immune complexes did not correlate with
pulmonary function or the extent of radiographic abnormalities.
Analysis of BAL fluid immune complexes. Immune complexes were detected in the concentrated
BAL fluid of 11 of 21 patients (52%) and 1 of 7 controls
(14%). Those patients with detectable immune complexes had values which ranged from 30 pg/ml to 85
pg/ml AHGG equivalents, with a mean of 49 5 9.2
(SEM) (see Table 2). The association between immune
complexes in BAL fluid and the percentage of
neutrophils in BAL fluid approached, but did not
achieve, statistical significance (P = 0.069). When
BAL fluid immune complexes were related to pulmonary function, there was a statistically significant
inverse relationship with forced vital capacity (P =
0.035) (see Table 4). The association between lavage
fluid immune complexes and total lung capacity approached statistical significance (P = 0.06). There was
no significant association between lavage fluid immune
complexes and lung diffusing capacity for carbon
monoxide (DLco) (P = 0.25). As shown in Table 2,
concentrated lavage fluid immune complexes did not
correlate with IgG levels in bronchoalveolar lavage
fluid, which suggests that the solid-phase Clq immunoassay is not detecting IgG that has been aggre-
Table 4. Relationship between bronchoalveolar lavage (BAL)
fluid immune complexes (IC) and pulmonary function test (PFT)
results
~
Concentrated BAL fluid
PFT*
FVC
FEVIIFVC
TLC
DLco
IC -
P
2
83 t 5
90*4
84 -t 5
0.04t
0.42
0.06
8
83
0.25
IC +
a t
87 2
67
68 k
7
*6
4
9
* FVC = forced vital capacity; FEVl = forced expiratory volume in
1 second; TLC = total lung capacity; DLco = lung diffusing
capacity for carbon monoxide. Values are % predicted.
t Mann-Whitney test.
LUNG DISEASE IN SCLERODERMA
gated during the process of concentration or storage.
Furthermore, the addition of native IgG to normal
bronchoalveolar lavage fluid, followed by concentration of the fluid to a 1-ml volume, did not result in
detectable immune complexes.
Three of 11 patients with immune complexes in
BAL, fluid had immune complexes in simultaneously
obtained serum. In each of the 3 cases, the level of
immune complexes in lavage fluid, expressed as pg/ml
equivalents of AHGGlmg lavage fluid albumin, exceeded the level of immune complexes in serum (similarly expressed as pg/ml equivalents of AHGG/mg
serum albumin). The Clq bindindalbumin in lavage
fluid exceeded that of serum by 8-68-fold (mean 45fold), suggesting either local immune complex formation or selective deposition of immune complexes
within the lower respiratory tract.
DISCUSSION
In this study of scleroderma lung disease, we
found immune complexes in the sera of 6 of 23 patients
and in the bronchoalveolar lavage fluid of 11 of 21
patients. The presence of serum immune complexes
was predictive of inflammatory cells in the bronchoalveolar lavage fluid and was statistically correlated
with the percentage of neutrophils in lavage fluid.
There was a statistically significant inverse correlation
between lavage fluid immune complexes and forced
vital capacity.
The present data showing serum immune complexes in 26% of scleroderma patients are consistent
with previous studies. In 3 large studies using a
solid-phase Clq binding assay, serum immune complexes were detected in 12-39% (mean 25%) of
scleroderma patients. More sensitive assays, e.g., the
Raji cell assay, have yielded positive results in a higher
proportion of scleroderma patients (15,17-19,21). We
elected to use a solid-phase C lq binding assay because
of its reproducibility and ease of performance, and
becaruse results of prior studies had suggested that
serum immune complexes detected by Clq binding
assays correlate with scleroderma lung involvement
(19,;!0). Seibold et a1 (19) noted that patients with
serum immune complexes detected by Clq binding
had evidence of pulmonary involvement (rales, radiographic evidence of fibrosis, and diminished DLco)
significantly more often than did patients without such
complexes. Using similar clinical criteria, Siminovitch
et all (20) observed a significant correlation between
lung involvement and serum immune complexes de-
529
tected by a Clq binding assay. Another study using a
Raji cell assay found a less significant relationship
between immune complexes and radiographic abnormalities or forced vital capacity (18).
Although we found no significant correlation
between serum immune complexes and radiographic
changes or pulmonary function test results, we did find
that all patients with serum immune complexes had
evidence of inflammatory lung disease, as defined by
the cellular composition of BAL fluid. It is not surprising that results of tests for serum immune complexes
may not correlate with those of clinical or physiologic
tests, since these are single samples and single-point
clinical observations (25). The association between
serum immune complexes and inflammatory cells in
lavage fluid does, however, suggest a potential role for
immune complexes in mediating lung injury. The
finding that over 50% of scleroderma patients had
immune complexes in lavage fluid, together with the
observation that those subjects with immune complexes had a significantly lower forced vital capacity,
provides further evidence that immune complexes
may play a role in mediating scleroderma lung disease.
There is both direct and indirect evidence that
immune complexes are capable of mediating lung
injury (26). By injecting immune complexes, Brentjens
et a1 induced chronic interstitial lung disease in rabbits, characterized by thickened alveolar walls, interstitial fibrosis, and deposition of fibrinogen (27). In
human interstitial lung disease, particularly IPF, immune complexes have been detected in serum, BAL
fluid, and lung tissue (11,28). Dreisin et a1 reported that
serum immune complexes were present in the majority
of IPF patients with active lung disease (by biopsy),
but were not present in those patients with inactive
(fibrotic) disease (11). Using a Clq binding assay,
Haslam et a1 detected serum immune complexes in
50% of IPF patients, including 1 of 4 patients who had
scleroderma (12). Furthermore, serum immune complexes have been correlated with immunoreactants in
the lung by the use of immunofluorescence studies of
lung biopsy specimens (11).
Using the newer technique of bronchoalveolar
lavage, Gadek and coworkers found a twofold increase
in Clq binding activity in IPF lavage fluid compared
with fluid from controls. Similar to our results, the
concentration of immune complexes in IPF lavage
fluid was found to be thirtyfold higher than that of IPF
serum (13). This suggests that the immune complexes
may be formed in the lung or selectively deposited in
the lung. Indeed, in 1 study of IPF patients, an
530
SILVER ET AL
increase in bronchoalveolar IgG-secreting cells was
shown (29).
Crystal and colleagues have postulated that
immune complexes play a central role in the pathogenesis of IPF ( 3 ) . They have shown that immune
complexes are capable of stimulating alveolar macrophages to release a neutrophil chemotactic factor
which, in turn, causes neutrophils to accumulate in the
lung. The latter are capable of inducing lung injury
through the release of proteolytic enzymes and oxygen
radicals (14). Recent studies have shown that the
neutrophil chemotactic factor released by stimulated
alveolar macrophages is leukotriene B4 (30). Our
previous study showing increased neutrophils and IgG
in many scleroderma lavage fluids (6), together with
the present data showing immune complexes in many
scleroderma lavage fluids, suggests that a similar
pathogenesis may be a factor in the development of
scleroderma lung disease.
The greater frequency of interstitial lung disease in scleroderma than in other connective tissue
diseases in which there is a higher frequency of
circulating immune complexes may be due to a number of factors: 1) pulmonary immune complex deposition may occur in all connective tissue diseases;
however, an underlying abnormal regulation of fibroblasts may lead to more frequent and severe interstitial
fibrosis in scleroderma; 2) in scleroderma lung disease,
immunoglobulins may be synthesized locally in the
lung, directed against unknown antigens, and circulating immune complexes may merely reflect spillover
from the lung or other tissues; 3 ) differences may exist
in the phlogistic properties of immune complexes in
the various connective tissue diseases; and 4) circulating immune complexes may deposit more readily in
the scleroderma lung due to abnormalities in capillary
permeability. Studies are now under way to define the
state of activation of the scleroderma alveolar
macrophage and to determine if products of the alveolar macrophage may play a role in modulating the
fibrotic process.
ACKNOWLEDGMENTS
The authors acknowledge the technical assistance of
Karen Prioleau and the secretarial assistance of Judy
Anderson and Connie Key.
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