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In situ expression of B7 and CD28 receptor families in skin lesions of patients with lupus erythematosus.

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ARTHRITIS & RHEUMATISM
Vol. 40,No. 5, May 1997, pp 814-821
0 1997, American College of Rheumatology
814
IN SITU EXPRESSION OF B7 AND CD28 RECEPTOR FAMILIES IN
SKIN LESIONS OF PATIENTS WITH LUPUS ERYTHEMATOSUS
RALF W. DENFELD, PETER KIND, RICHARD D. SONTHEIMER, ERWIN SCHOPF, and JAN C. SIMON
Objective. To examine the expression of costimulatory molecules of the B7 and CD28 receptor families
in active skin lesions of patients with systemic lupus
erythematosus (SLE), subacute cutaneous lupus erythematosus (SCLE), and chronic discoid lupus erythematosus (CDLE).
Methods. The in situ expression of B7-1, B7-2,
BB-1, and CD28 was studied by immunohistochemistry,
and B7-1 and B7-2 RNA expression was examined by
reverse transcription-polymerase chain reaction.
Results. Only in lesional skin from SLE, SCLE,
and CDLE patients did dermal and epidermal antigenpresenting cells (APC) express B7-1 and B7-2, particularly when in apposition to CD28+ T cells. These B7-1+
and B7-2+ APC bound CTLA-4 fusion protein. In
lesional (but not in nonlesional) skin, keratinocytes
expressed BB-1. The majority of infiltrating T cells were
CD28+. B7-1 and B7-2 RNA were expressed in lesional
skin from SLE, SCLE, and CDLE patients; when dermis
was separated from epidermis, only faint B7-1 and B7-2
RNA signals were detectable in the epidermis, indicating that dermal but not epidermal cells were the major
source of B7-1 and B7-2 RNA. During treatment, both
B7-1 and B7-2 protein and RNA expression were
reduced.
Conclusion. These in situ findings suggest that
costimulation via the B7-CD28 pathway may be important for the generation and/or propagation of T cell
activity in skin lesions of humans with lupus erythematosus. Thus, the manipulation of this pathway (e.g., by
Supported by a grant from the Deutsche Forschungsgemeinschaft (Si 397/2-3).
Ralf W. Denfeld, MD, Erwin Schopf, MD, Jan C. Simon,
MD: University of Freiburg, Freiburg, Germany; Peter Kind, MD:
University of Munich, Munich, Germany; Richard D. Sontheimer,
MD: Southwestern Medical Center, Dallas, Texas.
Address reprint requests to Ralf W. Denfeld, MD, University
of Freiburg, Department of Dermatology, Hauptstrasse 7, 79104
Freiburg, Germany.
Submitted for publication July 2, 1996; accepted in revised
form November 22, 1996.
CTLA-4 fusion protein) could be an important target for
the development of future therapies for LE.
Lupus erythematosus (LE), especially systemic
LE (SLE), is an autoimmune disease characterized by
functional alterations of both T and B lymphocytes and
a wide repertoire of clinical manifestations, including
cutaneous lesions with a patchy infiltrate of activated T
cells (1-3). The exact mechanisms by which these T cells
are activated within skin are still unknown.
Activation of T lymphocytes requires at least 2
signals from antigen-presenting cells (APC). The first
signal, the binding of the T cell receptor to its antigenmajor histocompatibility complex ligand, provides specificity to antigen. The second signal is mediated by
costimulatory molecules, of which a family of proteins,
called B7, appears to be the most potent. The B7
costimulatory pathway involves at least 2 molecules,
B7-1 (CD80) and B7-2 (CD86) on APC, both of which
can interact with their counterreceptors, CD28 and
CTLA-4, on T cells (4-7). In humans, there is evidence
of a third member of the B7 family (BB-1; identified by
the monoclonal antibody BB-1) (8-12), but its molecular
nature is still unknown. It has been shown that B7-CD28
interactions greatly augment T cell activation initiated
through the CD3-T cell receptor complex, resulting in
activated T helper cells and/or cytotoxic T cells (4-7,13).
Since selective inhibition of the B7-CD28 pathway can cause sustained antigen-specific T cell unresponsivenessin vitro (14-17), it has been postulated that
blocking B7-CD28 interactions might also cause
antigen-specific T cell tolerance in vivo. Indeed, several
recent experiments in rodents corroborate the apparent
significance of the B7-CD28 costimulatory pathway in
vivo (18-23). In a murine model of autoimmune disease
that closely resembles SLE in humans, the relevance of
B7-CD28 interactions was particularly highlighted (24).
In that study, Finck et al demonstrated that treatment of
lupus-prone mice with murine CTLA-4 fusion protein
(CTLA-4Ig), a B7-CD28 antagonist, blocked autoanti-
B7-1, B7-2, AND CD28 EXPRESSION IN LE
body production and prolonged life, even when treatment was delayed until the most advanced stage of
clinical illness.
This work in animal models has raised hope that
in humans, it might also be possible t o achieve sustained
inhibition of autoantigen-driven responses, such as LE,
even without the knowledge of the inciting autoantigens,
by interfering with B7-CD28 costimulation. However,
little is currently known about the role of B7-CD28
interaction in human LE. Although the results are
conflicting, in vitro data indicate that CD28 on T cells
from patients with SLE seems to be an important
immunoregulatory molecule (25,26). This prompted us
t o question whether B7-1, B7-2, BB-1, and CD28 are
expressed in the diseased skin of patients with SLE,
subacute cutaneous LE (SCLE), and chronic discoid LE
(CDLE). Our findings are presented below.
PATIENTS AND METHODS
Patients. After obtaining informed consent, 4-6-mm
punch biopsies were obtained from new skin lesions and from
nonlesional skin of patients with acute SLE (n = 6), acute
SCLE (n = 12), and acute CDLE (n = 8), as well as from
healthy control donors (n = 3). In some of these individuals,
suction blisters were raised by a Dermovac (Instrumentarium,
Helsinki, Finland), and epidermal roofs were removed
surgically.
All patients were diagnosed as having active LE based
on histologic and clinical features, including the American
College of Rheumatology criteria (27). Four SLE, 6 SCLE, and
6 CDLE patients were newly diagnosed; in the other patients,
the disease duration varied from 1year to 11years. At the time
of surgery, none of the patients was receiving immunosuppressive therapy; however, some patients were receiving antimalarial therapy (hydroxychloroquine). Repeat biopsies of
previously biopsied, formerly lesional sites were obtained 1
month and 3 months after initiation of therapy with systemic
corticosteroids. Samples were snap-frozen immediately and
stored in liquid nitrogen until used.
Monoclonal antibodies (MAb) and staining reagents.
MAb with specificity for the following human antigens were
used: anti-CD3 MAb (IOT3; murine IgGl [mIgGl]; Biozol,
Munich, Germany), anti-CD4 MAb (SK3; mIgGl), anti-CD8
MAb (SK1; mIgGl), anti-CD25 MAb (2A3; mIgGl), antiCD28 MAb (L293; mIgGl), anti-HLA-DR
MAb (L243;
rnIgGl), anti-CD14 MAb (MFP9; mIgGl), anti-B7-l MAb
(L307.4; mIgG1) (all from Becton Dickinson, Heidelberg,
Germany), and anti-B7-2 MAb (1T2.2; mIgG2a; Pharmingen,
Hamburg, Germany). Kindly provided by Dr. P. S. Linsley,
Seattle, WA, were anti-BB-1 MAb (BB-1; IgM, which crossreacts with B7-1) (8-12) and human CTLA-4/mIgG2a fusion
protein (which reacts with human B7-1 and B7-2). Control
reagents for mIgG1, mIgG2a, and mIgM were all purchased
from Dianova (Hamburg, Germany).
Immunohistochemistry. Five-micrometer serial cryostat sections were stained according to a 4-step immunohisto-
815
chemical staining protocol utilizing the ABC technique, as
described elsewhere (28). Double stainings were performed
using unconjugated primary MAb (anti-B7-1 MAb, anti-B7-2
MAb, anti-CD4 MAb, anti-CD8 MAb), followed by a (33conjugated goat F(ab’), anti-mouse IgG (H+L) antibody
(Dianova). Then fluorescein isothiocyanate (F1TC)conjugated MAb against HLA-DR, CD14, or CD28 were used
for counterstainings.
Single-positivestainings were either red ((33) or green
(FITC), whereas double-positive stainings appeared yellow.
Stainings were evaluated by 2 independent dermopathologists
using a Zeiss Axioskop equipped with a MClOO camera system
(Gottingen, Germany); their findings were concordant.
Reverse transcription-polymerase chain reaction (RTPCR). RNA extraction, RT-PCR, and the analysis of RT-PCR
products have been described in detail elsewhere (29). Briefly,
total RNA was isolated from biopsy samples using guanidinium isothiocyanate-containing lysis buffer with subsequent
CsCl gradient purification. Complementary DNA (cDNA) was
prepared using 1 pg of total cellular RNA. B7-1 and B7-2
cDNA were amplified by RT-PCR from total cDNA using
B7-1- and B7-2-specific sense and antisense primer pairs. For
each sample, controls were performed without reverse transcriptase, without template, and with p-actin-specific primers
to exclude degraded RNA preparations. We verified that the
number of cycles used for RT-PCR is suboptimal for RT-PCR
amplification, i.e., that the plateau level for the RT-PCR
product is not reached at the end of the reaction.
Twenty microliters of each RT-PCR reaction product
was electrophoresed on a 2% agarose gel, stained with
ethidium bromide, and Southern blotted. The identity of the
single DNA band observed was confirmed by hybridization to
fluorescein-1 l-dUTP-labeled probes using the ECL 3’oligolabeling and detection kit (Amersham, Braunschweig,
Germany) according to the manufacturer’s instructions.
RESULTS
Immunohistochemical detection of B7-1, B7-2,
BB-1, and their ligand CD28 in lesional skin of LE
patients. In the diseased skin of patients with SLE,
SCLE, and CDLE, B7-1 and B7-2 were expressed predominantly on dermal, but also on epidermal, APC
(dendritic cells, macrophages) as well as on T cells, but
not on keratinocytes (KC), as confirmed by double
stainings (Table 1 and Figures 1A-C). Importantly,
CTLA-4Ig, which is known to react with B7-1 and B7-2
in vitro (6), bound to B7-l+/B7-2+ dermal and epidermal APC in situ (Figure 1D). BB-1, as identified by BB-1
staining, was detected on the majority of KC (Figure
lE), particularly in SCLE. In addition, BB-1 was expressed OR APC that were infiltrating the dermis and
epidermis, although t o a much lesser extent than B7-1
and B7-2 (data not shown). CD28 was expressed by most
T cells that infiltrated the dermis and epidermis of
lesional skin (Figure ZF). Double stainings revealed
DENFELD ET AL
816
Table 1. Summary of the results of immunohistochemical stainings*
Normal skin
CDLE
SCLE
SLE
Lesional
Nonlesional
After therapyi
AntiB7-1
AntiB7-2
CTLA-4
fusion
protein
AntiBB-1
AntiCD28
013
818
10112
013
818
013
818
013
618
013
818
10112
10112
12/12
11/12
516
516
013
013
516
013
013
516
516
0/3
013
013
013
013
013
* Specimens were deemed positive when >20% of the keratinocytes,
dermal and epidermal antigen-presenting cells (i.e., dendritic cells or
macrophages), or T cells stained with the monoclonal antibody shown.
CDLE = chronic discoid lupus erythematosus; SCLE = subacute
cutaneous lupus erythematosus; SLE = systemic lupus erythematosus.
t Biopsies were obtained from formerly lesional skin 3 months after
initiation of therapy with systemic corticosteroids.
CD28 to be expressed on both CD4+ and CD8+ T cells,
with the CD4+ subset being more dominant (Figure
1G).
In the uninvolved skin of SLE, SCLE, and CDLE
patients and in the skin of healthy donors, B7-1, B7-2,
BB-1, and CD28 expression was negligible, and no
CTLA-41g binding was observed (Table 1). Followup of
3 patients with SLE treated with systemic corticosteroids
revealed a correlation between clinical improvement
and both the resolution of the infiltrate and the reduced
expression of B7-1, B7-2, BB-1, and CD28 in formerly
lesional skin (Table 1).
Distribution of B7-1 and B7-2 RNA in lesional
skin of LE patients. To compare B7-1 and B7-2 protein
expression with RNA expression, total cellular RNA was
prepared from the same snap-frozen skin specimen that
had been examined by immunohistochemistry, and B7-1
and B7-2 RNA expression was measured by RT-PCR
using specific primers followed by hybridization with
B7-1- and B7-2-specific probes. B7-1 RNA was found in
skin samples from 5 of 5 SLE patients, 3 of 5 SCLE
patients, and 5 of 6 CDLE patients (Figure 2A). Similarly, B7-2 RNA was detected in skin samples from 5 of
5 SLE, 4 of 5 SCLE, and 6 of 6 CDLE patients (Figure
2B). Remarkably, comparisons of the lesional and nonlesional skin from the same SLE patient revealed B7-1
and B7-2 RT-PCR signals in diseased skin, but no or
only weak signals in the uninvolved skin (Figures 3A and
B). As indicated by previous data from our laboratory
(29), it appeared very likely that these B7-1 and B7-2
RT-PCR signals were derived from infiltrating CD45+
cells of hematopoietic origin.
To address the possibility that the RT-PCR signals originated from KC, we analyzed the epidermal roof
of suction blisters from the diseased skin of SLE patients
for B7-1 and B7-2 RNA expression. Compared with
whole biopsy samples from the same patient, only faint
B7-1 and B7-2 RT-PCR signals were detectable in the
epidermis (Figures 3A and B). These signals are most
likely due to residual epidermal CD45+ cells. These
results confirm and complete our immunohistochemistry findings of no B7-1 or B7-2 expression on KC in
lesional skin from LE patients.
Finally, we wished to determine the influence of
systemic therapy on B7-1 and B7-2 RNA levels in
lesional skin of SLE patients. Prior to therapy, B7-1 and
B7-2 RT-PCR signals were clearly detectable (Figures
4A and B). During therapy with systemic corticosteroids,
however, both the B7-1 and B7-2 RT-PCR signals were
reduced dramatically, which indicates that a reduced
expression of B7-1 and B7-2 RNA in lesional skin correlates with clinical improvement (Figures 4A and B).
DISCUSSION
In the present study, we have demonstrated that
in lesional, but not nonlesional, skin of patients with
SLE, SCLE, and CDLE, epidermal and dermal APC
express B7-1 and B7-2, particularly when in apposition
to CD28+ T cells, which are predominantly of the
CD4+ T helper cell subset. Our RT-PCR data confirmed the immunohistochemical results, in that B7-1
and B7-2 RNA were not expressed by KC. It seems very
likely that B7-1 and B7-2 RNA originate from infiltrating CD45+ APC. These findings suggest that in LE,
B7-1+ and B7-2+ APC could contribute to the intracutaneous activation of CD28+ T cells, and thereby extend
our previous study showing that the B7-CD28 pathway
plays an important role in T cell-mediated skin diseases
(allergic contact dermatitis and lichen planus), but not in
non-T cell-mediated skin diseases (basal cell carcinoma) (28). Garcia-Cozar et a1 (30) have demonstrated
that peripheral blood-derived APC from SLE patients
fail to functionally up-regulate B7 expression in vitro.
However, it remains unclear whether similar defects of
B7 expression occur in APC that infiltrate the skin
lesions of patients with SLE, SCLE, and CDLE.
During systemic treatment with corticosteroids,
the expression of the B7 (shown at the protein and RNA
level) and CD28 receptor family of molecules is reduced
or even lost, which most likely reflects a resolution of the
cutaneous infiltrate. Thus, a therapeutic approach to
consider is more specific therapy for LE (lesional and/or
systemic) by influencing B7-CD28 interactions. Since
anti-B7-l MAb, anti-B7-2 MAb, and CTLA-41g show
strong binding to the APC, all 3 reagents could be
Figure 1. Immunohistochemical detection of €37-1, B7-2, BB-1, and CD28 in lesional skin from patients with lupus erythematosus (LE). A, Subacute
cutaneous LE (SCLE): B7-1 is weakly expressed by dermal antigen-presenting cells (APC) and T cells (arrowheads) but not by keratinocytes (KC)
(arrows) (monoclonal antibody [MAb] L307.4). B, Chronic discoid LE (CDLE): Strong B7-2 staining is detected on the dermal mononuclear
infiltrate and on epidermal APC (arrowheads) but not on KC (arrows) (MAb IT2.2). C, SCLE: Double staining, showing HLA-DR positive cells
(green) and HLA-DRIB7-2 double-positive cells (yellow) in the dermis (d) and epidermis (e) (MAb L243, MAb IT2.2) Most HLA-DR-expressing
APC also express B7-2 (arrowheads). D, SCLE: CTLA-4Ig, which binds B7-1 and B7-2 in vitro, stains B7-1+ and B7-2+ mononuclear cells (is.,
APC, T cells) (arrowheads) but not KC (arrows) in situ. E, SCLE: BB-1 is detected on most KC (arrows) (MAb BB-1). F, SLE: CD28 is expressed
by T cells infiltrating the dermis and epidermis (arrowheads) (MAb L293). G, SLE: Some T cells infiltrating the dermis (d) and epidermis ( e ) are
only CD28+ (green) (arrow); the majority are CD4+/CD28+ (yellow) (arrowheads) (MAb SK3, MAb L293). Bar = 40 pm in A, B, D, and F; 10
pm in C, E, and G.
DENFELD ET AL
818
A.
87-1
f
Figure 2. Expression of B7-1 and B7-2 RNA in lesional skin from patients with SLE, SCLE, and CDLE. A, Total
cellular RNA (1 pg) from the lesional skin of 3 SLE patients, 5 SCLE patients, 6 CDLE patients, and from Daudi cells
was used for reverse transcription-polymerase chain reaction (RT-PCR) using B7-l-specific primers. RT-PCR products
were analyzed by 2% agarose gel electrophoresis, transferred to membranes, and probed with dUTP-labeled
B7-l-specific internal oligonucleotide. Arrow marks a fragment of 672 bp, the predicted size of the B7-l-specific
RT-PCR product. B7-lspecifk RNA was detected in 3 of 3 SLE,3 of 5 SCLE, and 5 of 6 CDLE samples. For each
sample, controls were performed without reverse transcriptase, without template, and with 8-actinspecific primers to
exclude degraded RNA preparations (not shown). B, As described in A, RT-PCR was performed using B7-2-specific
primers followed by hybridization to a B7-2-specific probe. Arrow marks a fragment of 664 bp, the predicted size of the
B7-2-specific RT-PCR product. B7-2-specific RNA was detected in 3 of 3 SLE, 4 of 5 SCLE, and 6 of 6 CDLE samples.
See Figure 1 for other definitions.
utilized for more specific therapy in LE. (3nA-4Ig
might be the most suitable because it is the “natural
ligand” for B7-1 and B7-2 in a soluble form (6).
The relevance of the B7-CD28 pathway for therapy of autoimmune diseases has recently been shown in
3 in vivo models: nonobese diabetic (NOD) mice (31),
experimental allergic encephalomyelitis (EAE) (32,33),
and murine lupus (24,34). Lenschow et a1 (31) examined
the role of the B7-CD28 pathway in the development
and progression of autoimmune diabetes in the NOD
mouse model. These mice develop spontaneous insulitis
early in life, which progresses to diabetes. CTLA-41g and
anti-B7-2 MAb treatment of NOD mice prevented
diabetes when administered just before or at the onset of
insulitis.
Kuchroo et a1 (32) demonstrated in EAE, a
murine model of multiple sclerosis, that anti-B7-1 MAb
therapy significantly reduced the incidence of EAE by
altering the cytokine profile of the responding T cells.
Indeed, treatment with anti-B7-1 MAb at immunization
resulted in a predominant generation of antigen-specific
Th2 clones, which upon adoptive transfer, prevented
induction of EAE and abrogated established disease. In
addition, Perrin et a1 (33) showed that CTLA-41g could
also prevent the development of chronic relapsing EAE
in vivo. It is likely that the net outcome of B7-CD28
signaling influences commitment of precursors to the
Thl or Th2 lineage and/or their mutual interaction with
each other (35), which seems to be pivotal for halting
disease progression (31-33).
Finally, Finck et a1 (24) demonstrated in lupusprone mice, a murine model resembling SLE in humans,
that treatment with murine CTLA-41g blocked autoantibody production and prolonged life, even when
treatment was delayed until the most advanced stage of
clinical illness. Although they found that the absolute
numbers of T cells ((;1>4+, CD8+) and B cells were not
altered, they did not analyze the T helper subpopulations responsible for successful treatment. Their results
suggest that 2 major obstacles of immunotherapy could
be circumvented: a host immune response to the fusion
protein could be limited by using syngeneic CTLA-4Ig,
and no prolonged depletion of effector cells was observed. These results were confirmed by Nakajima et a1
(34), using both anti-B7-l MAb and anti-B7-2 MAb.
Our observation of human CTLA-41g binding to
APC in lesional skin from patients with LE could
indicate that human CTLA-41g is feasible for repeated
B7-1, B7-2, AND CD28 EXPRESSION IN LE
A:
87-1
r
I
819
cell-lymphocyte reactions. This has often been attributed to the poor ability of epithelial cells to provide
costimulation. But even when productive CD28 engagement is provided by a stimulatory MAb, allogeneic T
cells proliferate only weakly (36). This has been confirmed in vitro in studies of a KC cell line (A431) being
transfected with B7-1 (37) and in vivo in studies of mice
made transgenic for B7-1 on KC (38). In both instances,
only a weak T cell response was observed. Thus, it
remains unclear whether in lesional skin of LE patients,
BB-1-CD28 interaction provides costimulation at all.
Nevertheless, the outcome of such interaction between
KC and T cells in LE is unpredictable. It could lead to
either stimulation of T cells or T cell anergy, which is a
desired state, since the active down-regulation and/or
transition of T cell function would help resolve the
inflammatory process (36,39).
In conclusion, our in vivo results suggest that
costimulation via members of the B7 and CD28 receptor
Figure 3. Distribution of B7-1 and B7-2 RNA in lesional versus
nonlesional skin from patients with systemic lupus erythematosus
(SLE), and in different compartments of lesional SLE skin. A and B,
Reverse transcription-polymerase chain reaction (RT-PCR) was performed as described in Figure 2. Comparing lesional and nonlesional
skin of the same SLE patient, enhanced B7-1 (A) and B7-2 (B)
RT-PCR signals were found in lesional as compared with nonlesional
skin. In contrast to biopsy samples that contained dermal and epidermal tissue, only faint B7-1 (A) and B7-2 (B) RT-PCR signals were
detectable in the epidermis isolated from the same patient.
Y
!
Y
Q
2
Y
v)
5
E
cr,
courses of therapy, and that the effects of therapy on
overall immune competence may be limited to the
duration of therapy. This may be particularly important
in human LE, which is characterized by spontaneous
remissions and relapses. Therefore, it is desirable to
develop therapeutic strategies that could be used during
periods of relapse, but which would not cause adverse
effects that might extend into periods of relative
remission.
Furthermore, we show that in affected, but not in
unaffected, skin of SLE, SCLE, and CDLE patients, KC
express BB-1, which could contribute to the activation of
CD28+ T cells in the upper dermis and epidermis. It has
been hypothesized that KC are able to function as
“nonprofessional” APC, since they are able to express
major histocompatibility complex class I1 molecules and
multiple costimulatory ligands, i.e., BB-1 (9-12,36). A
variety of investigators have noted that KC are poor
stimulators of alloreactive T cells in mixed epithelial
A:
87-1
I
B:
Figure 4. Influence of systemic therapy on B7-1 and B7-2 RNA levels
in lesional skin from patients with systemic lupus erythematosus
(SLE). A and B, Reverse transcription-polymerase chain reaction
(RT-PCR) was performed as described in Figure 2. Prior to treatment,
B7-1 (A) and B7-2 (B) RT-PCR signals were clearly detectable in SLE
lesional skin. After 1 month of systemic therapy with corticosteroids,
B7-1 (A) and B7-2 (B) RT-PCR signals were reduced. After 3 months
of treatment, no B7-1 (A) or B7-2 (B) RT-PCR signals could be
detected.
DENFELD ET AL
820
families may be important for the generation and/or
propagation of T cell activity in human LE. Thus, the
manipulation of this costimulatory pathway may provide
a powerful new target for the development of future
therapies for lupus erythematosus and other autoimmune diseases.
ACKNOWLEDGMENTS
The authors thank B. Mai and U. Voith for excellent
technical support, and Professor Dr. H. H. Peter (Freiburg,
Germany) and Dr. P. S. Linsley (Seattle, WA) for critically
discussing the manuscript.
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