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Elevated expression of 1 and 2 integrins intercellular adhesion molecule 1 and endothelial leukocyte adhesion molecule 1 in the skin of patients with systemic sclerosis of recent onset.

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290
AND p2 INTEGRINS,
ELEVATED EXPRESSION OF
INTERCELLULAR ADHESION MOLECULE 1, AND
ENDOTHELIAL LEUKOCYTE ADHESION
MOLECULE 1 IN THE SKIN OF PATIENTS WITH
SYSTEMIC SCLEROSIS OF RECENT ONSET
STEPHAN SOLLBERG, JUHA PELTONEN, JOUNI UITTO. and SERGIO A. JIMENEZ
Objective. To investigate the possible role of
integrins and cell adhesion molecules in the pathogenesis
of the mononuclear cell infiltration and fibrosis of skin
that occurs in systemic sclerosis (SSc).
Methods. The presence and topographic distribution of pl, p2, and p4integrins, as well as of endothelial
leukocyte adhesion molecule 1 (ELAM-1) and intercellular adhesion molecule 1 (ICAM-l), was examined
immunohistochemically in affected skin from 8 patients
with rapidly progressive SSc of recent onset. The
expression of the p, integrin gene was also investigated
by in situ hybridization with a human sequence-specific
complementary DNA.
Results. The presence of p, integrin epitopes and
the corresponding messenger RNA within inflammatory
cells surrounding small vessels was demonstrated in SSc
skin but not in normal skin. Lymphocytes positive for pz
integrin were also found only in SSc skin, and they
appeared in close proximity to small blood vessels and
collagen bundles. Immunostaining for p4 integrin
._.
From the Department of Dermatology, the Department of
Medicine. and the Department of Biochemistry and Molecular
Biology, Jefferson Medical College, Thomas Jefferson University,
Philadelphia, Pennsylvania.
Supported in part by NIH grants AR-19101 and GM-28833,
by the Finnish Academy of Sciences, and by the Finnish Cultural
Fund. Dr. Sollberg’s work was supported by a grant from the
“Deutsche Forschungsgemeinschaft” (Germany, So 239/1-I).
Stephan Sollberg, MD: Department of Dermatology; Juha
Peltonen, MD, PhD: Department of Dermatology; Jouni Uitto, MD,
PhD: Department of Dermatology and Department of Biochemistry
and Molecular Biology; Sergio A. Jimenez, MD: Department of
Medicine and Department of Biochemistry and Molecular Biology.
Address reprint requests to Sergio A. Jimenez, MD, Thomas Jefferson University, SO9 Bluemle Life Sciences Building, 233
South 10th Street, Philadelphia, PA 19107.
Submitted for publication January 15, 1991; accepted October 31, 1991.
Arthritis and Rheumatism, Vol. 35, No. 3 (March 1992)
epitopes revealed no differences between normal and
SSc skin. ELAM-1 and ICAM-1 monoclonal antibodies,
which identify epitopes indicative of endothelial cell
activation, stained endothelial cells in SSc skin but not
normal skin.
Conclusion. These observations suggest that the
complex interactions of pl and p2 integrins, as well as
ELAM-1 and ICAM-I, may be intimately involved in
the pathogenesis of SSc, perhaps by mediating the
homing and targeting of pathogenetic lymphocytes to
the affected tissues.
A variety of important biologic processes, such
as embryonic development and differentiation, morphogenesis, and tissue remodeling associated with
repair reactions, require a precisely coordinated migration of cells, their attachment to the extracellular
matrix, and their interaction with homotypic or heterotypic cells in the surrounding tissues. These cellcell and cell-matrix interactions are mediated by a
large family of proteins endowed with highly specific
adhesive properties that permit the homing, localization, and anchorage of specific cell types to a given
tissue (for review, see refs. 1-3). In addition to the
important role that the adhesion proteins play in
normal biologic processes, it has recently become
apparent that these cell adhesion molecules are intimately involved in various inflammatory and immunologically mediated reactions and may be responsible,
at least in part, for the accumulation of inflammatory
cells in the affected tissues (for review, see ref. 4).
Among the large number of cell adhesion molecules described to date, the integrins represent the
most versatile and widely distributed group, being
responsible both for cell-cell and for cell-matrix inter-
INTEGRINS AND CELL ADHESION MOLECULES IN SSc
29 1
Table 1. Clinical characteristics of the systemic sclerosis patients studied
Skin involvement
Patient
Agelsex
1
56lF
2
3
4
45lM
Duration
(months)
Progression
33
22
20
50
6
401F
35lF
46lF
41lF
7
49lM
2
3
4
5
5
5
9
8
41lF
11
5
(%)*
43
53
23
19
System involvementt
Raynaud’s
phenomenon
Musculoskeletal
Gastrointestinal
+
+
+
+
+
+
+
+
+
-
++
+
+
+
-
+
+
+
+
Pulmonary
~
-
+
+
-
Cardiac
Renal
-
-
-
+
~
~
-
+
+
* Increase in the percentage of body surface affected during the 6 months preceding skin biopsy.
t Determined according to criteria described in ref. 10.
actions (for review, see refs. 1-6). They comprise a
superfamily of closely related dimeric glycoproteins,
each containing 1 a and 1 p subunit, noncovalently
bound to each other. The p subunits confer class
specificity to the integrins, and at least 5 subfamilies
have been identified, each containing 1 specific p
subunit (pI-p5).
Recent evidence suggests that PI integrins may
be involved in adhesion of lymphocytes to activated
endothelial cells, as exemplified by the binding of ~y4p1
integrin to the endothelial cell surface protein V cell
adhesion molecule I (VCAM-I), a member of the
immunoglobulin superfamily (for review, see ref. 3).
The p2 integrins are restricted to white blood cells and
play a role in leukocyte-leukocyte and in leukocyteendothelial cell interactions. The ligand for the lymphocyte integrin leukocyte function-associated antigen 1 (LFA-1) (aL&) is the glycoprotein intercellular
adhesion molecule 1 (ICAM-I), also a member of the
immunoglobulin superfamily . In general, the expression of ICAM-1 on various cell types is very low or
undetectable. However, during inflammation or following exposure to cytokines, high levels of ICAM-1
are produced by inflammatory epithelial and endothelial cells (for review, see ref. 3). Endothelial leukocyte
adhesion molecule 1 (ELAM-I), a member of the
selectin family, has been found to be inducible by
interleukin-1 , tumor necrosis factor a, or bacterial
lipopolysaccharides (7,8). It is believed to play an
important role in adhesion and extravasation of neutropbils, as well as in skin-homing of T lymphocytes at
sites of acute and chronic inflammation (7,8).
The critical role that the cell adhesion molecules play in the migration of activated lymphocytes
across endothelium and basement membranes, and in
their adherence to tissues where putative antigens are
nested, prompted us to study the expression and tissue
localization of these molecules in the skin of patients
with systemic sclerosis (SSc), a disease in which
accumulation of activated T lymphocyte subsets in
close topographic proximity to activated fibroblasts
has been demonstrated (9). We examined the expression and topographic distribution of epitopes for the
p,, p2, and p4 integrins, as well as for ICAM-1 and
ELAM-1, in dermal and epidermal tissue of patients
with early SSc, by immunohistochemical analysis using specific monoclonal antibodies. We also investigated the expression of the p1integrin subunit gene by
in situ hybridization with a specific complementary
DNA (cDNA).
PATIENTS AND METHODS
Patients. Eight patients with diffuse SSc of recent
onset (<12 months), rapid progression of skin sclerosis, and
truncal skin involvement (as described previously [lo]) were
studied (Table 1). All fulfilled the American College of
Rheumatology (formerly, the American Rheumatism Association) criteria for the classification of SSc ( l l ) , and none
were receiving D-penicillamine, corticosteroids, or immunosuppressive agents. Antinuclear antibodies, demonstrated
by immunofluorescence, were present in the sera of all
patients, in titers ranging from 1:160 to 1:2,560. Antitopoisomerase I (Scl-70) antibodies were present in only 2
patients (patients 4 and 5 ) . Anticentromere antibodies were
not detected in the sera of any of the patients.
Indirect immunofluorescence technique. Full-thickness excisional skin biopsies were obtained from the leading
edge of dorsal forearm lesions of the 8 SSc patients and from
site-matched skin from 4 healthy subjects, and were fixed
immediately in liquid nitrogen. For indirect immunofluorescence, 5 pm-thick frozen sections were rinsed with Tris
buffered saline (TBS; pH 7.6), and preincubated for at least
15 minutes in TBS containing 1% bovine serum albumin
(BSA) to block nonspecific binding.
The samples were then exposed to the following
292
SOLLBERG ET AL
Figure 1. lmmunodetection of p, and p4 integrin epitopes in normal skin and in affected skin from a patient with systemic sclerosis (SSc)
(patient 5 ) . A, Photomicrograph of hematoxylin-stained SSc skin. Note the presence of inflammatory cell infiltrates (arrows). B, lmmunofluorescence staining of SSc skin with a monoclonal antibody for p, inteprin epitopes. Note the intense staining reaction in association with
inflammatory cell infiltrates (solid arrows). Staining is also present on basal and suprabasal keratinocytes, and at the basal keratinocytehasement membrane interface (open arrows) e = epidermis. C,lmmunofluorescence staining of SSc skin with a monoclonal antibody for p4
inteprin epitopes. Note the linear staining at the area of the dermalepidennal basement membrane (openarrows) and on endothelial cells (solid
arrow), and the absence of staining within the dermal matrix. D, Higher magnification of immunofluorescence-stained inflammatory cell
infiltrates in SSc skin (solid arrows), using antibodies for p, integrin epitopes. The presence of p, integrin epitopes between collagen bundles
is yeen (open arrow). E,lmmunofluorescence staining of normal skin with a monoclonal antibody for PI integrin epitopes. Staining of the basal
and suprabasal keratinocytes. as well as at the basal keratinocyte-basement interface (open arrows) and on endothelial cells (solid arrows), is
seen. F, Immiinofluorescence staining of normal skin with a monoclonal antibody for p., integrin epitopes. Linear staining at the area of the
dermal-epidermd hasement membrane (open arrows), as well as on endothelial cells (solid arrows), is seen. (Bars = 300 pm except in D,where
bar = 75 p m . )
INTEGRINS AND CELL ADHESION MOLECULES IN SSc
Figure 2. Detection of p, integrin epitopes and messenger RNA in
affected skin from a patient with systemic sclerosis (SSc) (patient 5 ) .
The presence of p, epitopes is demonstrated by the brownish
precipitates of diaminobenzidine stain in the basal keratinocytes of
the epidermis (A) (arrows) and hair follicle (B) (arrows),and on
endothelial cells (C) (black arrows). Identical results were found in
normal skin. In contrast, only affected SSc skin contained inflammatory cell infiltrates, which expressed abundant p, integrin
epitopes (C) (white arrows). In situ hybridization with a p, integrin
complementary DNA revealed the presence of autoradiographically
detectable grains (D) (arrows) within the inflammatory cell infiltrate
shown in C. (Bars = 100 I.Lm in A and B;bar = 50 p n in C and D.)
monoclonal antibodies: 1) a rat monoclonal antibody that
recognizes the human p, integrin subunit (antibody 13) (12);
2) mouse monoclonal anti-p2 integrin antibody (catalog no.
293
A050; Telios Pharmaceuticals, San Diego, CA); 3) a mouse
monoclonal antibody that recognizes p4 integrin epitopes
(3Ei) (13). This antibody has been shown to stain epithelial
basement membranes, and its specificity has been demonstrated by immunoprecipitation of the a6p4 complex from
choriocarcinoma and colon carcinoma cells (Holmes E,
Engvall E: manuscript in preparation); 4) mouse monoclonal
anti-ELAM-l antibodies (catalog no. BBAl; R & D Systems, Minneapolis, MN); 5 ) mouse monoclonal antiICAM-1 antibodies (catalog no. BBA3; R & D Systems).
The sections were then washed for 60 minutes in 5
changes of TBS, and incubated with tetramethylrhodamine
isothiocyanate (TRITCfionjugated goat anti-rat or antimouse IgG secondary antibodies (Miles, Elkhart, IN). After
a 60-minute incubation at room temperature, the sections
were washed for 60 minutes in 5 changes of TBS, rinsed with
distilled water, air dried, mounted with Fluoromount (Fisher
Scientific, Pittsburgh, PA), and examined with a fluorescence microscope (Optiphot; Nikon, Garden City, NY)
equipped with filters for detection of TRITC. Representative
sections were photographed using Tri-X film (Eastman
Kodak, Rochester, NY). In control reactions, the primary
antibody was omitted or replaced with sera from nonimmunized animals.
Peroxidase-antiperoxidase immunostaining. Peroxidase-antiperoxidase (PAP) immunostaining was performed
using a slight modification of the method previously described in detail (14). Briefly, 5 pm-thick sections were
incubated in 0.01M HCI containing 10 units/ml pepsin (Sigma, St. Louis, MO). Endogenous peroxidase activity was
blocked by incubating the sections in 0.3% H,02 in methyl
alcohol. To prevent nonspecific antibody binding, the sections were preincubated for 30 minutes in a solution containing 1% BSA. For immunostaining, sections were first incubated with the anti-human p, integrin rat monoclonal
antibody described above. Swine anti-rat antiserum (Accurate Chemical & Scientific, Westbury, NY) was then used as
the linking antibody, and the sections were incubated with
rabbit PAP (Accurate Chemical & Scientific). Peroxidase
activity was detected by incubation with 3,3'-diaminobenzidine tetrahydrochloride (DAB; Eastman Kodak) in 0.01%
H@2*
In situ hybridization. Five micrometer-thick cryosections were cut from the snap-frozen biopsy samples, postfixed immediately with fresh 4% paraformaldehyde in phosphate buffered saline for 20 minutes, and pretreated as
described previously (15,16). The samples were prehybridized overnight, and then hybridized for 16 hours at 42°C in a
solution containing 0.1 pg/ml of 32P-labeled cDNA (specific
activity -1 x lo9 counts per minute/@, 50% formamide, 10
mM dithiothreitol, 1 mg/ml BSA, 0.6M NaCI, 10% (weight/
volume) dextran sulfate, 200 p g h l denatured and sheared
salmon sperm DNA, 0.5 mM EDTA, 0.02% (w/v) Ficoll, 0.02%
( w h ) polyvinyl pyrrolidone, and 10 mM Tris-HC1, pH 7.4.
After hybridization, the samples were washed to a
final stringency of 0.2X SSC ( l x SSC = 0.15M NaCl and
O.015M sodium citrate) at 42°C. The human p, integrin
cDNA utilized was obtained commercially (catalog no.
D003; Telios Pharmaceuticals). 32P-cDNA-messenger RNA
hybrids were detected by immersing the samples into Kodak
N T B J autoradiography emulsion diluted with an equal
volume of 0.6M ammonium acetate, and exposing them in a
294
SOLLBERG ET AL
Figure 3. lmmunodetection of pI and p4 integrin epitopes on an eccrine sweat gland and a hair follicle in affected skin from a patient with
systemic sclerosis (patient 3). A, Photomicrograph (black arrows show eccrine sweat glands), B, p, integrin epitope staining (arrows), and C,
p4integrin epitope staining (arrows) of eccrine sweat gland. D, Photomicrograph. E, PI integrin epitope staining (arrows). and F, p4integrin
epitope staining (arrows) of hair follicle. Identical results were found in normal skin. (Bars = 100 wm.)
desiccant-containing box for 10 days at 4°C. The samples
were developed with Kodak D-19 developer, stained with
hematoxylin, dehydrated with ethanol, cleared in xylene,
and mounted.
RESULTS
To characterize the distribution of p, integrins,
normal and SSc skin sections were stained with a rat
INTEGRINS AND CELL ADHESION MOLECULES IN SSc
295
Table 2. Semiquantitative analysis of the intensity of specific immunostainings of skin biopsy specimens from systemic sclerosis (SSc)
patients and healthy controls*
Endothelial cells
Plt
SSc patients
1
2
3
4
5
6
7
8
Controls
1
2
3
4
+++
+
++
+++
++
+++
+++
++
-
+
-
+
a
-
ND
-
ND
ND
-
Perivascular infiltrates
P4t
ELAM- 1
ICAM-I
Plt
a
P4t
+
+
+
+
+
+
+
+
+
+
+
+
++
++
+++
ND
++
++
++
+++
+
++
+++
++
+++
+++
++
++
-
-
-
ND
-
++
++
ND
++
++
ND
ND
ND
ND
-
-
-
+$
-
-
+
+
ND
+
++
-
ELAM- I
ICAM- I
-
-
-
-
ND
ND
-
ND
ND
ND
ND
ND
-
-
-
-
-
-
* ELAM-I = endothelial leukocyte adhesion molecule I ;ICAM-I = intercellular adhesion molecule I ; N D = not done, because of insufficient
tissue. Staining was graded - (absent), + (mild), + + (moderate), or + + + (strong).
t These patterns were observed in addition to the normal staining of basal keratinocytes, which was present in samples from all SSc patients
and all healthy controls (see Results).
$ In a second experiment, these signals were not detected after prolonged blocking of nonspecific binding with I% bovine serum albumin in I x
Tris buffered saline.
monoclonal antibody recognizing the extracellular domain of the p, integrin subunit. Intense epidermal
staining of basal and suprabasal keratinocytes and
along the surface of the basal cells apposing the
dermal-epidermal basement membrane was observed
in normal (Figure 1E) and SSc skin (Figures 1B and
2A). These results were similar to those recently
described for normal skin (17,18). Intense staining for
pl integrin epitopes was also observed on eccrine
sweat glands and along the basal cell layers of hair
follicles (Figures 2B, 3B, and 3E). In addition, most of
the dermal blood vessels showed the presence of p1
integrin epitopes, apparently localized in endothelial
cells (Figures IB, lE, and 2C). However, only SSc
skin samples showed the presence of PI integrin
epitopes in areas of perivascular lymphoid cell accumulation (Table 2 and Figures IB, lD, and 2C) and
between collagen bundles, apparently in association
with resident fibroblasts (Figure ID).
The specificity of these findings was established
by the absence of staining in perivascular infiltrates in
normal control specimens treated with the same antibody (Figure lE), and in normal control and SSc skin
samples when the first antibody was omitted. Furthermore, the pattern of immunostaining using p., integrin
antibodies was markedly different, as detailed below.
When the tissue distribution of p4 integrin
epitopes was examined, no differences between normal and SSc skin were demonstrated. As shown in
Figures IC, lF, 3C, and 3F, intense staining was
observed in control and SSc tissues in the basement
membranes at the dermal-epidermal junction and
within blood vessel walls, as well as surrounding the
eccrine sweat glands and hair follicles.
In situ hybridization with a human p1integrin
cDNA was performed using serial sections of the same
specimens used for immunostaining. These studies
showed positive hybridization signals exclusively in
the perivascular inflammatory cell infiltrates in SSc
skin samples, with the same localization as the p,
integrin epitopes (Figure 2D). The level of expression
of the pI integrin gene in the perivascular regions was
very high, as indicated by the absence of detectable
hybridization signals in the basal keratinocytes, which
are known to express low levels of transcripts for p,
integrin. No positive hybridization signals were detectable in 2 samples of normal skin examined in
parallel with the SSc samples. Furthermore, we did
not detect expression of the PI integrin gene in fibroblasts.
lmmunofluorescence staining using ELAM- 1
and ICAM-1 monoclonal antibodies clearly showed
the presence of the corresponding epitopes on endothelial cells in all SSc skin samples investigated. The
staining patterns were similar with both antibodies
(Figures 4A and 4C and Table 2). In contrast, neither
ELAM-1 nor ICAM-1 epitopes were detected in normal skin specimens that were processed in parallel,
296
SOLLBERG ET AL
Figure 4. lmmunodetection of endothelial leukocyte adhesion molecule 1 (ELAM-1). intercellular adhesion molecule 1 (ICAM-I), and p2
integrin epitopes in normal skin and in affected skin from a patient with systemic sclerosis (SSc) (patient 5 ) . Note the presence of activated
endothelial cells in SSc skin, as detected by ELAM-I antibody (A) (arrow) and ICAM-1 antibody (C) (arrow). The staining patterns obtained
with the 2 antibodies are similar. Also note p2 integrin epitopes, detectable only on small lymphocytes in SSc skin (arrows), in close proximity
to collagen bundles and blood vessels (+) (E). Staining of normal human skin with antibodies to ELAM-I (B), ICAM-1 (D), and
integrins (F)
gave negative results. (Bars = 300 pm; e = epidermis.)
INTEGRINS AND CELL ADHESION MOLECULES IN SSc
under identical experimental conditions (Figures 4B
and 4D and Table 2). It is possible that ICAM-I
present in other cell types (i.e., mononuclear cells and
adjacent fibroblasts) also contributed to the positive
immunostaining obtained with ICAM- 1 antibodies in
SSc skin, because the staining pattern with this particular antibody appeared slightly diffuse (Figure 4C).
Staining of SSc skin with pZ integrin antibodies revealed the presence of only a few positive cells,
apparently small lymphocytes (Figure 4E and Table 2).
These cells were scattered around smaller blood vessels in the upper dermis and between collagen bundles
in the upper and deeper dermis. No PZ staining was
found in healthy control skin (Figure 4F and Table 2).
DISCUSSION
SSc is a connective tissue disease of unknown
etiology, characterized by excessive collagen deposition in the skin and various internal organs (19,20).
Accumulation of inflammatory mononuclear cells is
frequently found in early cutaneous and visceral SSc
lesions (9,21). The close topographic and temporal
relationship between inflammatory cells and fibroblasts in affected SSc tissues suggests that interactions
between these cells may play a pathogenetic role in the
development of the fibrotic lesions that are the hallmark of the disease. However, the mechanisms that
result in the accumulation of mononuclear cells in
affected skin and visceral organs in SSc are not currently known.
The critical role that integrins and other adhesion molecules play in lymphocyte migration, tissue
localization, and adherence to the extracellular matrix
has been recently recognized (for review, see refs.
1-4). Furthermore, it has become apparent that cell
adhesion proteins are intimately involved in the pathogenesis of a variety of pathologic conditions, including
inflammation and immune-mediated tissue damage (for
review, see ref. 4). The results of the present study
demonstrate the accumulation of abundant amounts of
PI integrin epitopes in the perivascular inflammatory
infiltrates of SSc skin, but not in normal control skin.
Furthermore, in SSc skin, PI integrin epitopes were
observed scattered between collagen bundles, suggesting that these molecules were produced by resident
fibroblasts.
Clark (22) described an up-regulation of p,
integrin expression by fibroblasts in skin wounds during active tissue remodeling. The inflammatory reaction of SSc skin seems to involve a similar phenome-
297
non. Because there were no differences in the intensity
or topographic distribution of P4 epitopes between
normal skin and skin from SSc patients, the appearance of PI epitopes in perivascular cellular infiltrates
of SSc skin suggests that PI integrins may play an
important pathogenetic role in early SSc lesions. Furthermore, active expression of the PI integrin gene
was found only in perivascular inflammatory cell infiltrates in affected SSc tissues.
Positive immunostaining with monoclonal antibodies specific for the ELAM-I and ICAM-I cell
adhesion proteins was also found on endothelial cells
in SSc skin but not in normal skin. It is generally
accepted that the expression of these 2 proteins is
indicative of the presence of activated endothelial cells
(for review, see ref. 3). Our results suggest that
ICAM-1 epitopes in SSc skin are also present in cells
other than endothelial cells (i.e., mononuclear cells
and adjacent fibroblasts). These findings are conhistent
with previous observations that SSc fibroblasts display
increased expression of ICAM-1 in vitro (23). The
presence of ELAM-I and ICAM-1 epitopes on endothelial cells, coupled with the expression of pZ integrin
epitopes on lymphocytes in SSc skin but not in normal
skin, suggests that these molecules may be responsible
for the adhesion of pathogenetic lymphocytes to activated endothelial cells. We conclude that the elevated
expression of PI and Pz integrins and ICAM-I and
ELAM-1 adhesion proteins may be responsible for the
homing of pathogenetic lymphocytes to skin and their
adhesion to endothelial cells and that this sequence of
events may be of critical importance in the development of the early pathologic changes of SSc.
ACKNOWLEDGMENTS
We thank Leslie Wright for expert technical assistance and Verna Summers and Meredith Billman for assistance in the preparation of the manuscript. Dr. Eva Engvall,
La Jolla Cancer Research Foundation, kindly provided the
monoclonal antibodies to p4integrin.
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