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Increased interleukin-2 production in response to human type I collagen stimulation in patients with systemic sclerosis.

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580
INCREASED INTERLEUKIN-2 PRODUCTION IN
RESPONSE TO HUMAN TYPE I COLLAGEN
STIMULATION IN PATIENTS WITH
SYSTEMIC SCLEROSIS
EUGENIA HAWRYLKO, ARLENE SPERTUS, CAROL ANN MELE, NEILL OSTER,
and MARIANNE FRIERI
Peripheral blood mononuclear cells (PBMC)
from patients with systemic sclerosis (SSc) produced
increased amounts of interleukin-2 (IL-2), in a dosedependent manner, in response to stimulation with
human type I collagen, whereas PBMC from normal
subjects did not. At a dose of 50 p g human type I
collagen/106PBMC, PBMC from SSc patients (n = 17)
produced 8 times as much IL-2 as did PBMC from 16
normal subjects (P< 0.005) and 3 times as much as did
PBMC from a group of 13 rheumatoid arthritis patients
(P< 0.05). In contrast, IL-2 production by PBMC after
nonspecific stimulation with the mitogen, phytohemagglutinin, did not differ among the SSc, rheumatoid
arthritis, and normal control groups. Cell depletion
experiments indicated that the IL-%producing cells in
SSc patients are CD4+. Thus, SSc patients have CD4
cells that are specifically sensitized to human type I
collagen and can produce increased levels of IL-2.
Presented by Dr. Frieri at the 44th American Academy of
Allergy Immunology Meeting, Anaheim, CA, March 1988, and by
Dr. Spertus at the 52nd Annual Meeting of the American Rheumatism Association, Houston, TX, May 1988.
From the Department of Allergy and Immunology and the
Department of Medicine, Long Island College Hospital, Brooklyn,
and the Department of Pathology, Nassau County Medical Center,
East Meadow, New York.
Supported in part by a research grant from the Scleroderma
Society, Inc.
Eugenia Hawrylko, MD, PC: Department of Allergy and
Immunology, Long Island College Hospital; Arlene Spertus, MD:
Department of Medicine, Long Island College Hospital; Carol Ann
Mele, BA: Departinent of Allergy and Immunology, Long Island
College Hospital; Neil1 Oster, MD: Department of Pathology, Nassau County Medical Center; Marianne Frieri, PhD, MD: Department of Pathology, Nassau County Medical Center.
Address reprint requests to Eugenia Hawrylko, MD, PC,
160 East 32nd Street, New York, NY 10016.
Submitted for publication June 21, 1990; accepted in revised form November 14. 1990.
Arthritis and Rheumatism, Vol. 34, No. 5 (May 1991)
Measurement of IL-2 production stimulated by human
type I collagen may be useful in evaluating disease
activity, and further investigation of this process may
contribute to the delineation of the pathogenesis of SSc.
Scleroderma (systemic sclerosis; SSc) is a connective tissue disorder of unknown etiology, which is
associated with excess collagen production and abnormalities in humoral and cellular immunity. The early
cellular stage, with perivascular or diffuse cellular infiltrates of the dermis and subcutaneous tissue, is followed
by a fibrotic stage, with collagen deposition. Diffuse or
perivascular cellular infiltrates in the dermis or subcutaneous tissue of scleroderma patients have been shown to
predominantly consist of either T lymphocytes (1) or T
lymphocytes and monocytes (2,3).
During the progression from the early cellular
stage of SSc to the fibrotic stage, there are changes in
the type of collagen deposited (4).Antibodies to type I
and type IV collagens have been detected in the sera of
patients with SSc and have been correlated with the
presence of abnormal pulmonary diffusion capacity
( 5 ) . In contrast, rheumatoid arthritis (RA) patients
have cellular sensitivities to native types I1 and I11
collagen (6). Since the collagen contained in normal
skin is primarily type I (80% type I, 20% type 111) (4),
we used human type I collagen in devising an assay
that might have specificity for evaluating disease activity in SSc. Human type I collagen was used as the
antigenic stimulus for production of interleukin-2
(IL-2) by SSc patients, and the results were compared
with results from patients with RA and from normal
controls. The specificity of the response was also
investigated by measuring IL-2 production in both SSc
patients and RA patients after stimulation with the
TYPE I COLLAGEN-STIMULATED IL-2 PRODUCTION IN SSC
Table 1. Clinical characteristics of the systemic sclerosis patients
studied
Skin
Age1 involvePatient sex ment* Organ involvementt
2
3
4
661F
49lF
32lM
40lF
5
45lM
6
7
8
9
10
11
12
13
14
IS
49lF
62lF
60lF
49lF
S4lF
40lF
30iF
421F
321F
42lF
421F
51lF
1
16
17
CR
S
CTU
S
S
RS
CRSTU
RS
CRST
CRSTU
CRSTU
R
RSU
RS
R
RS
S
Esophagus, lung
Esophagus, lung, GI
Lung
Esophagus
Esophagus
Esophagus
Esophagus, GI
Esophagus
Lung, GI, esophagus
Esophagus
Esophagus, lung
Esophagus
Esophagus
Esophagus, kidney
-
-
Stage
Moderate
Late (generalized)
Early
Moderate
Moderate
Early
Moderate
Late (limited)
Moderate
Moderate
Diffuse
Early
Late (limited)
Early
Early
Moderate
Moderate
* C = calcinosis; R
T
t
= Raynaud’s phenomenon; S = sclerodactyly;
telangiectasias; U = ulcers.
GI = gastrointestinal tract.
=
nonspecific mitogen, phytohemagglutinin (PHA). Cell1
depletion experiments were used to identify the phenotype of the IL-2-producing cell.
PATIENTS AND METHODS
Patients and control subjects. Patients from New
York City and from Long Island were evaluated. The SSc
group consisted of 17 patients (15 women and 2 men) ranging
in age from 32 years to 66 years (mean ? SEM 46.2
2.5
years). The spectrum of disease ranged from early SSc
including the CREST variant (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias, with limited skin involvement) to an overlap
syndrome including mixed connective tissue disease, to late
diffuse disease with multiple organ involvement. Pulmonary
abnormalities included decreased carbon monoxide diffusing
capacity, restrictive lung disease, and pulmonary fibrosis.
Pertinent clinical characteristics of the patients are
shown in Table 1. Fifteen patients with thickening of the skin
met the American Rheumatism Association criteria for diagnosis of SSc (7), and 2 (patients 12 and 15) initially had only
Raynaud’s phenomenon, with subsequent progression to the
CREST syndrome. Patients were grouped according to
disease category, as follows: early disease with limited
involvement (<3 years duration), moderate or diffuse disease (affecting the face, trunk, and proximal and distal portions
of the extremities), or late disease (>5 years duration with
progressive systemic organ involvement, subdivided into late
limited or late generalized). Ofthe 17 patients, 5 were classified
as having early-stage disease, 9 had moderate or diffuse disease, and 3 had late-stage disease (Table 1).
The RA group consisted of 13 patients (10 women
*
58 1
*
and 3 men) ranging in age from 18 years to 75 years (mean
SEM 53.3 IfI 4.9 years). All 13 met the American Rheumatism Association criteria for the diagnosis of RA (8). Entry
into this study was limited to SSc and RA patients who had
not received immunosuppressive drugs, steroids, or penicillamine for at least 2 months prior to the study. One RA
patient was receiving aspirin.
Sixteen healthy adult blood donors (10 men and 6
women) served as controls. The protocol was approved by
the Long Island College Hospital and Nassau County Medical Center Institutional Review Boards, and informed consent was obtained from all subjects.
Cell culture. Peripheral blood mononuclear cells
(PBMC) were separated from heparinized blood by FicollPaque density gradient centrifugation (Pharmacia, Piscataway, NJ), washed 3 times, adjusted to a final concentration
of 1 x lo6 viable cells per ml in RPMI 1640 (MA Bioproducts, Walkersville, MD) with 2 mM L-glutamine, 100
unitdm1 penicillin, 100 p d m l streptomycin (Gibco, Grand
Island, NY), and 10% heat-inactivated fetal calf serum (FCS;
Gibco) (complete medium), and placed in a 96-well, flatbottom microtiter plate (Linbro, Flow, McLean, VA) at a
final volume of 200 pl/well. Type I collagen derived from
human placenta (Southern Biotech Association, Birmingham, AL) was added to the cultures at a final concentration
of 50 pg/ml, and PHA (Gibco) was added at a final concentration of 200 pdml. Plates were incubated at 37°C in a
humid 5% CO, atmosphere. Media controls were also included.
Cells were routinely cultured for 5 days with human
type I collagen and for 2 days with PHA. Supernatants were
harvested by centrifugation and stored in test tubes at -80°C
until assayed for IL-2.
IL-2 assay. IL-2 activity in culture supernatants was
measured by their ability to maintain an IL-2-dependent
marmoset T cell line, OH-1 (9), kindly provided by Dr.
Ronald L. Brown, NIH. Eight serial 2-fold dilutions of the
test supernatant in complete medium containing RPMI 1640,
penicillin, streptomycin, L-glutamine, and 10% FCS were
incubated with 5 X lo4 OH-1 cells in a total volume of 200 pl
in flat-bottom microtiter plates (Linbro) (9). After 20 hours in
a humid 5% CO, atmosphere at 3TC, cultures were pulsed
with 1 pCi of tritiated thymidine (3H-TdR; specific activity
6.7 Cilmmole; New England Nuclear, Boston, MA). Samples were harvested 4 hours later on a MASH cell harvester
(Skatron, Sterling, VA). 3H-TdR incorporation was counted
in a liquid scintillation counter (Beckman Instruments, San
Ramon, CA). IL-2 results were quantified by probit analysis.
IL-2 activity was expressed in units obtained from serial
dilutions of commercial human IL-2 (Cellular Products,
Buffalo, NY). Each value represents the mean of triplicate
determinations.
Cell depletion. PBMC were suspended at a concentration of lo7 viable cells/ml in complete medium containing
monoclonal antibodies OKT4 (human T helperhnducer cells)
or OKT8 (human T suppressorkytotoxic cells) (Ortho Diagnostic Systems, Raritan, NJ) for 45 minutes at 4 ° C washed
with phosphate buffered saline, resuspended, and incubated
for an additional 60 minutes at 37°C in a 1:5 dilution of
newborn rabbit serum (Accugenics, Garden Grove, CA)
selected for low cytotoxicity and high complement activity.
HAWRYLKO ET AL
582
Cells were then layered twice on heat-inactivated FCS,
centrifuged, and washed twice in complete medium before
addition to cultures at a concentration of 1 x lo6 viable
cells/ml of complete medium. Immunofluorescence studies
showed that after treatment with antibody and complement,
<4% of the cells showed positive staining.
Statistical analysis. Student's 2-tailed t-test was used
to compare differences between groups. P values less than
0.05 were considered significant.
n=13
n=17
X
X
X
i
RESULTS
Dose-response to human type I collagen. PBMC
from 6 patients with SSc and 3 normal donors were
cultured with various doses of human type I collagen,
and their IL-2 production was assayed on day 5. IL-2
:
:
'1
1 .
1
RA
Normal
ssc
Figure 2. Interleukin-2 (IL-2) production by peripheral blood
mononuclear cells from normal donors, systemic sclerosis (SSc)
patients, and rheumatoid arthritis (RA) patients, after 5 days of
culture in the absence (0)or presence (0)of 50 pg human type I
collagen. x = early-stage disease; * = late-stage disease. Horizontal
lines and shaded areas represent the mean 2 SEM.
1
1
0'
I
I
I
I
0
20
so
100
Human C o l l a g e n T y p e I (flgm)/lO
6
cell8
Figure 1. Interleukin-2 (IL-2) production by peripheral blood
mononuclear cells from 6 systemic sclerosis patients (0)and 3
normal donors (O), after 5 days of culture with various doses of
human type I collagen. Each point represents the mean of duplicate
or triplicate assays. The number at the right of each line is the
patient or control subject identification number.
production increased in a dose-dependent manner in
response to stimulation with human type I collagen in
5 of the 6 SSc patients, but not in normal subjects
(Figure 1). The 1 borderline responder in the SSc
group (patient 6) had early-stage disease and normal
lymphocyte subsets (Frieri M et al: unpublished results). On the basis of these findings, a dose of 50 pg
human type I collagen was used to stimulate IL-2
production in subsequent experiments.
Comparison of IL-2 production by SSc patients
and RA patients. Upon stimulation with human type I
collagen, PBMC from the 17 SSc patients produced an
average of 8 times as much IL-2 as did PBMC from the
16 healthy subjects (P< 0.005) and more than 3 times
as much IL-2 as did PBMC from the 13 RA patients (P
< 0.05) (Figure 2 and Table 2). The highest IL-2 values
were found in 4 patients with early-stage SSc, although
patient 6, who also had early disease, showed only a
TYPE I COLLAGEN-STIMULATED IL-2 PRODUCTION IN SSc
583
Table 2. Interleukin-2 production by peripheral blood mononuclear cells stimulated with human type I collagen*
Group
Normal
(n = 16)
Systemic sclerosis
(n = 17)
Rheumatoid arthritis
(n = 13)
60
Unstimulated
cells
P
Type I
collagenstimulated
cells
0.28 f 0.05
-
0.51 f 0.08
-
0.40 2 0.07
NS
4.06 2 1.03
cO.005
0.20
NS
1.27
5
0.05
* 0.32
n = 16
P
c0.02
n= 17
50
-E
-
%
40
u)
* Values are the
mean 5 SEM units/ml. P values are versus the
normal group, determined by Student’s 2-tailed t-test. NS = no1
significant.
.-C
X
3
:
N
I
IF
30
borderline response (1 .O units IL-2/ml); this might
reflect a lack of T cell activation. The 3 lowest values
in the SSc patients, which were similar to the values in
the normal group, were found in those with late-stage
disease. In contrast, in the RA group, the 3 patients
with disease of long duration showed the highest levels
of IL-2 production (Figure 2). Nonspecific stimulation
with the mitogen, PHA, resulted in similar levels of
IL-2 production by the normal, SSc, and RA groups
(Figure 3 and Table 3).
Phenotype of the IL->producing cells. PBMC
were depleted of CD4+ (helperhnducer) T cells and
CD8 + (suppressorkytotoxic) T cells by treatment
with anti-OKT4 and complement or anti-OKT8 and
complement, respectively, prior to culture with either
human type I collagen or PHA. Human type I collagen-stimulated IL-2 production by PBMC from SSc
patients was significantly reduced by depletion of
CD4+ cells (P < 0.05), whereas depletion of CD8+
cells had no effect (Figure 4A). Depletion of CD4+ or
CD8+ cells from normal PBMC had no significant
effect on the low levels of IL-2 produced (Figure 4A).
Thus, SSc patients appear to have CD4+ cells that are
specifically sensitized to human type I collagen. In
contrast, in PHA-stimulated cultures, depletion of
CD4-t cells significantly reduced the high levels of
IL-2 produced by PBMC from both normal subjects
and SSc patients, but CD8+ cell depletion had no
significant effect in either group (Figure 4B). Thus, the
nonspecific response to PHA by SSc patients does not
differ significantly from the response seen in normal
controls.
DISCUSSION
Our findings in the present study clearly show
that CD4+ cells from patients with scleroderma produce significantly increased amounts of interleukin-2
i
20
@
7
10
T
*
I
ssc
Normal
RA
Figure 3. Interleukin-2 (IL-2) production by peripheral blood
mononuclear cells from normal donors, systemic sclerosis (SSc)
patients, and rheumatoid arthritis (RA) patients, after 2 days of
or presence (0)of 200 ffi phytohemagculture in the absence (0)
glutinin. x = early-stage disease; * = late-stage disease. Horizontal
lines and shaded areas represent the mean f SEM.
after stimulation with human type I collagen, especially in the early stages of disease. In patients whose
disease was at a late stage, there was a negligible
Table 3. Interleukin-2 production by PHA-stimulated peripheral
blood mononuclear cells stimulated with phytohemagglutinin*
Group
Normal
(n = 16)
Systemic sclerosis
(n = 17)
Rheumatoid arthritis
(n = 13)
Unstimulated
cells
P
Phytohemagglutininstimulated
cells
0.53 2 0.12
-
16.04
f 2.04
1.04 5 0.23
NS
21.07
5
2.66
NS
0.35
NS
22.27
k
5.00
NS
2
0.12
P
-
* Values are the mean ? SEM units/ml. P values are versus the
normal group, determined by Student’s 2-tailed t-test. NS = not
significant.
584
HAWRYLKO ET AL
@ PHA
@ collagen
30-
I
25-
20.
...
..
...
..
...
....
...
..,
...
...._<
...
.. .. .,
...
...
...
...
...
*..
15.
,..
,..
. . I
*- :::;:;
...
...
10
5
T
&q ...
..
0
Normal
ssc
ssc
Normal
Figure 4. Interleukin-2(IL-2) production by peripheral blood mononuclear cells from 3 normal
donors and 3 systemic sclerosis (SSc) patients, cultured with human type I collagen (A) or
phytohemagglutinin (PHA) (B)after treatment with OKT4 and complement (a),OKT8 and
complement (U), or complement alone (0).
Values are the mean -+ SEM. * = P < 0.05
compared with cells treated with complement alone.
response, indistinguishable from that found in normal
individuals. These results differ from the findings in
RA patients, in whom there was little increase in IL-2
production except in patients with late-stage disease,
whose IL-2 values were comparable with those in SSc
patients with moderate or diffuse disease. These findings lend support to the notion that T cell activation by
human type I collagen is involved in the pathogenesis
of SSc. In contrast, nonspecific stimulation of SSc
lymphocytes with PHA resulted in levels of IL-2
production that did not differ from results in the
normal or RA groups. This enhanced production of
IL-2 by SSc PBMC stimulated by human type I
collagen, but not by the mitogen PHA, further indicates that the mechanism occurring in these patients,
and absent in normal individuals, is a sensitization to
human type I collagen as opposed to a polyclonal
activation.
The development of scleroderma-like lesions in
chronic graft-versus-host disease in rats (10) and humans (1 1,12), the modulation by lymphocytes of fibroblast proliferation and of collagen, glycosaminoglycan,
and protein synthesis (13-15), and the presence of
cutaneous or subcutaneous perivascular mononuclear
cell infiltrates with activated T cells, occurring predominantly in the early stage of the disease (2,3),
support the notion that there is an immunologically
mediated mechanism operating in SSc (for review, see
refs. 16 and 17). Since antigen presentation and T cell
activation are fundamental to the initiation of an
immunologic response, identification of the initiating
antigen(s) should facilitate the development of assays
to measure specific immunologic activation, which
would be useful for early diagnosis and monitoring of
disease activity in SSc. Although the number of patients in our study was small, our findings indicate that
sensitization to human type I collagen occurs early in
SSc but is not detectable in the chronic stage. In RA
TYPE I COLLAGEN-STIMULATED IL-2 PRODUCTION IN SSC
patients, in contrast, the response to human type I
collagen was not significant except in those with
late-stage disease. It is known that patients with
idiopathic pulmonary fibrosis have cell-mediated immunity to human type I collagen, detected by migration inhibition factor production and specific cytolytic
assays (14). Since patients with chronic RA also tendl
to develop pulmonary fibrosis, the increased IL-2
production stimulated by human type 1 collagen in our
3 RA patients with late disease may reflect the presence of pulmonary fibrosis.
The pathogenesis of scleroderma has been divided into a cellular stage characterized by a perivascular or diffuse cellular infiltration of the dermis and
subcutaneous tissue, consisting of lymphocytes and
monocytes in close proximity to fibroblasts, prior to
the stimulation of collagen production, and a fibrotic
stage associated with deposition of collagen. Normal
skin contains 80% type I collagen and 20% type 111
collagen, but in the early stage of SSc there is increased synthesis of type 111 collagen over type I,
which reverts to normal when disease activity subsides. Fibrotic tissue contains a normal proportion of
types I and 111 collagen (18). Evidence for cellmediated immunity to human skin collagen in SSc, as
demonstrated using a chemotactic assay, has been
reported (19). However, lymphocyte transformation,
as measured by 3H-TdR incorporation in response to
human collagen, was not observed (19). Earlier studies
of lymphocyte transformation by collagen have
yielded variable results, but this may be explained by
the facts that rat type I collagen, which may differ from
the human type I collagen used in our studies, was
used, that techniques differed, and that the patients’
disease stages may have differed (see refs. 1, 20, and
2 1). Increased lymphocyte blastogenesis in response
to human type I collagen in patients with early-stage
scleroderma has recently been reported (22). To our
knowledge, human type I collagen has not previously
been used to measure IL-2 production.
Our results with the nonspecific mitogen, PHA,
show no significant difference among the SSc, RA, and
normal groups in IL-2 production after PHA stimulation and are consistent with the results of some studies
(21,23,24) but differ from those of 1 study, which
showed lymphocyte proliferation in response to PHA
to be lower in SSc patients. This was attributed to
monocyte-induced inhibition, and indomethacin counteracted this inhibition (25). However, as seen in
Figure 3, our results in the SSc patients with late
585
disease clustered at the lower end of the range of
values.
Umehara et a1 demonstrated enhanced production Of IL-2 by PHA-stimulated PBMC from SSC
Patients compared with normal controls (26). HOWever, their study differed from ours in several respects,
most significantly in that indomethacin was added to
the cultures to remove putative monocytes. They
noted in their discussion that without indomethacin,
SSc patients’ IL-2 production stimulated by PHA,
although higher than that in controls, was not statistically different from control levels, results which are
consistent with ours. Alcocer-Varela et a1 (27) reported that PHA-stimulated lymphocytes from SSc
patients both produced IL-2 and responded to exogenous IL-2 to the same degree as did those from normal
subjects, also consistent with our results.
A more recent study, which measured ,total
serum IL-2, showed significantly elevated levels in
SSc patients, lower levels in RA patients, and virtually
nonexistent levels in normal subjects, using 2 assays:
an IL-2-dependent cytotoxic T cell line and a commercial enzyme-linked immunosorbent assay test kit (28).
Those investigators also demonstrated a positive correlation between the serum IL-2 level and the degree
of skin involvement (28).
How do our findings relate to the pathogenesis
of SSc? Our study is the first to show that human type
I collagen stimulates IL-2 production in patients with
SSc. There is no study showing that IL-2 can directly
cause fibroblast proliferation and/or collagen synthesis, although supernatants of antigen- or mitogenstimulated lymphocytes in vitro have been demonstrated to stimulate fibroblast collagen synthesis
(13,29,30). A likely scenario is that activated T cells
attract mononuclear cells that release soluble factors
that can recruit fibroblasts and influence the expansion
of fibroblast proliferation, which generates the extracellular matrix.
A recent study showed that transforming
growth factor p, which is expressed by activated
lymphocytes, caused marked enhancement in the production of types I and 111 collagen by cultured normal
dermal fibroblasts (31). If the sensitized lymphocyte is
key to the development of SSc, it is crucial to know
the nature of the sensitizing antigen(s). Our study is
the first to date to show that human type I collagen
stimulates IL-2, but the role of other human collagens
remains to be evaluated. If it can be documented that
SSc is an immunologically mediated disease (32), then
a multitude of diagnostic and therapeutic modalities,
HAWRYLKO ET AL
586
such as specific cytokine inhibitors or immunization
with specific T cell receptors, could become available
in the near future.
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