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Serum levels of soluble
interleukin-2 receptor in patients with ANCA-associated vasculitis
Oscar Arranz, Jordi Ara, Rosa
Rodríguez, Anna Saurina, Eduard Mirapeix, Alejandro Darnell - Nephrology
Service, Hospital Clinic, University of Barcelona, IDIBAPS, Barcelona -
Spain |
JNEPHROL 2000; 13: 59-64
ABSTRACT: Serum soluble interleukin-2 receptor (sIL-2R) concentrations
were determined using the ELISA method in 19 cases of ANCA-associated
vasculitis. These patients were classified as 7 cases of Wegener's
granulomatosis (WG) and 12 cases of microscopic polyangiitis (MPA). Elevated
levels of slL-2R were present in the sera of these patients. Levels of serum
sIL-2R were not significantly different in patients with WG and MPA either in
the active or inactive phase, so the results were expressed as a unified ANCA
associated vasculitis group. Concentrations of serum sIL-2R were significantly
higher in ANCA-associated vasculitis during the active phase than during the
inactive phase (p<0.05), and serum sIL-2R levels were significantly increased
in these patients, in the active or inactive stage, compared with a group of
healthy subjects (p<0.05). In patients with vasculitis, serum sIL-2R levels
correlated with serum levels of C-reactive protein (p<0.05). In the active
phase, concentrations of serum sIL-2R correlated to creatinine concentrations.
No correlation was found between sIL-2R and ANCA levels in any of the stages of
the disease. These findings suggest cellular immune activation in ANCA
associated vasculitis.
Key words: Soluble
interleukin-2 receptor, Vasculitis, Wegener's granulomatosis, Microscopic
polyangiitis, anti-neutrophil cytoplasmic
antibodies
Introduction
Considered an early marker of
lymphocytic activation, the interleukin-2 receptor (IL-2R) has been found in
several cell lines such as T and B lymphocytes, macrophages and natural killer
(NK) cells. The interaction of IL-2 with IL-2R leads to the stimulation of a
complex set of signal transduction pathways resulting in T cell proliferation, T
and B cell growth, generation of lymphokine-activated killer cells, and the
augmentation, proliferation and maturation of NK cells (1).
Rubin et al (2)
described a soluble form of the IL-2R (sIL-2R) which appeared in chemically
activated lymphocyte culture supernatants when IL-2R cell surface expression
began to decline. In
vivo sIL-2R increases proportionally to
the time of stimulation in peripheral blood mononuclear cells (3). The specific
role of sIL-2R in the immune response has not been fully described yet, but
recent reports showed high serum levels of sIL-2R in different autoimmune
diseases such as rheumatoid arthritis (4), primary Sjögren's syndrome (3),
systemic lupus erythematosus (4-7), Churg-Strauss syndrome (8) and Wegener's
granulomatosis (WG) (9-10).
WG, microscopic polyangiitis (MPA) and
Churg-Strauss syndrome are a group of autoimmune diseases classified as
antineutrophil cytoplasmic antibody (ANCA) associated vasculitis. Serum sIL-2R
values correlate with disease activity in WG (9-10) and in Churg-Strauss
syndrome (8) patients. Little is known about the serum sIL-2R levels in patients
with MPA (11).
The kidney in ANCA-associated vasculitis presents focal and
segmental necrotizing glomerular lesions and marked interstitial and
intraglomerular leukocyte infiltration. Renal ANCA-associated vasculitis biopsy
specimens show intraglomerular leukocyte infiltration mainly of macrophages, but
also a small number of T cells (12). In recent years, evidence of T-cell
involvement in the pathogenesis of ANCA-associated vasculitis has increased,
specially in WG (9-10) and it is reasonable to assume that parameters assessing
T-cell activity may reflect disease activity (9).
At present, the laboratory
markers considered to reflect clinical activity in ANCA-associated vasculitis
are C-reactive protein (CRP) and ANCA levels. Elevated CRP levels are a
non-specific serum indicator of inflammation and tissue damage. Their serum
concentrations may correlate closely with disease activity in patients with WG
and MPA (13-14), although the elevation of CRP is not always specifically
related to clinical activity in vasculitis. The usefulness of ANCA for
monitoring clinical activity in ANCA-associated vasculitis is controversial
because some authors find a good correlation between ANCA levels and disease
activity (15-19) while others do not (20, 21).
The aim of our study was to
clarify the correlations between serum levels of sIL-2R and disease activity in
patients with ANCA-associated small-vessel vasculitis.
Patients and methods
Patients
The sera of 19 patients with
ANCA-associated vasculitis (7 WG and 12 MPA) were analysed. The diagnosis of WG
and MPA is based on the accepted criteria of the Chappel-Hill conference (22).
All patients with kidney involvement had renal biopsy-proven vasculitis. Serum
samples were obtained in the active phase (at diagnosis) and in remission (3 to
9 months later).
All patients were treated with immunosupressive drugs
including cyclophosphamide (2 mg/kg) and steroids (1 mg/kg with subsequent
tapering) for the induction of remission and cyclophosphamide plus low doses of
steroids in the remission period. With this treatment all patients achieved
clinical remission.
ANCA in serum converted from positive to negative in all
subjects. Sera of patients in an inactive phase were obtained after this
conversion to negative. The clinical, analytical and serological features are
summarised in Table I.
From our group of 19 patients, we chose a subgroup of
five cases for a further follow-up of the disease. We obtained serum samples
from them in the active phase with positive ANCA values, in remission with
negative ANCA values, and at an intermediate stage of the disease when they had
reached clinical remission but still had positive ANCA.
Eight healthy
individuals were chosen as controls and their serum sIL-2R concentration was
analysed. None of the subjects had any obvious neoplasia, liver disease or
active infection.
TABLE I - CLINICAL FEATURES AND LEVELS OF CRP, ANCA AND
CREATININE IN PATIENTS CLASSIFIED BY DISEASE
(WG AND MPA)
|
|
WG |
MPA |
Total vasculitis |
|
Number of patients |
7 |
12 |
19 |
|
Men/Women |
2/5 |
10/2 |
12/7 |
|
Age (years) |
59.71 ± 20.73 (21-84) |
59.92 ± 11.60 (40-79) |
59.84 ± 15.01 (21-84) |
|
Organ involvement (%) |
|
|
|
|
K |
86 |
100 |
94.7 |
|
L |
57 |
0 |
21 |
|
S |
14 |
17 |
15.8 |
|
CRE (mg/dl) |
|
|
|
|
Active |
4.91 ± 4.09 |
3.88 ± 2.53 |
4.26 ± 3.12 |
|
Inactive |
2.67 ± 2.88 |
1.85 ± 1.00 |
2.15 ± 1.88 |
|
CRP (mg/dl) |
|
|
|
|
Active |
6.30 ± 4.85 |
4.25 ± 2.72 |
5.02 ± 3.65 |
|
Inactive |
0.18 ± 0.23 |
0.48 ± 0.48 |
0.37 ± 0.42 |
|
ANCA (iu/ml) |
|
|
|
|
Active |
108.57 ± 30.30 |
77.50 ± 33.69 |
88.95 ± 35.17 |
|
Inactive |
2.71 ± 2.06 |
8.33 ± 12.04 |
6.26 ±
9.88 |
The ANCA pattern was anti-PR3 in
the 7 cases of WG and anti-MPO in the 12 cases of MPA. Values are the mean+/-SD.
CRE = creatinine; CRP=C-reactive protein; ANCA=antineutrophil cytoplasmic
antibody; K=kidney; L=lung; S=skin
Vasculitis activity
Vasculitis activity was assessed with
clinical and biological parameters at diagnosis. Biological activity was
assessed by measuring the CRP serum concentration (normal values below 0.8
mg/dl). Remission was defined as absence of clinical activity, with normal CRP
levels. Renal remission was defined by the absence of microhematuria or blood
cell casts, with improved or stable renal function.
ANCA assays
Screening for ANCA was performed by
indirect immunofluorescence on ethanol-fixed human neutrophils (23). The 19
positive sera were further studied by antigenic-specific ELISA for the detection
of autoantibodies directed against proteinase 3 (PR3) or myeloperoxidase (MPO).
The ANCA determination was done in parallel with the clinical evaluation and the
determination of CRP and sIL-2R levels.
ELISA-MPO was performed as follows.
Microtiters were sensitised overnight with 0.15 µg of human MPO (Calbiochem La
Jolla, USA) at 4°C in a carbonate buffer, pH 9.6. Plates were blocked with
PBS-BSA 1% and washed twice with phosphate buffered saline (PBS)-Tween 20 0.05
%. Patients' sera and controls were tested at 1/100 dilution in PBS-Tw20-BSA (1%
BSA, 0.05% Tw20). After incubation for 1h at room temperature, a 1/1000 dilution
of goat anti-human IgG conjugated with alkaline phosphatase was applied (Dako,
Barcelona, Spain). The optical density was read at 405 nm. For quantitative
ELISA anti-PR3 we employed a commercial kit (Disprokit, Hamburg, Germany). Sera
with <10 IU were considered negative.
Quantification of CRP
Serum concentrations of CRP were
measured by a standard nephelometry method.
sIL-2R
sIL-2R were measured by sandwich ELISA
according to the manufacturer's directions (R&D Systems, Minneapolis, USA).
Briefly, microtiters plates were coated with a monoclonal antibody specific for
sIL-2R. Receptors in serum were recognised by the immobilised antibody and the
enzyme-linked polyclonal antibody specific for sIL-2R. After incubation with
alkaline phosphatase, color absorbance was read at 450 nm.
Statistical analysis
All values were expressed as mean ±
standard deviation. Student's and F-value tests were used to compare groups. The
Spearman rank coefficient was calculated to determine the correlation between
the variables studied. p-values less than 0.05 were considered signifi-cant.
Results
The mean serum levels of sIL-2R in
active and inactive disease in patients with WG and MPA are summarised in Table
II. There were no differences between WG and MPA groups (p>0.05) in the
active or remission phases. Henceforth, results are pooled as a total vasculitis
group.
TABLE II - SERUM CONCENTRATION (MEAN±SD) OF sIL-2R IN PATIENTS
WITH VASCULITIS AT THE TIME OF ACTIVITY, IN REMISSION AND IN HEALTHY CONTROLS
|
|
No. of cases sIL-2R (pg/ml)
|
sIL-2R (pg/ml) |
|
Active phase |
|
|
|
Total vasculitis |
19 |
1278.76 ± 819.34 (258.75-2852.80)
|
|
WG |
7 |
1470.40 ± 763.15 (555.67-1470.40)
|
|
MPA |
12 |
1166.97 ± 862.47 (258.75-2852.80)
|
|
Inactive phase |
|
|
|
Total vasculitis |
19 |
739.00 ± 470.32 (276.96-1799.54)
|
|
WG |
7 |
576.82 ± 349.59 (279.15-1113.26)
|
|
MPA |
12 |
833.61 ± 518.46 (276.96-1799.54)
|
|
Controls |
|
|
|
Healthy subjects |
8 |
258.06 ± 144.43 (88.38-525.47)
|
sIL-2R=soluble interleukin-2
receptor
Mean serum sIL-2R levels in the active
phase were significantly higher than in remission (p<0.05). However, in 4 of
19 cases, serum levels of sIL-2R did not diminish from the active to inactive
stage of the disease (Fig. 1).
|
 Fig. 1- Serum sIL-2R in 19 patients with active and
inactive vasculitis.
|
|
We found significant differences
between serum sIL-2R levels in the active vasculitis patients and the
control group (p<0.05) and between the inactive vasculitis group and
the controls (p<0.05) (Fig. 2).
The sera of the subgroup of five
patients were analysed in three phases of their disease. Serum levels of
sIL-2R in the active phase were higher than in the intermediate phase when
the patients were in clinical remission but with ANCA still positive
(p<0.05). sIL-2R values at the intermediate phase were not
significantly different from the clinically inactive phase with ANCA
negative (p>0.05) (Fig. 3). A slight positive correlation was observed
between serum sIL-2R and CRP levels (r=0.47, p<0.05). A significant
correlation was found between sIL-2R and creatinine concentration in the
active phase of vasculitis (r=0.6, p<0.05), but not in the inactive
phase. No relationships were observed between sIL-2R and ANCA levels in
these patients. |
Discussion
Evidence of T-cell involvement in the
pathogenesis of small-vessel vasculitis has recently increased (9, 10). Biopsy
specimens in ANCA-associated vasculitis reveal a large number of macrophages and
T lymphocytes at glomerular and interstitial locations (12), which are positive
for HLA-DR and IL-2R (12, 24) markers. Circulating T lymphocytes of WG patients
also express a high density of membrane-anchored IL-2R markers (25). It seems
that these T cells provide help for ANCA production, and several studies
have demonstrated in
vitro that the purified antigens PR3 and
MPO activate T-cells and induce their proliferation (27-30).
|
IL-2 is a cytokine mainly secreted
by T lymphocytes. It is involved in the T helper response, promoting
membrane IL-2 receptor (IL-2R) expression and T-cell proliferation. IL-2R
expression and sIL-2R release are defined features of T and B lymphocytes
involved in an immune response, although activated T cells release this
molecule to a much greater extent than B cells (31). Serum sIL-2R
concentration is therefore considered a marker of T cell activation.
Studying 19 cases of ANCA-associated vasculitis we found that mean serum
levels of sIL-2R were not significantly different in WG or MPA, reflecting
a similar pattern of sIL-2R release to serum.o we considered it more
interesting to study serum sIL-2R values in a unified ANCA-associated
vasculitis group. Mean serum sIL-2R levels were higher in the active phase
than in healthy subjects. |
|
Fig. 2- Serum sIL-2R in patients with active vasculitis (1), inactive
vasculitis (2) and in healthy donors
(3).
|
These results agree with previous
studies about sIL-2R levels in several autoimmune diseases (3, 4, 9, 32, 33).
Therefore, T cells are involved in the regulation of immunological processes in
ANCA-associated vasculitis. Moreover, sIL-2R levels of patients in remission,
with negative ANCA levels and normal CRP values, were also higher than in
controls.
These data are similar to those presented by Lai et al (11) who
consider these results as an evidence against the role of T cells in
ANCA-associated vasculitis. However, different studies reveal the importance of
the cellular immune response in autoimmune disease (6, 8), including
ANCA-associated vasculitis (9, 10, 12). We propose there is a persistent
immunological background in patients in remission. Therefore, higher serum
sIL-2R levels in remission could imply that T lymphocytes remain active because
the disease autoantigen is still present.
In general, we found that serum
sIL-2R levels decreased from the active phase to remission and we observed a
slight positive correlation between serum sIL-2R and CRP levels. These results
suggest that changes in serum sIL-2R may reflect disease activity in patients
with ANCA-associated vasculitis. In addition, no differences were found between
serum levels of sIL-2R in patients in the inactive phase with positive ANCA and
several months later in the inactive phase when they had achieved ANCA
seroconversion, suggesting a better correlation between serum sIL-2R values and
disease activity than ANCA levels.
|
Fig. 3 - Serum sIL-2R in five
patients with vasculitis during the active phase with positive ANCA,
during the inactive phase with positive ANCA, and during the inactive
phase, with negative ANCA.
|
|
Danielli et al (34) studied a
group of SLE patients where serum sIL-2R was apparently more accurate than
the usual immunological parameters (ANA, anti-dsDNA antibodies, anti-Sm
antibody, low serum complement C4 fraction) in indicating the activity and
severity of the disease. Wolf et al (6) found similar results for SLE.
However, the usefulness of serum sIL-2R levels as a marker of clinical
activity in vasculitis is problematic because they may be increased in a
number of diseases, including infections. Moreover, 21% of our patients
had higher levels of serum sIL-2R in the inactive phase than in the active
phase of the disease, although we confirmed that they had no infection.
ANCA is a good marker for diagnosis in several forms of small-vessel
vasculitis, such as WG, MPA or idiopathic rapidly progressive
glomerulonephritis and it keeps high sensitivity and specificity in these
diseases (35). |
In contrast to sIL-2R, which is released
by T and other cell lines (2), ANCA are exclusively secreted by B lymphocytes.
We did not find any correlation between ANCA and sIL-2R levels in our vasculitis
patients, reflecting the presence of different immunological mechanisms
associated to disease activation.
The measurable levels of serum sIL-2R
reflect their balance between synthesis, release to serum from cells, and
clearance. Although we have some knowledge about synthesis and release of
sIL-2R, little is known about their clearance. Previous studies reported that
serum sIL-2R levels correlated with serum creatinine in crescentic
glomerulonephritis, reflecting, at least in part, local immune activation and
IL-2R induction on T cells within damaged glomeruli (24). This is in accordance
with our finding of a significant positive correlation between sIL-2R values and
creatinine concentration in the active phase in vasculitis patients with renal
failure. In the light of the high molecular weight of peripheral mononuclear
blood cell IL-2R (2), it is assumed that the released form of this molecule,
sIL-2R, cannot pass through the basement membrane and therefore cannot be
cleared by renal filtration.
In conclusion, similar levels of sIL-2R are
found in patients with WG or MPA in the active or inactive phase. Patients with
vasculitis have higher serum sIL-2R concentrations in the active phase than in
the inactive phase, suggesting a cellular immune response. Finally, sIL-2R
levels, are higher in the remission phase of vasculitis than in healthy
subjects. Some immunological background activity is therefore possible in these
patients. However, in order to check these data, it would be interesting to make
serial measurements of serum sIL-2R in patients with ANCA-associated vasculitis.
Reprints requests to: Oscar Arranz
Linuesa, M.D. - Nephrology
Service Hospital Clínic Barcelona C/Villarroel
170 08036 Barcelona, Spain arranz@medicina.ub.es
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Received: July 05,
1999 Revised: October 01, 1999
Accepted: November 18, 1999