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T cytotoxic and helper cells are markedly increased and t suppressor and inducer cells are markedly decreased in rheumatoid synovial fluids.

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737
T CYTOTOXIC AND HELPER CELLS ARE MARKEDLY
INCREASED, AND T SUPPRESSOR AND INDUCER
CELLS ARE MARKEDLY DECREASED, IN
RHEUMATOID SYNOVIAL FLUIDS
MAKOTO GOTO, TERUMASA MIYAMQTO, KUSU KI NISHIOKA, and SHOJI UCHIDA
Synovial fluid lymphocytes and paired peripheral
blood lymphocytes from 28 patients with rheumatoid
arthritis were analyzed by 2-dimensional flow cytometry. We found that the composition of the lymphocyte
population is different in synovial fluid compared with
that in peripheral blood, in that there were increased
proportions of Ia+ Leu-2a+/Leu-15- (T cytotoxic) cells
and Leu-3a+/Leu-8- (T helper) cells, together with
marked decreases in Leu-2a+/Leu-15 (T suppressor)
cells and Leu3a+/Leu3+ (T inducer) cells. These
findings suggest that the unique composition of synovial
fluid lymphocytes might be the result of T cell activation
by some mechanism that is not known.
+
Determination of the precise distribution of
well-defined lymphocyte subpopulations at the site of
an immune reaction might provide clues about destructive activity in the diseased area. With advances
in technology, including monoclonal antibodies
(MAbs) and flow cytometry, we are now able to
analyze lymphocyte subpopulations in better detail.
-__
From the Department of Medicine and Physical Therapy.
Faculty of Medicine, University of Tokyo, the Rheumatology Clinical Center, Tokyo Women’s Medical College, and the Division of
Rheumatic Diseases, Tokyo Metropolitan Bokuto Hospital, Tokyo,
Japan.
Makoto Goto, MD: Department of Medicine and Physical
Therapy, Faculty of Medicine, University of Tokyo; Terumasa
Miyarnoto, MD: Department of Medicine and Physical Therapy,
Faculty of Medicine, University of Tokyo; Kusuki Nishioka, MD:
Rheurnatology Clinical Center, Tokyo Women’s Medical College;
Shoji Uchida, MD: Division of Rheumatic Diseases, Tokyo Metropolitan Bokuto Hospital.
Address reprint requests to Dr. M. Goto, Department of
Medicine and Physical Therapy, Faculty of Medicine, University of
Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.
Submitted for publication August 12, 1986; accepted in
revised form January 28, 1987.
Arthritis and Rheumatism, Vol. 30, No. 7 (July 1987)
For example, T suppressor cells (Leu-2a+/Leu-15+)
can be distinguished from T cytotoxic cells (Leu2a+/Leu-15-) in the Leu-2a+ fraction by use of a
combination of Leu-2a and Leu-15 MAbs (1). T helper
cells are found in the Leu-3a+/Leu-8- fraction, and T
inducer cells are part of the Leu-3a+/Leu-8+ subset (2).
Despite intensive investigation, the etiology of
rheumatoid arthritis (RA) is still not known (3). We
have recently demonstrated that there is a marked
decrease in Leu-2a+/Leu-15+ cells in the peripheral
blood lymphocytes (PBL) of patients with active RA,
and that there is a significant inverse correlation
between the percentage of Leu-2a+/Leu-15+ cells and
RA disease activity as evaluated by the Lansbury
index (4). However, RA is primarily a disease of the
joints, and levels of PBL may not be an appropriate
index for such disease activity. Immunocompetent
cells and their products are abundant in the synovial
fluid (SF). Most are polymorphonuclear cells, but
15-2096 are mononuclear. Of these, T cells predominate (--90%).
In this paper, we describe our studies of the T
lymphocyte subpopulations in PB and SF samples
taken from patients with RA. We noted a significant
decrease in T suppressor and T inducer cells, and an
increase in T cytotoxic and T helper cells in RA SF.
There was also marked enhancement of activated T
cells (Ideu-4+/HLA-DR+) in all RA patients tested. A
significant correlation was found between the percentage of ta+ T cells and the percentage of Leu-2a+/Leu15- cells in RA SF. Furthermore, a significant inverse
correlation was observed between the percentage of T
cytotoxic cells and that of T helper cells in SF lymphocytes (SFL), which may indicate that the anti-
738
GOT0 ET AL
gen(s) at which the activated SF T cytotoxic cells are
directed is possibly on the T helper cell.
PATIENTS AND METHODS
Study population. Synovial fluid was obtained by
arthrocentesis from 34 patients (4 men and 30 women) who
had definite or classic RA (5). Their ages ranged from 22-75,
with a mean age ( i S D ) of 41.8 2 16.8. Peripheral blood
samples were obtained from 28 of the patients (24 women
and 4 men) at the time of arthrocentesis, so that the
difference between SFL and PBL in the same subject could
be assessed. At the time of evaluation, all patients had been
treated with nonsteroidal antiinflammatory agents. In addition, 10 patients were receiving 100-300 mg of D-penicillamine daily. No patient had received an intraarticular injection of steroid within 1 month before the study.
RA disease activity was monitored by use of the
Lansbury index (6). In this study, the index included the
duration of morning stiffness, erythrocyte sedimentation
rate, grip strength, and joint score. The mean 2 SD level of
disease activity in this series of RA patients was 55.3 i
19.1% (range 18-95).
Sixty-nine apparently healthy, age- and sex-matched
subjects (59 women and 10 men) served as controls for the
PBL studies. Their mean age (+SD) was 41.7 i 17.0. Four
patients who had osteoarthritis (OA) (2 women and 2 men)
also served as controls for both the SFL and the PBL
studies. Their ages ranged from 43-73.
Purification of lymphocytes. SFL were purified using
a method previously described (7). Briefly, heparinized S F
was treated with hyaluronidase to reduce viscosity, and the
remaining large aggregates were removed through a nylonmesh filter. The purified SFL were obtained using a FicollHypaque (Pharmacia, Uppsala, Sweden) centrifugation procedure, as described elsewhere (8). Contamination by
% positive
cells
PBL
SFL
control (n =69)
R A (n=28)
Figure 1. Percentage of Leu-4+/HLA-DR+ cells in peripheral
blood lymphocytes (PBL) of control subjects, and in PBL and
simultaneously obtained synovial fluid lymphocytes (SFL) of pa-
tients with rheumatoid arthritis (RA). A line connects the PBL and
SFL values of each RA patient. Values are mean k SD (see Patients
and Methods for details).
(r=O.65, P<O.Ol)
0‘
I
I
I
I
I
20
40
60
80
100
Lansbury’s activity index (%)
Figure 2. Correlation between the level of rheumatoid arthritis
(RA) disease activity (measured by the Lansbury index) and the
percentage of Leu-4+1HLA-DR+ cells in RA synovial fluid lymphocytes. The mean ( S D ) disease activity level was 55.3 -t 19.1%
(range 18-95) (see Patients and Methods for details).
nonlymphoid cells was assessed by Wright’s staining, and
the SFLs were usually -90% lymphoid cells. PBLs were
separated by centrifugation on Ficoll-Hypaque, as described (8).
The recovery of SFL was comparable with that of
PBL in the RA patients (1.18 -+ 1.62 x lo6 cells/ml and 1.78
0.6 x lo6 cellslml, respectively). Recovery of sufficient
SFL for further investigation was not possible in any of the
4 OA patients studied (0.01 i 0.01 x lo6 cells/ml).
Single-color immunofluorescence studies. A standard,
direct immunofluorescence test was performed using the
reagents described below. All MAbs used in these studies
were obtained from Becton Dickinson Monoclonal Center
(Mountain View, CA). Anti-Leu-2a, anti-Leu-4, and antiLeu-8 MAbs were conjugated with fluorescein isothiocyanate (FITC). Anti-Leu-3a, anti-Leu-15, and antiHLA-DR were conjugated with phycoerythrin B (PEB).
Two-color immunofluorescence studies. The PBLs or
SFLs were stained for 2-color immunofluorescence as described previously (1,2,4). Briefly, cell pellets were incubated with FITC-conjugated MAbs, then washed in medium.
PEB-conjugated MAbs were added, and the cells were
incubated for another 15 minutes at 4°C. After 2 washes, the
cells were fixed in 1% paraformaldehyde/0.85% saline solution and stored at 4°C until they were analyzed by flow
cytometry.
All reagents were titrated prior to use, and optimum
concentrations were used in all assays. Flow cytometry was
performed with a dual-laser FACS IV system (Becton
Dickinson FACS Division, Sunnyvale, CA). Fluorescence
excitation of FITC and PEB was achieved using the 488-nm
line of an argop laser.
Cell enumeration. Typically, 10,OOO cells were analyzed for single-color immunofluorescence and 7 0 . 0 r d q
*
T CELL SUBSETS IN RA SF
739
were analyzed for 2-color immunofluorescence. Dead cells,
erythrocytes, platelets, monocytes, and granulocytes were
excluded from analysis by setting an appropriate threshold
trigger on the low forward-angle and 90" light-scatter parameters. In determining the percentage of positive cells, a
marker was set on the appropriate control histogram such
that 0.3%, or fewer, of the cells were to the right of this
channel marker. By using this as a reference point, the
percentage of cells in the specific antibody-stained sample
histogram was calculated, as described elsewhere (4).
HLA-DR+ cells were quantitated using a conventional
fluorescence microscope (Leitz, Wetzlar, FRG), and counting 200 cells per slide.
% positive
C€?IIS
SFL
P
8 9
RESULTS
1-3 1
Levels of Ia+ T cells in SFL and PBL. As shown
in Figure 1, Ia+ T cells (Leu-4+/HLA-DR+) were
elevated in RA SFL, as compared with their levels in
PBL from either the RA patients or the healthy control
subjects ( P < 0.001). About 75% of the T cells in the
SFLs were stained with Ia MAbs. There was a significant correlation between the percentage of Leu4+/HLA-DR+ cells in the SFLs and the level of
disease activity (Figure 2).
Ia antigens were also detected in 85% of the
Leu-2a+ fraction (Leu-2a+/HLA-DR+) and in 63% of
the Leu-3a+ fraction (Leu-3a+/HLA-DR+). This
finding was similar to that reported by Burmester et a1
(9). In addition, Figure 3 illustrates the significant
correlation (r = 0.63, P < 0.001) of Leu-4+/HLADR+ cells and Leu-2a+/Leu-15- cells in RA SFL.
Thus, Ia antigens might be expressed on Leu-
4 7
il
Control (n =69)
Figure 4. Percentage of Leu-2a+/Leu-15+ cells in patients with
rheumatoid arthritis. See Figure 1 for definitions and explanations.
2a+/L,eu-15- (T cytotoxic) cells. However, 3-color
flow cytometric analysis should be performed to clarify this finding.
Single-color immunofluorescence analysis of PBL
and SFL subpopulations in RA patients. The PBL and
SFL subsets that were reactive with single antibodies
to surface antigens were as follows. In RA PBL, the
positive
%cell:s
PBL
SFL
Leu2a +LeulS% positive cells
4
0
63, P<O. 001)
(r = O .
1
0
40.
36 4
f9
20 '
4
0
12 1
i4.8
01
I
I
I
20
60
40
Leu4
+
HLA-DR
I
80
% positive cells
+
Figure 3. Correlation between the percentage of Leu-4+/HLADR+ cells and the percentage of Leu-2a+/Leu-15- cells in rheumatoid arthritis synovial fluid lymphocytes.
Control (n =69)
RA (n=28)
Figure 5. Percentage of Leu-2a+/Leu-15- cells in patients with
rheumatoid arthritis. See Figure 1 for definitions and explanations.
GOT0 ET AL
740
%positive
cells
PBL
I
I
SFL
41.8
18 5
11.4
14.6
L
I
Control (n =69)
I
R A (n=28)
Figure 6. Percentage of Leu-3a+/Leu-8+ cells in patients with
rheumatoid arthritis. See Figure 1 for definitions and explanations.
mean t SD percentage of cells reacting with anti-Leu2a (23.3 2 7.0%) and anti-Leu-4 (71.4 i 7.1%) was
slightly reduced in comparison with that in normal
PBL (28.3 t 7.9% and 79.2 2 7.4%, respectively). The
Leu-3a+ cells (50.3 t 6.7% versus 46.6 2 7.3%) and
Leu-3a+:Leu-2a+ ratios (2.41 t 0.98 versus 1.71 ~t
0.61) were increased in RA PBL compared with those
in control PBL. However, the differences in PBL
levels in the RA patients versus the control subjects
were not statistically significant. The Leu-2a+ (40.3 t
8.6%) and Leu-4+ (86.4 t 8.2%) SFL subpopulations
PBL
in RA patients were significantly increased ( P < 0.01),
and the Leu-3a+ :Leu-2a+ ratio (1.1 2 0.4) was markedly decreased, in comparison with those in RA PBL
and with those in control PBL. More Leu-4+ T cells
were found in RA SFL (because of an increase in
Leu-2at cells) than in the corresponding PBL.
Two-color analysis of T cell subsets in PBL and
SFL. The anti-Leu-2a+ and anti-Leu-3a+ cell populations were characterized by use of MAbs Leu-8 and
Leu-15. As shown in Figure 4, the mean 2 SD
percentage of Leu-2a+/Leu- 15+ (T suppressor) cells
in PBL was 12.1 t 5.4% in healthy control subjects
and 8.9 t 3.7% in RA patients. In S F L , the percentage
of T suppressor cells was 4.7 S 1.7% in RA patients.
The difference between the levels of PBL and SFL in
RA patients was significant at P < 0.01.
The percentages of T cytotoxic (Leu-2a+/Leu15-), T helper (Leu-3a+/Leu-8-), and T inducer
(Leu-3a+/Leu-8+) cells in PBL were similar in RA
patients and normal control subjects (Figures 5-7).
However, these 3 T cell subsets showed very different
percentages in SFL compared with their corresponding PBL. The percentages of T cytotoxic and T helper
cells in RA SFL were significantly increased compared
with PBL from the same patients and compared with
PBL from control subjects (P < 0.001) (Figures 5 and 7).
Leu3atLeu8% positive
cells
SFL
% positive
cells
20
-
(r=-0.67,
0
P<O.OOl)
I
I
I
20
40
60
Leu2a+Leu1 5- % positive cells
-
Control
(n=69)
RA (n=28)
Figure 7. Percentage of Leu-3at/Leu-8- cells in patients with
rheumatoid arthritis. See Figure 1 for definitions and explanations.
Figure 8. Correlation between Leu-2a+/Leu-15- cells and Leu3a+/Leu-X- cells in rheumatoid arthritis synovial fluid lymphocytes. The correlation was inverse, and it was statistically
significant.
T CELL SUBSETS IN RA SF
Interestingly, there was a striking inverse correlation (r = -0.67, P < 0.001) between the percentage of Leu-2a+/Leu-15- cells and that of Leu3a+/’Leu-8- cells in RA SFL (Figure 8). In addition,
there: was an inverse correlation between Leu3a+/Leu-8- cells and Leu-4a+/HLA-DR+ cells in
SFL (r = -0.53, P < 0.002), which, based on the
above data, was expected.
In contrast to the levels of T cytotoxic cells and
T helper cells, the T inducer cells were markedly
decreased in RA SFL compared with those in RA PBL
and compared with those in normal PBL (P < 0.001)
(Figure 6). No double-marker T cells (Leu-2a+/Leu3a+) were detected in any of the PBLs or SFLs in this
series.
741
Table 1. Characteristic changes in T cell subsets in rheumatoid
arthritis
T cell subset
T suppressor
(Leu-2a+/Leu-15+)
T cytotoxic
(Leu-Za+/Leu-l5-)
T inducer
(Leu-3a + /Leu-8 + )
T helper
(Leu-3a +/Leu-&)
T HLA-DR
(Leu-4+/HLA-DR+)
Synovial fluid
lymphocytes
Peripheral blood
lymphocytes
Decreased*
Decreasedt
Increased*
-f
Decreased
-f
Increased
-f
Increased
Increasedt
* Significant versus peripheral blood lymphocytes from rheumatoid
arthritis patients and those from normal subjects.
7 Significant versus peripheral blood lymphocytes from normal
subjects.
t Percentages are similar to those of peripheral blood lymphocytes
from normal subjects.
DISCUSSION
The results of the present study confirm our
previous findings (7) and the findings of other investigators (9-13) in that, in RA SFL, there were almost
equal percentages of Leu-3a+ and Leu-2a+ cells, and
that 45-90% of the T cells were Ia+ (activated). We
have also extended these observations by analyzing
the functional subsets of SFL, using a combination of
2 MAbs. The findings are summarized in Table 1. The
lymphocyte composition of the S F differs from that of
the PB in the increased proportions of la+ Leu2a+/Leu-15- and Leu-3a+/Leu-8- T cells, together
with marked decreases in Leu-2a+/Leu- 15+ and Leu3a+ /Leu-8+ cells. These changes in the SFL composition do not appear to be an artifact of drug treatment,
but a finding that is unique to the disease, as was noted
in IPBL (4). For example, when patients receiving
D-plenicillamine were compared with those who were
not receiving D-penicillamine, there was no significant
diaerence between the 2 groups in terms of the percentages of T suppressor, T cytotoxic, T helper, T
inducer, and activated T cells.
A decrease in the percentage of T suppressor
cells might be related to defective T suppressor cell
function in RA SFL, which has been demonstrated
previously. Biberfeld et a1 (14) demonstrated radiosensitive suppressor cell activity, with low levels of
IgG Fc receptor-positive T cells, in RA SF. We do not
know if the decrease in T inducer cells is directly
related to the loss of T suppressor cells. Whatever the
reason for it, the loss of T suppressor cells might be
one of the major phenomena occurring in RA SFL and
RA PBL, although the percentages of T cell subsets in
both PBL and SFL change over time, according to the
level of disease activity (4,15).
The functional characteristics of 2-colordefined T cells were previously analyzed by sequential
cell sorter techniques (1,2). The Leu-2a+/Leu-l5+
subset was unique in its ability to suppress the proliferative responses of other T cell subsets stimulated
with mitogens (l), and in its ability to suppress B cell
differentiation (16). The Leu-2a+ precursor and effector T cytotoxic cells generated in allogeneic mixed
lymphocyte cultures and reactive against class I alloantigens are Leu-2a+/Leu-15- (17).
Using the autologous mixed leukocyte reaction
as a T cell-dependent stimulus for immunoglobulin
synthesis, it was observed that the T helper fraction
for antibody formation lies within the Leu-3a+/Leu8- subset of T cells (2). In contrast, antigen-primed
(for example, purified protein derivative) Leu-3a+/Leu8+ inducer cells can directly activate Leu-2a+/Leu15+ precursors of antigen-specific T suppressor cells
in the absence of antigen-pulsed autologous non-T
cells (18). However, the phenotype of cells determined
by 2-color immunofluorescence has been evaluated in
only a limited number of systems related to the functional properties of those cells. Moreover, it is not
known whether the phenotypically defined cell subsets
(for example, T suppressor cells) in diseases such as
RA show exactly the same T suppressor cell function
as do normal cells (1,2). Consequently, we must
recognize the limitations of phenotypic analysis.
The significant increases in Ia+ activated T
cells (Leu-4a+/HLA-DR+), T cytotoxic cells (Leu-
742
GOT0 ET AL
2a+/Leu-15-), and T helper cells (Leu-3a+/Leu-8-)
may be closely related to each other and, possibly, to
the immunopathogenesis of RA. In this study, we
present 2 lines of relevant evidence. First, there was a
marked correlation between the percentage of Leu2a+/Leu-15- cells and the percentage of L e u d + /
HLA-DR+ cells; the number of the latter subset was
always greater than that of the former in the same SFL
sample. Furthermore, HLA-DR antigens were expressed on both Leu-2a+ cells and Leu-3a+ cells in
RA SFL, but they were predominantly expressed on
the former cell subset. This finding is similar to that
observed by Burmester et a1 (9). These data indicate
that a majority of the Leu-2a+/Leu-15- T cytotoxic
cells in RA SFL may express Ia antigens on their
surfaces .
Second, there was a clear inverse correlation
between Leu-Za+/Leu-lS- T cytotoxic cells and Leu3ai-/Leu-8- T helper cells in RA SFL. Thus, the
activated T cytotoxic cells could be regulating the T
helper cells in the SF. Most of the Leu-3a+ cells (63%)
were also determined to be Ia+. These Ia+ T helper
cells may produce several lymphokines, such as 7interferon, interleukin-2, and B cell differentiation
factor (19-21), and may be related to the production of
autoantibodies, such as rheumatoid factor. Hence,
joint destruction would ensue.
The finding that activated T cytotoxic cells
were significantly increased in SF was interesting,
because a virus(es) is thought to be the antigenic
stimulus for rheumatoid synovitis. Some investigators
have proposed a pathogenetic role for Epstein-Barr
virus in RA (22,23). In this regard, it is tempting to
make a conjecture that SFL T helper cells and T
cytotoxic cells can be activated by the putative “X”
antigen and produce several lymphokines that have
potentially destructive activity in joints (3). Our discussion is obviously speculative, and these preliminary findings will have to be extended. Additional
experiments would include the analysis of patients
with other rheumatic diseases and functional analyses
of the 2-color immunofluorescence-determined synovial fluid lymphocytes. However, if our findings are
confirmed, they may provide new insight into the
pathogenesis of rheumatoid arthritis.
ACKNOWLEDGMENTS
We thank K. Kodama and S. Kuge, Japan Immunomonitoring Center, for technical assistance, and Dr. N.
J. Zvaifler, University of California at San Diego Medical
Center, for helpful comments.
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T CELL SUBSETS IN RA SF
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743
19. Cessario TC, Andrews BS, Martin DA, Jason M,
Tredwell T, Friou G, Tilles J: Interferon in synovial fluid
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Immunol 127:1899-1902, 1981
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