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Immunohistologic characterization of synovial membrane lymphocytes in rheumatoid arthritis.

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Synovial membrane biopsy specimens from 15
rheumatoid arthritis patients were examined using routine histologic stains and monoclonal antibodies directed
against cell surface antigens. Three patterns of lymphoid cell infiltrates were recognized: 1) diffuse infiltration of T cells that surrounded clusters of germinal
center B cells (3 patients); 2) diffuse T cell infiltration,
lacking germinal centers (8 patients); and 3) proliferation of subsynovial fibroblasts, with relatively few lymphoid cells (4 patients). The synovial, subsynovial, and
perivascular tissues in each of the patterns exhibited a
high frequency of HLA-DR antigen, HLA-DS antigen,
transferrin receptor, and/or epidermal growth factor
receptor. In contrast, normal or osteoarthritic synovial
tissues did not display a marked increase of these
antigens or receptors. Cells bearing natural killer antigen were infrequent in each of these patterns. Active
synovitis, synovial effusions, anemia, and elevated sedimentation rate were present in rheumatoid arthritis
patients with each of the three histologic patterns.
Immunohistologic characterization of synovial mem-
. -.
From the Department of Basic and Clinical Research.
Scripps Clinic and Research Foundation. La Jolla. California.
This work was supported by NIH grants AM 21 175 and CA
28746. Publication number 2941UCR from the Research Institute of
Scripps Clinic.
Carol I*. Young, MD: Thomas C. Adamson. 111. MD:
current address: Rees-Stealy Medical Group. 2001 Fourth Avenue,
San Diego. CA 9’2101: John 11. Vaughan. MD; Robert Fox, MD,
Address reprint requests to Kobert I. Fox, MD. Scripps
Clinic and Research Foundation, 10666 North Torrey Pines Road.
BCR4. La Jolla, CA 92037.
Submitted for publication June 10. 1983: accepted in revised form August 15, 1983.
Arthritis and Rheumatism, Vol. 27, No. 1 (January 1984)
brane infiltrates by these monoclonal antibodies provides additional information about pathogenesis of rheumatoid arthritis and may help in predicting responses to
different therapeutic modalities.
When many rheumatoid arthritis (RA) patients
first see a rheumatologist, they have a history of
longstanding activc disease that has previously been
treated with multiple medications. Their responses to
subsequent medications are quite variable, and laboratory tests to predict prognosis or response to therapy
would aid in disease management for individual patients. As an initial step in the achievement of these
aims and to better understand pathogenesis of R A , we
have used monoclonal antibodies and immunohistologic techniques to characterize the mononuclear cells
infiltrating the synovial membranes.
Recent studies have used monoclonal antibodies directed against T cell subsets and HLA-DR
antigens in frozen tissue sections of synovial membrane (1-6). We wished to expand these studies by
examining tissue sections for additional cell surface
markers on T cells and B cells that may be present in a
patient’s synovial tissue but not necessarily present in
the blood or synovial fluid. We have also used newly
developed antibodies that detect antigens on synovial
lining cells and vascular endothelial cells (anti-transferrin receptor and anti-epidermal growth factor receptor antibodies). These antibodies provide information about the site of inflammation not available from
the study of blood or synovial fluid lymphocytes.
Table 1.
Clinical and laboratory data for I5 rheumatoid arthritis (RA) patients*
of KFi
Total or
mean 2 SD
I5/l I
KF titer
1:1.920 c YO5
ESK. mmi
= 43
5 I .83n
1 :3,055 c 2.888
I x3.776
I :2.720
Age at
onset RA
11.6 :!-2.0
11.8’ 1.9
12.3 I
of RA
agent history$.
X I 8
13 2 I I
14 5 5
I?I 9
* RF = rheumatoid factor. calculated for patients who were seropositive: ESR = erythrocyte sedimentation rate
t Years from onset RA to surgery for synovial membrane biopsy.
t Number of patients treated with gold, D-penicillamine. azathioprine, and/or cyclophosphamide.
Patient population. Synovial tissue was obtained
from 15 patients with definite or classic rheumatoid arthritis
who underwent synovectomy or total joint replacement at
Scripps Clinic from July 1980 through June 1987. Their
clinical characteristics and laboratory findings are summarized in Table I . Briefly, RA patients with each of the three
patterns of lymphoid cell infiltrates had active synovitis
manifested by joint swelling. pain, stiffness. and recurrent
synovial effusions containing elevated white cell counts and
protein content (7). Slow-acting agents (gold. penicillamine.
and/or azathioprine) and intraarticular steroids had been
used in patients with each pattern. Synovial membrane
samples used as controls were obtained from 8 patients with
osteoarthritis at the time of joint replacement and from 2
patients with previously normal joints, undergoing surgery
for knee trauma.
Preparation of synovial membrane samples. Synovial
tissue, obtained at the time of surgery. was embedded in
optimal temperature cutting compound (Miles Laboratories,
Naperville. IL). oriented to assure cross sections containing
the synoviocyte layer, frozen using a mixture of isopentanel
dry ice, and stored at -70°C (8). Multiple samples from
ditrerent regions of each synovium were chosen for study,
since it is known that the histologic appearance can vary
from site to site within the joint (9.10). ‘Ihe particular pattern
(i.e.. pattern I , 2 , or 3) was assigned on the basis of
evaluation of multiple frozen tissue and paraffin-embedded
specimens taken from different regions of the joint. A
separate portion of tissue was digested with collagensse
(Sigma, St. Louis, MO) for 16 hours at 37°C to obtain cell
suspensions. This was followed by centrifugation over Ficoll-Hypaque to obtain mononuclear cells ( I I ) .
Monoclonal antibodies. Monoclonal antibodies used
in this study included anti-’l’ cell antibodies Leu-Za. Leu-3a,
Leu-4 (Becton-Dickinson, Mountain View, CA) (17). In
normal peripheral blood, suppressor/cytotoxic cells are included in the Leu-2a subset and helpcr/inducer cells in the
Leu-3a subset (12). However. it is not possible to simply
equate lymphocyte phenotype and function ( 1 3-17). Monoclonal antibody B532 (a gift from Dr. Dennis Frisman at
University of California, San Diego) reacts with B cells
found in the germinal centers of normal lymph nodes and
tonsils but not with peripheral blood B cells (8,181 or
synovial fluid B cells (Young CIS: unpublished observations). Two-color immunofluorescence staining studies have
shown that B532’ cells bear surface immunoglobulin, and in
vitro functional studies have demonstrated that B532 ’ cells
synthesize immunoglobulin after mitogen stimulation in the
presence of ’I cells. Antibody F45 has been characterized in
our laboratory as reacting with the same subset of natural
killer cells as antibody HNK-I (19). based on two-color
immunofluorescence staining methods and in vitio functional analysis (Fox RI. Fraenkel F: unpublished observations).
Antibody L22 reacts with the transferrin receptor. since it
immunoprecipitates the same 90,000 dalton molecule as
antibody B3/25 described by Trowbridge and Omary (20)
(Fox RI, Dillman R: unpublished observations). Monoclonal
antibodies SC2 and ,I+eu-lO (Becton-Dickinson)‘detect cell
surface HLA-DK and HLA-DS antigens, respectively
(7.21). Antibodies SC2. L22. and F45 are produced in our
laboratory. Monoclonal antibody 455 to epidermal growth
factor receptor, received from Dr. John Mendelson ( 2 2 ) .was
selected for its ability to inhibit the binding of purified
epidermal growth factor to the A43 1 adenocarcinoma cell
line. Myeloma proteins MOPC-21. GPC7, and HO-22, with
no known anti-human activity. were used as negative controls.
Enumeration of lymphocyte subsets by immunohistologic and cytofluorometric analysis. Serial sections of frozen
synovial membrane were stained with mouse monoclonal
antibody Leu-2a. Leu-3a. Leu-4, or control myeloma protein, followed by biotin conjugated goat F(ab’)? anti-mouse
IgG (’fago, Burlingame, CA), avidin conjugated horse radish
peroxidase (Vector, Burlingame. CA). and substrate diaminobenzidine (DAB) (Sigma) (8). Because of their more intense
staining characteristics. antibody SCZ, Leu-10, L22. 455,
and F45 could be used with peroxidase conjugated F(ab’)?
anti-mouse Ig (‘I‘ago) and DAB. Coded slides were read by at
least two different observers. Cell suspensions derived from
synovial membranes were incubated with monoclonal antibody and fluorescein-conjugated F(ab’)2anti-mouse Ig, followed by cytofluorometric analysis (7) using a FACS IV
Immunohistology of RA synovial membrane.
Three histologic patterns of RA synovial membrane,
based on the distribution of lymphoid cell infiltrates,
were observed.
Pattern 1, characterized by presence of germinal ccnters, was seen in biopsy specimens from 3 of 15
patients. Figure 1A illustrates a hematoxylin and eosin
stained RA synovial membrane section that contains a
germinal center. Lymphoid cells in these germinal
centers were stained with monoclonal antibody B532
(Figure I B), using the immunopcroxidasc technique.
Leu-4 ' T cells (Figure 1 D) were located predominant-
Figure 2. Synovial membrane with pattern 2 infiltrate was stained
with: A. Hematoxylin-eosin; B, Antibody B532; C. Control protein
MOPC-21; D. Antibody I,cu-4.
ly around the germinal centers and were more numer-
ous than the B cells. No significant staining was noted
Figure 1. Frozen tissue sections of rheumatoid arthritis synovial
membrane with pattern 1 infiltrate. A, A germinal center (arrow)
detected by hematoxylin-eosin stain. B, C, D, Irnmunoperoxidase
technique has been used to stain serial tissue sections: B,Antibody
B532' cells within the germinal center; D,T cells (antibody Leu-4.')
surrounding the germinal center. C, A control myeloma antibody
(MOPC 21) was used (original magnification x 50).
with the control myeloma antibody (Figure IC).
Pattern 2 was charactcrized by the presence of
many lymphoid cells (Figure 2A), but germinal centers
were absent. This pattern was observed in 8 of 15
patients. Lymphoid cells in pattern 2 were predominantly Leu-4' T cells (Figure 2D), although R532'
B cells (Figure 2B) were scattered throughout the
sections in 4 (50%) of the 8 biopsy specimens. The
absence of clusters of B532- cells was consistent with
the absence of germinal centers on routine hematoxylin and eosin stains. When control myeloma protein
MOPC 21 (Figure 2C) was used, only rarely were
positive cells (less than 2%) seen in some biopsy
specimens. Although the basis for this occasional
false-positive staining remains unknown, these results
emphasize the need to use control myeloma proteins
of the Same class and concentration as the specific
monoclonal antibodies being
Pattern 3 showed fibroblastic proliferation with
few (less than 50 per high power
lymphoid cells (Figure 3A). The majority of the mono-
lymphocytes reacted with this antibody. Synovial tissue obtained from osteoarthritic joints or from normal
joints with traumatic injury showed relatively few
lymphocytes, no proliferation of synovial and subsynovial fibroblasts, and little vascular proliferation,
when routine histologic stains were used. Using monoclonal antibodies, approximately half the synovial
lining cells were stained by anti-HLA-DR and HLADS antibodies; the subsynovial fibroblasts were not
reactive. Only rare Leu-4' T cells or B532' B cells
were present, and staining with anti-transferrin receptor or with anti-epidermal growth factor receptor was
much less frequent than in the RA synovium.
Cytofluorometric analysis. To more accurately
quantitate the proportion of mononuclear cells in RA
synovial membrane, cytofluorometric analysis was
performed on cell suspensions eluted from synovial
membranes by collagenase digestion. More T cells (56
Figure 3. A. Synovial membrane with pattern 3 infiltrate was
stained with hematoxylin-eosin to show that only rare mononuclear
cells were present. B and C, Staining with antibodies R532 and
control myeloma MOPC-21. respectively. D, Reaction with antibody Leu-4. Arrow denotes positive staining.
nuclear cells were Leu-4 ' T cells (arrow in Figure 3D).
B532- B cells were rarely found (Figure 3B).
All RA synovial membrane biopsy specimens
demonstrated strongly positive staining with antiHLA-DR (antibody SC2) (Figures 4A and 5A). A
similar pattern and intensity of staining of all synovial
membrane biopsy specimens was noted with antiHLA-DS (antibody Leu-10) (Figures 4B and 5B).
Transferrin receptors were demonstrated by staining
with antibody 1 2 2 . Subsynovial cells, which were
reactive in all three histologic patterns (Figures 4C and
SC), were more prominent in pattern 3. Epidermal
growth factor receptor (detected by antibody 455) was
present on the vascular endothelial cells (Figures 4D
and 5D); weaker staining was noted in the subsynovia]
fibroblasts of some patients. In all 3 patterns, only rare
(less than 20/o)were reactive with antibody F45
that detects the natural killer subset; this Was true
even in patients in whom up to 40% of peripheral blood
Figure 4. Pattern I rheumatoid arthritis synovial membrane was
stained with: A, Monoclonal antibody SC2 (anti-HLA-DK); B.
Antibody (anti-HLA-DS); C. Antibody L22 (anti-transferrin
receptor): D, Antibody 455 (anti+pidermal growth factor receptor).
The space in the central part of the figure is the synovial cavity.
Arrow denotes positive staining.
12% Leu 4’ cells) than B cells (8 7% I3532 ’ or 6 2
2% IgD’ cells) were present. Lymphocytes stained
with F45 comprised less than 3%, detected by cytofluorometry. A high frequency of HLA-DR+ cells (47
? 12%) was present. Very few (<lo%) transferrin
receptor cells were present. This is consistent with the
infrequent staining of mononuclear cells on synovial
tissue sections (Figures 4C and 5C), even though
subsynovial fibroblasts were stained in these tissues.
This selective expression of activation antigens has
previously been noted on synovial fluid T cells (7). We
found a positive correlation between the two methods
(immunoperoxidase stained sections and cytofluorographic analysis of cell suspensions) for enumeration
of the proportions of phenotypically distinct mononuclear cells.
Analysis of peripheral blood lymphocytes
(PBL) from these patients demonstrated a predom2
Figure 5. Pattern 3 rheumatoid arthritis synovial membrane was
stained with the same panel of antibodies as used in Figure 4
including: A , Anti-HLA-DR; B, Anti-11I.A-DS; C, Anti-[ransferrin
receptor; D, Anti-epidermal growth f x t o r receptor. Arrow denotes
positive staining.
inance of T cells (50-75% Leu-4’ cells) in all cases. In
contrast to our prior study in which untreated RA
patients’ PBL had a predominance of Leu-3a+ cells
(ratio of Lcu-3dLeu-2a reactive cells = 2.4 2 0.3) (7),
the previously treated KA patients in this study
showed a wide variation in the proportion of their
lymphocyte subsets (ratio of Leu-3dLeu-2a reactive
cells = 0.9-2.4), There was no apparent correlation
between pattern of synovial membrane infiltrate and
ratio of subsets in their PBL. In 2 patients with pattern
3 infiltrate, synovial fluid lymphocytes were predominantly T cells, with ratios of Leu-3dLeu-2a reactive
cells equaling I . 1 and 1.7, respectively; a high number
of Ia+ T cells (21-40%) was present in each case.
Clinical features. KA patients with pattern 1
were older at onset of symptoms (U < 0.05, Student’s
t-test) and the duration of their symptoms before joint
surgery was shorter than that of patients with patterns
2 or 3 (Table 1). All patients with pattern 3 had been
treated with remittive agents, while 1 patient with
pattern 1, and 2 patients with pattern 2 had not received
these drugs. Continued active synovitis was present in
patients with each pattern based on physical examination of the joints, radiographic evidence of progressive
erosive joint destruction, and recurrent synovial effusions with high white blood cell counts and protein
content. In particular, our 4 patients with pattern 3 did
not appear to represent “burned out” inactive disease.
Patients with pattern 3 were mildly anemic (hemoglobin = 12.3 5 0.7), 75% had erythrocyte sedimentation
rate of greater than 30 mm/hour (mean 66 t 48
mm/hour), and all had rheumatoid factor titer greater
than 1:640 (Table 1).
Evaluation of hematoxylin-eosin stained synovial
membranes. Since architecture of tissue is preserved in paraffin-embedded sections stained with
hematoxylin-eosin, we compared results of assays on
frozen tissue with those using routine histologic stains.
We found that germinal centers (detected by antibody
B532’ I3 cells) were more easily seen in the frozen
tissue sections, especially when such germinal centers
were small. The patterns found on frozen sections
were in close agreement with those noted on the
paraffin-embedded sections. Comparison of synovial
samples obtained from different joints of the same
individuals over periods up to 4 years demonstrated
similar patterns of mononuclear cell infiltration in each
patient. The range of joints biopsied for our immunohistologic studies is summarized in Table 2 and demonstrates that each pattern can be seen in any of the
joints biopsied.
Table 2. Range of joints biopsied and synovial immunohistologic
patterns observed
1 knee
2 wrists
I hip
3 knees
4 wrists
1 hip
2 knees*
2 wrists
* Two synovial membrane biopsies obtained 16 months apart from
the left knee of I patient, the first at arthroscopic biopsy and the
second at replacement arthroplasty. Synovial membrane biopsies
from the 4 other knees and 2 hips were obtained at replacement
arthroplasty and from the 8 wrists at synovectomy.
Three patterns of lymphoid cell infiltration of
rheumatoid synovial membrane are described. These
are characterized by abundant lymphoid infiltrates
with germinal centers (pattern l), abundant lymphoid
infiltrates without germinal centers (pattern 2), and
fibroblastic/synovial proliferation with few lymphoid
cells (pattern 3). Recent studies have emphasized
synovial membrane biopsy specimens with heavy
mononuclear cell infiltrates in order to characterize
the cell-cell interactions that may occur. Previous
studies by Fassbender and colleagues (reviewed in
reference 23) have used routine histochemical stains to
demonstrate the relative paucity of mononuclear cells
in biopsy specimens obtained from some patients with
active synovitis. Our results extend these observations
by demonstrating a high frequency of dcndritic typc
cells (HLA-DR+ , HLA-DS’, nonspecific esterasc
negative) in biopsy specimens lacking lymphocytic
infiltrates. Further, a high frequency of cells bearing
transferrin receptor (TR) or epidermal growth factor
receptor (EGFR) were found in these specimens. Such
antigens provide markers for synoviocyte and fibroblast proliferation that occurs in the absence of direct
T cell-synoviocyte contact and that may result from
the action of soluble factors (24,25).
The presence of particular cell types in synovial
membrane that are not present in blood (such as B532
B cells, HLA-DR+/DS+ dendritic cells, and cells
bearing EGFR and TR) are potentially important since
such cells provide possible targets for selective drug
therapy or immunoregulation. B532+ B cells are not
specific for RA synovium since they also may be found
in normal lymph nodes or in the inflammatory infiltrates in primary Sjogren’s syndrome (8). Conversely,
few natural killer-like cells (< 3% antibody F45 reactive cells) were present in synovial membrane, although up to 40% of PBL were reactive. Taken
together with previous studies on lymphocyte subsets
in RA patients (7,16,26-29), the present study suggests
the importance of “homing” of lymphocyte subpopulations (30-32) to different subregions of synovium or
synovial fluid.
Several different mechanisms may be responsible for the presence of distinct patterns of synovial
membrane infiltration. A single patient may progress
through different patterns, such as the evolution from
pattern 1 through pattern 2 to pattern 3. The rate of
progression through these various phases would depend on particular genetic and environmental factors,
including medications. An alternative hypothesis is
that distinct patterns exist in patients with early untreated disease and that such patterns persist throughout the disease course. Further studies in animal
models of RA and prospective studies of untreated RA
patients will be necessary to resolve these questions.
In summary, we have found different patterns
of synovial membrane infiltration in patients with
active progressive RA. These results are in agreement
with a preliminary report by Malone et al (33). These
different patterns of infiltration may provide prognostic information or help predict responses to particular
therapies in a manner analogous to the use of renal
biopsy for patients with glomerulonephritis. However,
long-term clinical followup using standardized treatment protocols will be necessary to evaluate the
potential value of these measurements in rheumatologic practice.
We wish to thank Ms Darla Harlow, Robert Buhrow,
and David Finney for their excellent technical assistance.
We are grateful to the members of the Divisions of Orthopedic Surgery (Drs. C. Colwell, R. Thorne, M . Hamer, and P.
Hirshman) and Rheumatology (Drs. C. A. Robinson, G . W.
Williams, P. K . Hench, J. G. Curd, and E. Tan) for allowing
us to study their patients and Ms Shari Brewster for her
secretarial assistance. Finally, we particularly wish to thank
our Department of Pathology (Drs. J. Robb, G. Bordin, and
W. S. Nichols) for their help in obtaining samples and the
interpretation of pathologic Specimens and Dr. Frank Kozin
for helpful discussions throughout these studies. We thank
Dr. John Mendelson and Dennis Frisman (University of
California, San Diego) for generous gifts of antibodies 455
and €3532, respectively.
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The Second Carl M. Peanon Memorial Symposium: Frontiers of Rheumatology
March 15-17, 1984, Rancho Mirage, CA. Sponsored by the Annenberg Center for Health Sciences in
association with the UCLA School of Medicine, Division of Rheumatology and the Southern California chapter of
the Arthritis Foundation. CME credit available. Registration fee is $330/MDs; $180/fellows, trainees, and other
health professionals. For additional information, contact Annenberg Center, for Health Sciences, Eisenhower
Medical Center, 39000 Bob Hope Drive, Rancho Mirage, CA 92270, 800-321-3690 (toll-free, national), 800621-7322 (toll-free, California).
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arthritis, characterization, membranes, synovial, lymphocytes, rheumatoid, immunohistological
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