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Surface characteristics of synovial fluid and peripheral blood lymphocytes in inflammatory arthritis.

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SURFACE CHARACTERISTICS OF
SYNOVIAL FLUID AND PERIPHERAL
BLOOD LYMPHOCYTES IN
INFLAMMATORY ARTHRITIS
ALAN I. BRENNER, MORTON A. SCHEINBERG, and EDGAR S. CATHCART
I n order to characterize the T- and B-cell populations of inflammatory arthritides, synovial fluid and
peripheral blood lymphocytes from patients with rheumatoid arthritis (RA), systemic lupus erythematosus
(SLE), juvenile rheumatoid arthritis (JRA), and
rheumatoid variant diseases (RV) were studied. Normal peripheral blood lymphocytes were examined as
controls. T cells were identified by spontaneous sheep
red blood cell (E) rosette formation. B cells were
From the Arthritis and Connective Tissue Disease Section of the Evans Department of Clinical Research, University
Hospital, the Thorndike Memorial Laboratory, Boston City Hospital, and the Department of Medicine, Boston University School
of Medicine, Boston, Massachusetts.
Investigations supported by grants from the United
States Public Health Service, National Institute of Arthritis and
Metabolic Diseases (AM-04599 and TI-AM 5285), from the General Clinical Research Centers Branch of the Division of Research Sources, National Institutes of Health (RR-533), from
the Massachusetts Chapter of The Arthritis Foundation, from
The Arthritis Foundation, and from the John A. Hartford
Foundation.
Presented in part at the VI Pan-American Congress on
Rheumatic Diseases, June 19, 1974. Toronto, Ontario, Canada.
Alan I. Brenner. M.D.: Clinical and Research Fellow
in Medicine, Boston University School of Medicine; Morton A.
Scheinberg. M.D.: Clinical and Research Fellow in Medicine,
Boston University School of Medicine; Edgar S. Cathcart, M.D.:
Associate Professor of Medicine, Boston University School of
Medicine.
Address reprint requests to Edgar S. Cathcart, M.D.:
Arthritis Section, Boston University School of Medicine, 75 East
Newton Street, Boston, Massachusetts
02118.
Submitted for publication September 25, 1974; accepted
January 27, 1975.
Arthritis and Rheumatism, Vol. 18, No. 4 (July-August 1975)
determined by complement receptor lymphocyte
(EAC) rosette formation and by the presence of
surface immunoglobulins (SIg) utilizing fluoresceinated polyvalent antiglobulin. Synovial fluids were
analyzed in terms of duration, mucin quality, white
cell count, and differential. Synovial fluid and peripheral blood lymphocytes from patients with RA and
R V were distributed in T- and B-cell percentages
similar to those found in normal peripheral blood.
In contrast, significant T-cell depression was observed
in the percentage of synovial fluid and peripheral
blood lymphocytes of SLE and JRA patients. This
depression was apparent in comparison with normal
peripheral blood and with the synovial fluid and
peripheral blood from R A patients. Bcell percentages
were similar in all patient groups and in comparison
to normal peripheral blood lymphocytes. N o differences were noted in B-cell percentages when the EAC
and SIg techniques of identification were compared.
The percentage of cells bearing neither T- nor Bcell markers (null cells) was enumerated for each
patient group and found to be significantly elevated
in the synovial fluid and peripheral blood of SLE
and JRA patients. Though the mean synovial fluid
and peripheral blood null cell percentages in R A
patients were similar to those in controls, a definite
bimodal distribution was found in the synovial fluids.
These data suggest that evaluation of T-, B-,and nullcell populations may be clinically useful in differen-
BRENNER E T AL
298
tiating patients with SLE and JRA from those with
rheumatoid arthritis and variant diseases.
T h e investigation of the inflammatory arthritides, especially the study of synovial fluids, has focused
primarily o n fluid-phase reactants, ie immunoglobulins
(l), rheumatoid factors (2), complement components
(3), a n d proteolytic enzymes (4,5). Studies delineating
T a n d B lymphocytes i n rheumatologic conditions are
sparse a n d limited in several respects. Although several investigators (6-8) have studied rheumatoid synovial fluid and peripheral blood lymphocytes, each
series has been limited i n t h e number of surfacemarking techniques a n d there has been no general
agreement on the comparisons between rheumatoid
a n d normal peripheral blood lymphocytes, or between rheumatoid peripheral blood a n d synovial fluid
lymphocytes. Furthermore there has been no work
comparing various inflammatory arthritides for Ta n d B-lymphocyte percentages i n blood a n d synovial
fluid.
Because of the presence of d e novo immunoglobulin synthesis (9), a B-cell function, a n d macrophage migration inhibitory factor production (lo), a
predominantly T-cell function, i n inflammatory synovial fluid, a n d because of the suggestion that peripheral blood T-lymphocyte depression may correlate with
certain pathogenic features of systemic lupus erythematosus (1 1), the surface characteristics of peripheral
blood a n d synovial fluid lymphocytes from patients
with inflammatory arthritides have been studied.
These studies demonstrated that T-cells are depressed
i n JRA, as well as in SLE, whereas the proportions
of T a n d B lymphocytes from patients with RA a n d
its variants were not significantly different from those
of controls.
MATERIALS AND METHODS
Clinical Characteristics of the Patient Population.
T h e peripheral blood and synovial fluids of 30 patients
with a variety of inflammatory arthritides as well as peripheral blood lymphocytes from 11 normal volunteers were
studied.
Rheumatoid Arthritis
All of the 14 patients studied had classic disease by
the criteria of Ropes et a1 (12), and all had a positive
sheep cell agglutination test (SCAT). A t the time of the
study, none of the patients was being treated with corticosteroids, and none had ever received cytotoxic drugs. One
patient had both a positive antinuclear antibody test
(ANA) (homogeneous pattern) and hypocomplementemia
(C3 89 mg%; normal: 120-160 mg%). This patient, a
59-year-old man with evidence of cutaneous vasculitis, had
nodular deforming rheumatoid arthritis and none of the
classification criteria for SLE other than positive ANA.
Systemic Lupus Erythematosus
Five patients, selected only for the presence of joint
effusions, were examined. A t the time of study, all were
separable from the RA patients by the preliminary classification criteria for SLE (13). Four patients had positive
ANAs in a homogeneous or peripheral pattern; none had
hypocomplementemia or exhibited renal failure. None of
the patients had received cytotoxic drugs, but 1 of the 5
was receiving corticosteroids (10 mg of prednisone per day)
for control of her polyarthritis.
Juvenile Rheumatoid Arthritis
Six patients were studied. Five of the 6 had the
onset of their oligo- or polyarthritis before age 16, although only 2 were less than 16 years of age at the time
of study. The sixth, although 34 years old at the onset
of his illness, had a febrile presentation with rash and polyarthritis typical of those patients described by Bywaters
(14) and by Bujak et a1 (15) as having adult Still's disease.
One patient had a positive ANA and a positive SCAT.
She was a 62-year-old woman who had had continuous
deforming polyarthritis since age 6. None of these patients
demonstrated hypocomplementemia, none had evidence
of polyserositis, and only 1, a 9-year-old boy with JKA and
secondary amyloidosis, had evidence of renal disease.
Rheumatoid Variants
This group of 5 patients included 3 with psoriatic
arthritis, 1 with Reiter's syndrome, and 1 with inflammatory bowel disease, ankylosing spondylitis, and peripheral
polyarthritis.
Lymphocyte Studies. Peripheral blood and synovial
fluid samples were obtained simultaneously from each patient. Lymphocytes for all surface marker studies were
separated from heparinized blood or synovial fluid by FicolHypaque centrifugation according to the method of Boyum
(16). Heparinized synovial fluid was first treated with hyaluronidase (Wydase, Wyeth Laboratories, Philadelphia,
Pennsylvania, Lot No. 4732403) according to a modification of the method of Hedberg (17); otherwise the techniques were similar for corresponding fluid and blood
lymphocytes.
Following aspiration, 5 ml of blood or synovial fluid
were layered onto 3 ml of Ficol-Hypaque and centrifuged
at 1200 rpm for 40 minutes. The lymphocyte-rich interface layer was then carefully removed and washed twice
in Hanks balanced salt solution (HBSS). The cells were
then counted in a hemocytometer chamber and, for E and
EAC rosette studies, adjusted in HBSS to a concentration
of 4 x 106 cells/ml.
T lymphocytes were detected by sheep red blood
cell (E) rosette formation according to the method of
Jondal et a1 (18). 1 x lo6 lymphocytes in 0.25 ml of HBSS
SURFACE CHARACTERISTICS OF SYNOVIAL FLUID
299
Table 1. Synovial Fluid Characteristics of Study Population
Much
Patient
Number
Diagnosis
Rheumatoid arthritis
Systemic lupus erythematosus
Juvenile rheumatoid arthritis
Variants
Good
Fair
Poor
14
5
0
1
5
4
6
1
0
2
2
9
0
3
3
5
were combined with an equal volume of a 0.5% washed
sheep red cell suspension, incubated at 37°C for 15 minutes,
centrifuged at 1000 rpm at 4°C for 5 minutes, and then
allowed to incubate as a pellet at 4°C for a further 8-12
hours. B lymphocytes were identified by the complement
receptor technique described by Bianco et a1 (19). Washed
sheep red blood cells (E) were first incubated with a sublytic concentration of 19s amboceptor (A) and then with
mouse complement (C) to form the complement carrier
system 19s EAC. 1 x 106 lymphocytes in 0.25 ml of HBSS
were combined with 0.25 ml of a 0.5% suspension of 19s
EAC and incubated at 37°C for 30 minutes. One drop of
a suspension of latex particles (Dow Diagnostics, No. 54217)
was added to each reaction in order to identify, by phagocytosis, macrophages and any remaining polymorphonudear
leukocytes that also carry surface complement receptors.
The percentage of E or EAC rosettes formed was determined by counting a total of 200 rosetting and nonrosetteforming lymphocytes in each reaction. Each determination
was performed in duplicate, and the results were expressed
as the average percent of rosetting cells.
B lymphocytes were identified by the presence of
surface immunoglobulins according to a modification of
the method of Aisenberg and Bloch (20). Following FicolHypaque centrifugation, lymphocytes were resuspended in
HBSS containing 10% fetal calf serum and 0.1% Na Azide.
2 x 106 lymphocytes in 0.1 ml of medium were then
combined with 0.1 ml of a fluorescein-conjugated polyvalent goat antihuman antiserum (Meloy Laboratories,
Springfield, Virginia, Lot No. C201-22 031) and incubated
at 4°C for 30 minutes. The lymphocytes were washed twice
in the same medium, resuspended in one drop of glycerol/
HBSS (50/50 v/v). and read in a Leitz fluorescent microscope through an FITC primary and -65 and +45 barrier
filters.
WBC
Mean
Lymphocytes,
Mean Percentage
10500
4260
48
56
39
21
20530
21940
RESULTS
Synovial Fluid Studies. The results of routine
synovial fluid analyses are presented in T a b l e 1.
Mucin tests were recorded as good, fair, or poor; white
counts and percentages of lymphocytes are given, as
means of the groups studied. When compared to all
other groups, patients with SLE exhibited better
mucin tests, significantly lower white counts, and
higher percentages of lymphocytes.
Lymphocyte Studies. T- and B-lymphocyte
determinations by E and EAC rosette formation a n d
surface immunoglobulin studies were carried o u t o n
all patients ( T a b l e 2). Because of their small number,
the patients with rheumatoid variant diseases were
combined a n d the results expressed as the means of
t h e group; by this method, t h e results obtained were
similar to those f o u n d in rheumatoid arthritis. For
statistical comparisons, the studies have been limited
to the RA, SLE, and J R A groups. Unless noted all
statistical evaluations were performed by the t test.
Peripheral Blood Studies
D a t a on the peripheral blood lymphocytes
from 11 normal subjects a n d from the patients with
RA, SLE, a n d JRA are presented i n Table 1. W h e n
normal lymphocytes were compared with the patient
groups for the mean percentage of E rosettes formed,
0.05) difference between
there was significant (P
3%) a n d SLE (55 f 11%) lymphocytes,
normal (66
<
+_
Table 2. Results of T - and B-Lymphocyte Studies
~~
~~~
~
~~
B Cells
T Cells,
E Rosettes
Diagnosis
Rheumatoid arthritis
Systemic lupus erythematosus
Juvenile rheumatoid arthritis
Rheumatoid variants*
Normal
EAC Rosettes
SIg Cells
Peripheral
Blood
Synovial
Fluid
Peripheral
Blood
Synovial
Fluid
Peripheral
Blood
Synovial
Fluid
6 9 2 8%
55+ 11%
58 k 4%
58 f 20%
66+ 3%
76+ 11%
44+ 7%
43+ 14%
54 + 15%
17f 9%
18 + 10%
23* 9%
1 7 k 10%
1 8 2 5%
13+6%
l3+8%
19+5%
25-C8%
1 8 k 10%
17+ 5%
16+ 9%
9 + 4y0
1 9 2 11%
9 + 2%
*Variant results are not included in statistical studies.
-
-
2 0 k 8%
14+ 6y0
16C 4%
-
BRENNER E T AL
300
NULL CELLS
MEAN PERCENTAGES IN SYNOVIAL FLUID
100
Fig 1. Mean percentages of null cells (see text) in the synovial
fluid of patients with RA, SLE, and JRA.
as well as a significant ( P < 0.001) depression in the
E rosettes formed by JRA peripheral blood lymphocytes (58 f 4y0). A significant depression in E rosette
formation was also noted when the lymphocytes of
RA patients (69 f 8y0)were compared to those from
patients with SLE ( P < 0.05) and with JRA ( P <
0.01). EAC rosette formation demonstrated no significant differences either when normal lymphocytes were
compared to patient populations, or when the various
patients groups were compared with each other.
Synovial Fluid Studies
Table 1 shows that 76 2 11% E rosettes were
found in rheumatoid synovial fluids, whereas the 44
f 7y0 found in SLE and the 43 f 14y0 found in JRA
fluids were significantly ( P < 0.001) depressed. A
further finding was the complete lack of overlap when
E rosette percentages from RA fluids were compared
to those of SLE and JRA fluids.
EAC determinations again differed little between the three groups. When compared with normal
peripheral blood lymphocytes, however, rheumatoid
synovial fluid EAC appeared significantly depressed
( P < 0.05).
EAC vs Surface Immunoglobulin
as a B-Cell Marker
As can be seen in Table 1, synovial fluid studies
revealed no significant differences between simultaneous EAC and surface immunoglobulin determina-
tions. Similar results were obtained in peripheral
blood studies, in both normal lymphocytes and in
cells from all the patient groups.
Null Cells
Null cells were defined as the percentage of
lymphocytes bearing neither T- nor B-cell surface
markers. T h e mean null cell percentage from 11
normal subjects was 18%. Wide variations in standard
deviation made comparisons by mean and standard
deviation unsuitable; however by use of the MannWliitney U test, in comparing synovial fluid null
cells from rheumatoid patients (mean: 13'%) with
those from patients with SLE (mean: 43Y0) and from
JRA patients (mean: 38y0),significant elevations in
SLE ( P < 0.002) and JRA ( P < 0.02) synovial fluid
null cell percentages were evident (Figure 1). A bimodal distribution was noted in the synovial fluid null
cell percentages from patients with RA, with one
group (5 patients) having 0-4% null cells, and another
group (5 patients) having 15-30y0 null cells. No
clinical or laboratory marker, including Westergren
sedimentation rate, the presence of rheumatoid or
antinuclear factor, the degree of clinical activity at
the time of study, or routine synovial fluid analysis,
could differentiate these two subgroups within the
rheumatoid population.
DISCUSSION
Functional lymphocyte studied by mitogenic
stimulation and mixed lymphocyte culture reactions
have indicated abnormal 'r- and B-cell activity in SLE
( 1 1). Moreover, several researchers have commented
on peripheral blood T-cell depression in SLE, using
both sheep red blood cell rosette formation and rabbit
antihuman thymocyte serum as markers (21-23).
Scheinberg and Cathcart have correlated this T-cell
depression both with clinical activity at the time of
the study and with the degree of lymphopenia (11).
Lymphocyte studies in rheumatoid arthritis, on
the other hand, have produced widely divergent results. In terms of functional measurements Stratton
(24) as well as Panayi (25) has reported poor synovial
fluid response to phytohemagglutinin and pokeweed
mitogen. Stratton however reported a normal rheumatoid peripheral blood response to several mitogens,
whereas Panayi found rheumatoid peripheral blood
lymphocyte responses to be depressed.
Several authors have studied the percentages of
T and B lymphocytes in the peripheral blood and
SURFACE CHARACTERISTICS OF SYNOVIAL FLUID
synovial fluid of patients with rheumatoid arthritis.
Again the results appear contradictory. Keith and
Currey, employing 30-minute 4OC incubation, found
20-4OOj, E-rosetting T cells in the peripheral blood
and synovial fluid of rheumatoid patients, and obtained similar results from normal peripheral blood
(6). Froland et al (8) studied peripheral blood and
synovial fluid lymphocytes from a rather heterogenous
group of inflammatory arthritides. They reported
higher T-cell percentages in the synovial fluid and
peripheral blood than in normal peripheral blood,
though the mean percentages were low (20-300/,) and
the standard deviations high.
Papamichail and coworkers (26) showed a
marked increase in rheumatoid peripheral blood
SIg staining, notably in IgG-bearing cells (31%). In
contrast Mellbye et al (7) reported a decrease in rheumatoid peripheral blood B lymphocytes by both SIg
and EAC markers. I n synovial fluid studies in rheumatoid patients, Froland et al (8) reported less than
1% SIg-bearing cells whereas Mellbye et al (7) found
fluid SIg cells present in higher percentages than in
either rheumatoid or normal peripheral blood.
T h e wide variations in reported results of Tand B-lymphocyte percentages have several possible
explanations. Jondal et a1 (18) have clearly shown
that prolonged 4OC incubation is required for complete E-rosette formation. Immunoglobulin capping,
endocytosis, and loss of surface marker have been
studied at 37OC; studies at 4"C, using Na Azide to
inhibit cellular metabolism, should result in more
complete surface immunofluorescent staining (27). Recently, Winfield et al, working at 4OC, have found
very high percentages of immunoglobulin-bearing
lymphocytes i n the peripheral blood of patients with
RA and SLE. They have shown that the bulk of these
immunoglobulins may be removed by overnight incubation at 37°C and by elution techniques, and that
they represent lymphotoxic antibodies adherent to the
cell surfaces (28).
T h e present studies reveal a relative depression in rheumatoid synovial fluid B lymphocytes by
EAC rosette formation, as intimated by Mellbye et al
(7), but fail to confirm any significant difference between simultaneous EAC and SIg determinations,
whether in peripheral blood or synovial fluid. A
significant depression in the percentage of T lymphocytes in the peripheral blood of patients with SLE
was confirmed. It was also found that T cells are
significantly depressed in the synovial fluid of patients
301
with SLE and in both the peripheral blood and
synovial fluid of patients with JRA. T o our knowledge these are the first reported studies of T- and
B-lymphocyte abnormalities in JRA. Panush et al (29)
as well as Hoyeraal (30) have studied cellular immune
mechanisms in J R A by both in vivo skin testing and
in vitro techniques of lymphocyte stimulation and
MIF production. Both groups found impaired skin
test responses in JRA patients which would be in
keeping with our finding of T-cell depression. T h a t
this depression is not a manifestation of an excess of
immunoglobulin-producing B cells may be inferred
by the stable percentages of both EAC and SIg lymphocytes, and by the proportionate increase in null
cells in both of these conditions. I n terms of pathogenesis one important feature of T-cell depression
may be the loss of normal T-cell mediated B-cell suppression and the subsequent production, by B cells, of
excessive antibody products that are especially prominent in SLE. T h e striking difference between T-cell
percentages in RA and those in SLE and J R A also
suggests the possibility either that the pathogenic
mechanisms are dissimilar, or that host responses to
similar insults are handled in dissimilar fashion.
T h e high percentage of null cells i n the peripheral blood of patients with SLE has been reported
previously by this laboratory (11). Similar high null
cell percentages in SLE synovial fluid as well as in
both peripheral blood and synovial fluid from patients
with JRA are newly demonstrated by these studies.
T-cell depression and a concomitant rise in the percentage of apparently unreactive null cells may explain the observation by Hoyeraal (30) of a negative
correlation between impaired skin reactivity and the
number of circulating peripheral blood lymphocytes
in patients with JRA. I n contrast to the present findings, recent studies by Winchester et al demonstrate
an increased percentage of null cells in RA but not
in SLE synovial fluid. These results may be explained
either by differences in disease activity, by exposure to
steroids or cytostatic agents, or by technical variations
that await further standardization (31).
T h e bimodal nature of the null cell population
in rheumatoid synovial fluid has been commented on
by Williams and coworkers (21). Although we did
not observe two statistically separable populations of
T cells as did Williams, a distinct depression of
synovial fluid B lymphocytes by EAC rosette formation was found, and this probably contributed to the
null cell population. This finding could not be cor-
BRENNER E T AL
302
related with any of the usual clinical or laboratory
parameters of disease activity; however, synovial fluids
were not studied for the presence of antigen-antibody
complexes or for variations i n complement levels.
T h u s it has been demonstrated that i n clearly
defined patient populations significant T-cell depression a n d null cell elevation do occur in systemic
lupus erythematosus a n d juvenile rheumatoid arthritis. Further studies of large numbers of patients are
necessary before these differences i n lymphocyte populations can be considered clinically useful.
ACKNOWLEDGMENTS
T h e authors would like to thank Dr. Alan C. Aisenberg for his expert advice on the surface immunoglobulin
staining technique, Dr. Hebert Kayne for statistical analysis,
and Mr. David Feigenbaum for photographic assistance.
We also gratefully acknowledge the technical assistance of
Ms. Lindy Burnett.
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