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Granulopoiesis in systemic lupus erythematosus.

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516
GRANULOPOIESIS IN
SYSTEMIC LUPUS ERYTHEMATOSUS
KAZUO YAMASAKI, YOSHIYUKI NIHO, and TOSHIYUKI YANASE
The pathogenesis of granulopoietic failure in
systemic lupus erythematosus (SLE) was studied. In 16
Japanese women with SLE, a decreased number of
granulocyte/monocyte progenitor cells (CFU-C) in the
bone marrow was demonstrated, and the number of
CFU-C correlated significantly with the peripheral
blood granulocytelmonocyte count. The peripheral and
bone marrow T lymphocytes suppressed the colony
formation of autologous or allogeneic bone marrow
CFU-C. These findings suggest that the decreased marrow CFU-C may be due to suppression by T lymphocytes, an event that may play an important role in the
pathogenesis of granulopoietic failure in SLE.
In patients with systemic lupus erythematosus
(SLE), the hematologic abnormalities include anemia,
leukopenia, and/or thrombocytopenia. Goeckerman
(I) in 1923 was the first to describe leukopenia in
patients with SLE. Other investigators later reported
that leukopenia is common in patients with this disease
(2-4). Although a decrease in peripheral blood lymphocytes has been emphasized, there is actually a
much greater absolute drop in the circulating granulocyte count in leukopenic patients with SLE (4). Although the mechanism of granulocytopenia in SLE is
unknown, the depletion may be related to decreased
granulocyte production in the bone marrow.
From the First Department of Internal Medicine, Faculty of
Medicine, Kyushu University, Fukuoka, Japan.
Kazuo Yamasaki, MD: Instructor; Yoshiyuki Niho, MD:
Lecturer; Toshiyuki Yanase, MD: Professor and Chairman, and
Dean of the Faculty of Medicine.
Address reprint requests to Kazuo Yamasaki, MD, First
Department of Internal Medicine, Faculty of Medicine, Kyushu
University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812, Japan.
Submitted for publication June 7, 1982; accepted in revised
form October 21, 1982.
Arthritis and Rheumatism, Vol. 26, No. 4 (April 1983)
To estimate the production of granulocytes, a
count of nucleated cells of the bone marrow alone is
not very useful. Rather, the granulocyte/monocyte
colony formation in vitro is determined in studies of
the granulopoietic process. This was the approach we
used to study the number of granulocyte/monocyte
progenitor cells (CFU-C) in the bone marrow of patients with SLE. Recently, T lymphocytes derived
from peripheral blood and bone marrow of patients
with aplastic anemia have been shown to possess
suppressor activity in vitro (5,6).
We now report that the number of CFU-C in the
bone marrow was decreased significantly in patients
with SLE compared with controls. Peripheral blood T
lymphocytes from 3 SLE patients tended to suppress
the CFU-C growth from allogeneic normal bone marrow. Furthermore, depletion and re-addition experiments of bone marrow T lymphocytes performed on 2
SLE patients showed similar effects. T lymphocytes
from SLE patients on corticosteroid therapy did not
suppress the CFU-C growth from allogeneic normal
bone marrow.
PATIENTS AND METHODS
Patients and controls. Sixteen Japanese women with
SLE were studied. All patients met the diagnostic criteria for
the classification of SLE from the American Rheumatism
Association (7). The clinical profiles of the patients are listed
in Table 1. Only patients 2, 10, and 13 had the inactive form
of the disease. SLE was considered active when clinical
findings such as arthralgia or arthritis, rash, serositis, oral
ulcer, glomerulonephritis, neurologic abnormalities, or hematologic changes were associated with a low level of CHSO
andor high level of anti-native DNA antibody.
N o patient was receiving corticosteroid or immunosuppressive therapy at the time of the study. Patients 3, 12,
517
GRANULOPOIESIS IN SLE
Table 1.
Hematologic and clinical findings of patients with systemic lupus erythematosus*
~~~~~
~
Peripheral blood
Patient
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Hb
gddl
WBC
/mm3
G
L
M
%
%
%
11.2
10.7
10.8
9.6
1.4
11.0
8.6
10.8
9.8
9.2
11.3
9.3
12.6
9.4
8.1
10.8
4,200
3,600
2,500
2,700
2,900
3,100
2,900
4,400
3,600
3,300
2,950
2,800
3,100
2,900
2,600
4,700
43
42
83
73
45
14
65
70
81
65
64
41
54
77
47
62
56
48
I5
25
49
26
24
26
14
25
32
59
43
21
38
30
I
10
2
2
6
0
11
4
5
10
4
0
3
2
15
8
Platelets
x
1 0 4 1 ~ ~ 3
19.0
12.6
9.8
6.8
7.1
28.5
12.0
ND
14.3
13.1
9.4
10.2
8.8
14.5
ND
26.0
BM
NCC
x 104/mm3
12.2
5.1
4.5
8.5
7.1
27.6
20.9
34.9
13.8
13.3
48.8
7.7
17.3
24.0
3.9
47.5
Laboratory data?
CH5O
<I8
24
11
17
<I8
18
10
12
<I2
33
16
11
37
17
30
20
Anti-DNA
antibodies
12
8
>I01
>%
>80
28
52
>lo6
80
10
34
173
I1
272
80
336
CFU-CS
112.2
109.7
110.5
100.0
12.0
121.2
134.0
167.0
150.7
134.5
104.5
101.o
101.8
139.5
110.5
129.7
* The following abbreviations are used: Hb = hemoglobin; WBC = white blood cells; G = granulocytes; L = lymphocytes; M = monocytes;
BM NCC = bone mamow nucleated cell count; CHSO = total hemolytic complement activity; CFU-C = granulocyte/monocyte progenitor cells;
ND = not done.
t Normal values: CH5O = 29-49 units/ml; anti-DNA antibodies = < 10 unitslml.
t Mean number of CFU-C per 2 x Id nonadherent bone marrow cells.
and 16 had previously received corticosteroid therapy for a
short time, and patients 7,8, 11, and 14 had previously been
treated with nonsteroidal antiinflammatory drugs for a short
time. Only patient 8 had been given a blood transfusion.
Thirteen (patients 1, 2,4-7,9-11, 13-16) had been pregnant.
Thirteen of the 16 patients had leukocyte counts below
4,000/mm3, and 9 had neutrophil counts below 2,000/mm3. In
patient 3, myelocytes and metamyelocytes were detected in
the peripheral blood. Fifteen of 16 patients were anemic (less
than 12.0 g d d l hemoglobin), and 5 of the 14 patients tested
had platelet counts less than lOO,OOO/mrn’.
Bone marrow samples were obtained from all 16
patients; in only 2 patients was marrow cellularity less than
50,000/mm3.The cellular distribution was fairly normal in all
cases, and there was no proliferation of abnormal cells.
There was no remarkable increase in lymphocytes in any
patient.
Controls were as follows: 2 were healthy volunteers,
5 were anemic patients with no leukocytic abnormalities, 3
had malignant lymphoma with no invasion of lymphoma
cells into the bone marrow. One patient with BehGet’s
disease and 3 with rheumatoid arthritis were simultaneously
studied. The leukocyte counts of these 14 persons were
within normal ranges. Bone marrow samples were also
obtained from all the controls. Written permission for all
tests was obtained from each of these 30 individuals.
Bone marrow specimens. Approximately 2 ml of bone
marrow fluid aspirated at the time of routine examination
was centrifuged at 200g for 10 minutes, and the buffy coat
was removed with a Pasteur pipette.
For bone marrow culture, the buffy coat was washed
twice with a-MEM, and marrow cells were resuspended in
a-MEM supplemented 20% fetal calf serum. To remove the
adherent cells, the cell suspension was placed in a glass Petri
dish according to the method of Messner et al (8). In this
way, the nonadherent bone marrow cells were suspended in
a-MEM.
Colony formation procedure. Nonadherent bone marrow cells in a final concentration of 2 x 16 cells/d were
plated in quadruplicates into 35-mm Lux standard Petri
dishes in a 1-ml mixture containing a-MEM, 0.8% methylcellulose, 20% fetal calf serum, and 10% conditioned medium
which contained colony-stimulating factor (CSF) (9). For the
source of CSF, the supernatant was prepared from the
culture medium of human placental tissue by the method of
Burgess et a1 (10). The human placental conditioned medium
(HPCM) was shown to stimulate the CFU-C maximally at a
concentration of 10%. The plates were incubated at 37°C
under 5% COZ in a humidified atmosphere for 14 days and
were then examined under an inverted microscope. A group
of 20 or more cells was defined as a colony (9). In each
experiment, the mean and standard deviations were calculated from colony numbers in 4 plates.
Assay for the effect of peripheral T lymphocytes on
normal bone marrow CFU-C. The mononuclear cells were
separated from freshly drawn peripheral blood in preservative-free heparin using gradient density sedimentation (1 1).
The mononuclear cells were washed in culture medium and
then incubated at 37°C in glass Petri dishes for 30 minutes in
5% COZ to remove adherent cells. Nonadherent cells were
washed out and suspended in a-MEM containing 20% fetal
calf serum. T lymphocytes were isolated from the suspension by binding to sheep red cells with E-rosette assay (12).
After hemolysis of sheep red cells and washing twice,
approximately 95% of the cells were viable. After isolation,
the cells were E-rosette positive. Coculture experiments
were then carried out as follows: lo5 T lymphocytes were
added to a 1-ml mixture containing a-MEM, 0.8% methylcel-
518
YAMASAKI ET AL
lulose, 20% fetal calf serum, 10% HPCM, and 16 nonadherent bone marrow cells from healthy volunteers. After culture
for 14 days, the colonies were counted.
Assay for the effect of bone marrow T lymphocytes on
autologous bone marrow CFU-C. Normal bone marrow contains a small fraction of T lymphocytes (13). To clarify
whether bone marrow T lymphocytes affect autologous
CFU-C, T lymphocyte-depleted bone marrow cells were
cultured for colony formation at the concentration of lo5
cells/ml. T lymphocyte depletion was accomplished by binding to sheep red cells with the E-rosette assay (12) using
bone marrow mononuclear cells obtained by gradient density sedimentation (1 1). T lymphocytes were re-added to the
specimen as follows: after hemolysis of sheep red cells and
washing, 3 x lo4 bone marrow T lymphocytes were added to
a 1-ml mixture containing a-MEM, 0.8% rnethylcellulose,
20% fetal calf serum, 10% HPCM, and 10’ autologous T
lymphocyte-depleted bone marrow mononuclear cells. After
culture for 14 days, the colonies were counted.
Statistical analysis. Differences between the mean
values were evaluated statistically using Student’s t-test, and
correlations were analyzed by linear regression and determination of correlation coefficients.
RESULTS
Numbers of granulocytelmonocyte progenitor
cells. The numbers of CFU-C in each patient with S L E
are shown in Table 1. The mean number of CFU-C in
16 patients with SLE was 119.1 -+ 23.2 (SD) per 2 x
lo5 nonadherent bone marrow (NA-BM) cells. However, in the control group (2 healthy volunteers, 5
patients with anemia but no leukocytic abnormalities,
and 3 patients with malignant lymphoma but no invasion of lymphoma cells into the bone marrow), the
mean number was 150.8 12.6 (SD) per 2 x 10’ NABM cells. In S L E patients, there was a significant
decrease (P < 0.01) in the number of CFU-C compared with findings in the controls. In 1 patient with
BehGet’s disease and 3 with rheumatoid arthritis but
no leukopenia, the mean number of CFU-C was 157.1
f 23.3 (SD) per 2 x lo5 NA-BM cells. In these
patients with collagen diseases but no leukopenia,
decrease in the number of CFU-C was not evident.
Next, 16 patients with S L E were classified into
neutropenic (less than 2,000/mm3) and non-neutropenic groups. In the neutropenic population (9 patients) the mean number of CFU-C was 105.l ? 16. l
(SD) per 2 x lo’ NA-BM cells. In the non-neutropenic
population (7 patients) the mean number of CFU-C
was 137.0 ? 18.0 (SD) per 2 x lo’ NA-BM cells. Thus,
the neutropenic patients had low numbers of CFU-C,
compared with non-neutropenic patients (P < 0.01).
Relationship between the numbers of CFU-C and
the peripheral granulocytelmonocyte counts. Since
*
CFU-C is thought to differentiate in the bone marrow
and form mature granulocytes and monocytes, the
correlation between the numbers of CFU-C and the
peripheral granulocyte/monocyte counts was examined. As shown in Figure 1, the correlation was
statistically significant (r = 0.822, P < 0.01). The
number of CFU-C per 1 ml of the marrow fluid was
also calculated using the nucleated cell counts of
marrow fluid. The correlation between these corrected
numbers and the peripheral granulocyte/monocyte
counts was statistically significant (r = 0.709, P <
0.01).
Cell mediated suppression on the granulopoiesis.
To clarify the possibility of cell mediated suppression
on the granulopoiesis in SLE, we studied the effect of
T lymphocytes from SLE patients on granulocyte/
monocyte colony formation by autologous and allogeneic bone marrow cells. The results are shown as
percent recovery, under the assumption that the colony numbers were 100% without the addition of T
lymphocytes.
Figure 2 shows the effect of peripheral T lymphocytes from patients 12, 14, and 16 with S L E (MF,
RN, and YI), before corticosteroid therapy, on normal
CFU-C. Patients 14 (RN) and 16 (YI) had histories of
pregnancy only, and patient 12 (MF) had no history of
either pregnancy or blood transfusion. The colony
formation was suppressed significantly by the addition
of lo5 peripheral T lymphocytes (P < 0.01, P < 0.01,
and P < 0.05, respectively). These phenomena were
not detected in 3 healthy individuals.
Figure 3 shows the effect of peripheral T lymphocytes from these 3 SLE patients before and during
corticosteroid therapy. The inhibitory effect seen before corticosteroid therapy had disappeared. After the
200
1
Y
0
I r 0 111
PCO 01
0
1000
2000
3000
4 0 0 0 (Im’l
peripheral granulocylalrnonocyte count
Figure 1. Relationship between the numbers of granulocytelmonocyte progenitor cells (CFU-C) and the peripheral granulocyte/
monocyte counts.
GRANULOPOIESIS IN SLE
519
T
.
P c 0.01
PcO.05
..
t
administration of corticosteroids, the peripheral granulocyte counts were elevated from 1 , 148/mm3to 6,020/
mm3 in patient 12 (MF). In patients 14 (RN) and 16
(YI), peripheral granulocyte counts were also elevated
from 2,233/mm3 to 6,8M/mm3 and from 2,914/mm3 to
5, 1M/mm3, respectively.
Figure 4 shows the effect of bone marrow T
lymphocytes on autologous CFU-Cin patients 13 and
14 (RK and RN) with SLE. Both had a normal
pregnancy but had never received a blood transfusion.
The colony formation was suppressed significantly
( P < 0.01 and P < 0.05, respectively) by the readdition of autologous bone marrow T lymphocytes,
although this suppression was not evident in 2 healthy
volunteers.
DISCUSSION
MF RN Y I
S L E
T-cell added
Normal
T-cell added
Figure 2. Granulocytelmonocyte progenitor ctll (CFU-C) growth
by normal bone marrow cells cocultured with peripheral T lymphocytes obtained from patients 12, 14, and 16 (MF, RN, and YI) with
systemic lupus erythematosus before corticosteroid therapy and
from 3 healthy individuals.
T
Although mechanisms of leukopenia in systemic lupus erythematosus have been extensively discussed (14-21), no conclusions have been reached.
Possible mechanisms of the production of granulocytopenia in patients with SLE include: 1) increased
peripheral destruction of granulocytes, 2) changes in
pco.01
** p C O . 0 5
MFI'
/
/
1
A
before
therapy
during
t hetapy
Figure 3. Effects of peripheral T lymphocytes from patients 12, 14,
and 16 (MF, RN, and YI) with systemic lupus erythematosus on
normal granulocytehonocyte progenitor cells (CFU-C) before and
during corticosteroid therapy.
R N RK
S L E
T-cell
re-added
Normal
T-cell
re-added
Figure 4. Effects of bone marrow T lymphocytes o n autologous
granulocytehonocyte progenitor cells (CFU-C) in patients 13 and
14 (RK and RN) with systemic lupus erythematosus and 2 healthy
individuals.
YAMASAKI ET AL
marginal and splenic pool, and 3) decreased marrow
production.
To estimate the production of granulocytes in
the bone marrow, nucleated cell count with differential
count has been used. In the report of Kimball et a1
(18), 7 of 21 patients with SLE had marrow hypocellularity. Michael et al (4) reported that 4 of 32 patients
were probably hypoplastic. Differential counts of bone
marrow cells do not show characteristic findings in
SLE. Since peripheral granulocytes are the progeny of
CFU-C in the bone marrow, studies on CFU-C do
provide pertinent information. Greenberg and Schrier
(21) assayed the number of CFU-C in leukopenic
patients. In patients with aplastic anemia, the number
of CFU-C is reported to be decreased compared with
findings in disease-free individuals (22,23). We found
the number of CFU-C in the bone marrow to be
significantly decreased in patients with SLE in comparison with the control group, and these riumbers
correlated strongly with the peripheral granulocyte/
monocyte counts. The neutropenic patients with SLE
had lower numbers of CFU-C than did the nonneutropenic patients. Our results suggest that the decrease in
number of CFU-C in the bone marrow may play an
important role in the mechanism of granulocytopenia
in SLE. There may be obstacles to the proliferation
and differentiation of CFU-C in SLE patients.
Recent observation indicated that lymphocytes,
especially T lymphocytes, may play a role in the
pathogenesis of aplastic anemia (5,6,24-26). Furthermore, Bagby and Gabourel (27) reported the T lymphocyte-mediated suppression of granulopoiesis in
rheumatic disorders, and Abdou et a1 (28) reported the
suppressor cell-mediated neutropenia in Felty’s syndrome. Thus, the concept of suppression of progenitor
cell growth by lymphocytes is not new.
However, the possibility of lymphocyte-mediated suppression of granulopoiesis prompted us to
examine the leukopenia seen in S L E for the possible
role of suppressor activity at the level of the progenitor
cells. In the present study, peripheral T lymphocytes
from patients with S L E who were not receiving corticosteroids inhibited the colony formation of CFU-C in
vitro by bone marrow from healthy individuals. In
addition, bone marrow T lymphocytes also inhibited
the colony formation of CFU-C in vitro by autologous
bone marrow cells from patients with SLE. I n the
patients with S L E from whom lymphocytes or marrow
cells were used for coculture experiments, patients 13,
14, and 16 had been pregnant but had not received
blood transfusions. Patient 12 had no history of either
blood transfusion or pregnancy. Thus, the possibility
that suppression is mediated by alloimmunization or
sensitization to HLA antigen can be ruled out (29).
Recent reports have suggested that the T lymphocytes involved in the pathogenesis of granulopoietic failure in aplastic anemia are of the “suppressor/
cytotoxic” subset (30,3 1). The suppressive effects of
normal activated T cells bearing the receptors for the
Fc fragment of IgG on autologous and allogeneic
marrow cells have also been demonstrated (32). Recent studies suggested that the OKT8 population of
lymphocytes may be responsible for the granulocytopenia in patients with lymphoproliferative disorders
(33). The same subset of T lymphocytes may possibly
be related to the suppression of granulopoiesis in
patients with SLE.
A number of cytotoxic and suppressor functions of T lymphocytes are inhibited by glucocorticoids (34.35). We found that T lymphocytes from SLE
patients on corticosteroids did not inhibit the granulocyte/monocyte colony formation by normal marrow
cells. After steroid therapy, granulocyte counts in
these patients were elevated.
Although it remains uncertain whether the in
vitro inhibition of granulocyte/monocyte colony formation by T lymphocytes from patients with SLE is
mainly responsible for the granulocytopenia seen in
vivo, a population of suppressor cells on CFU-C was
demonstrated in our SLE patients.
ACKNOWLEDGMENTS
We are grateful to Drs. T. Kusaba, T. Sakata, and K .
Kajiyama for pertinent suggestions, to M. Ohara for comments on the manuscript, and T. Wakana and N . Yamasaki
for secretarial services.
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