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Natural killer function in systemic lupus erythematosus.

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NATURAL KILLER FUNCTION IN
SYSTEMIC LUPUS ERYTHEMATOSUS
THOMAS HOFFMAN
Peripheral blood lymphocytes from patients with
systemic lupus erythematosus (SLE)demonstrated significantly less cytotoxicity against two different lymphoblastoid cell lines and one myeloid cell line than peripheral blood lymphocytes from normal individuals.
Short-term culture and other attempts to remove interfering immune complexes failed to restore low natural
killer (NK) function. Six day culture in fetal calf serum
resulted in increased cytotoxicity by mononuclear cells
from normal individuals and some SLE patients, but this
effect was shown to be dependent on Fc-, not Fc+, effector cells. Suppressor cells were not demonstrable as a
cause for decreased NK activity.
Systemic lupus erythematosus (SLE) has been
associated with numerous immunologic aberrations (I),
ranging from abnormalities of antibody formation to
defects in cellular immunity. Recently studies in humans and a mouse (NZB) model have found impaired
cytotoxic functions as well, notably those involving
antibody-dependent cell cytotoxicity (ADCC) (2) and
cell-mediated lympholysis (CML) (3,4).
Much interest of late has focused on cytotoxic
immune functions which take place in the absence of
exogenous antibody or known prior sensitization. Socalled natural killing (NK) or spontaneous cell-mediFrom the Rockefeller University, 1230 York Avenue, New
York, NY 10021.
Thomas Hoffman, MD: National Cancer Institute, Bethesda,
Maryland.
Address reprint requests to Thomas Hoffman, MD, National
Cancer Institute, Building 10, Room 8B-03, Bethesda, M D 20205.
Submitted for publication June 28, 1979; accepted in revised
form August 23, 1979.
Arthritis and Rheumatism, Vol. 23, No. 1 (January 1980)
ated cytotoxicity has been implicated in host defense
against tumors, viruses, and foreign tissue (5).
Studies of effector cells involved in natural cytotoxicity in humans have established their similarity to
those participating in antibody-dependent cell cytotoxicity (K cells), principally by the presence of Fc receptors (6,7). In light of previous reports (2) and our
own observations (8) documenting impaired ADCC in
SLE by immune complexes, antibodies or innate abnormalities of Fc receptor-bearing cell populations, it
seemed relevant to study natural killer function as
well. We chose to assess NK function in patients with
SLE by utilizing radioactive 5'Cr-labeled human lymphoblastoid cell lines (LCL) as targets. The principal
problems addressed were: Does natural cytotoxicity reflect pathophysiologic or clinical changes in patients
with SLE? What role might the interactions of Fc receptors with antibody or immune complexes play in enhancing or impairing cytotoxic function?
MATERIALS AND METHODS
Patient selection. Thirty-one SLE patients (25 females, 6 males) were studied. All attended the SLE clinic at
the Rockefeller University Hospital. Each patient satisfied the
American Rheumatism Association (ARA) clinical criteria for
the diagnosis of systemic lupus erythematosus and had
strongly positive diagnostic serologies, i.e., antinuclear antibody and anti-DNA antibodies in high titer. Patients were
initially classified as having active or inactive disease based on
the clinician's subjective evaluation of the presence or absence
of systemic symptoms or organ involvement, followed by laboratory documentation of lymphopenia, hypocomplementemia, and elevated erythrocyte sedimentation rate. Healthy
laboratory personnel or volunteers served as controls.
Cell isolation and culture. Mononuclear cells were isolated from heparinized venous blood on Ficoll-Hypaque gra-
NATURAL KILLER FUNCTION IN SLE
Table 1. Natural cytotoxicity against lymphoblastoid cell lines by
peripheral blood lymphocytes from patients with systemic lupus
erythematosus or normal individuals
% "Cr released from cell lines:
1301
Normal
Males (20)
Females (26)
All (46)
SLE
Males (6)
Females (25)
All (31)
31
counts released in the presence of medium or detergent (Nonidet P-40), respectively.
Statistical analysis. P values were derived by an application of Student's t-test.
Raji
K562
RESULTS
43.9 f 16.7
3 1.5 f 14.9
37.0 -r- 16.7
29.7 f 17.1
26.5 f 17.1
27.9 f 17.0
43.6 f 14.2
30.6 f 14.2
36.1 f 15.2
13.6 f 15.7*
19.0 -r- 12.3t
18.0 f 12.9*
7.8 f 8.6t
11.9 f 9.4*
11.0 f 9.2*
18.0 f 24.0*
19.2 f 14.8t
19.0 f 16.6*
Natural killing of LCL by normal individuals or
SLE patients. Incubation of peripheral blood mononuclear cells from normal individuals together with
"Cr-labeled lymphoblastoid cell lines for 4 hours at
37°C uniformly resulted in lysis as measured by the release of radioactive label into the supernatant. Because
some cell lines tested in preliminary experiments were
somewhat more readily lysed than others, three representative lines of different lineages were chosen for this
study: 1301 (T), Raji (B), K562 (myeloid). Cytotoxicity
was related in a logarithmic fashion to the ratio of effector cells to targets. In most instances three effector:target (C/T) ratios were tested-100: 1, 50: 1, 10: 1,
but for purposes of comparison, data for only the highest ratio are shown.
Normal individuals displayed a wide range of
* P < 0.001; normal versus SLE.
t P < 0.01; normal versus SLE.
dients. Where indicated, monocytes were removed by adherence t o plastic, or by a magnet subsequent to their
phagocytosis of iron particles. E rosette forming and non-E
rosette forming cells were isolated as described (9). Checks for
purity of subpopulations were accomplished by examining
fixed slides for characteristic a-naphthyl-acetate acid esterase
staining (10). Criteria for preparations suitable for use were: T
cells: > 95%; B cells: < 5% characteristic large granule-positive
staining; monocyte-depletion: < 5% diffuse cytoplasmic staining. Lymphocytes with Fc receptors were enumerated or isolated after Ficoll-Hypaque density gradient separation by using bovine erythrocytes coated with rabbit IgG antibody
(EAG) as described (1 1).
Cells (2 X 106/2ml RPMI) were cultured in 15 mm diameter Linbro (Bellco, Vineland, New Jersey) wells in concentrations of fetal calf serum (FCS) (Reheis, Phoenix, Arizona) as noted. Cultures were maintained for 6 days in a
humidified environment with 5% CO, at 37°C without disturbance or rocking. Cells were harvested by vigorous resuspension with a Pasteur pipette followed by two additional washes
with medium.
Cytotoxicity assays. Lymphoblastoid cell lines were
maintained in continuous suspension culture in RPMI-1 0%
FCS. Five 10 X lo5 cells in 0.3 ml FCS were labeled with 300
pCi "Cr (New England Nuclear, Boston, Massachusetts) for 2
hours to achieve approximately I cpm/cell, then washed three
times with phosphate buffered saline (PBS), 5% FCS, and resuspended at 2 X 104/ml in RPMI 20% FCS. One hundred
microliters of effector cells at concentrations ranging from 2 x
106/ml to 2 x 10S/ml were incubated in triplicate with 100 pl
of targets (E/T 100: 1 to 10: 1) for 4 hours at 37OC (5% CO,)
in V-bottom microtiter plates (Cooke, Alexandria, Virginia).
At the end of the 4-hour incubation period, plates were centrifuged in the cold at 400 rpm for 10 minutes; 100 pl of supernate were removed and counted in a gamma cc inter. Specific
cytotoxicity (7) was calculated according to the following formula:
C exp - C background
Y=
C total - C background
Where C exp equals counts released into the supernatant in
the presence of effector cells, C background or C total equals
70
60
-
55
-
45
0)
Y,
[3
Q,
50
40
7
(D
L
0
$?
35
30
v
% 25
.-+
V
' 2 20
0
'0
15
0"
10
4-
5
0
8
I
8
il,
active
SLE
Figure 1. Natural killing by peripheral blood mononuclear cells by
use of S'Cr-labeled 1301 (T) LCL as targets at an effector: target ratio
100:1. Values for normal individuals and SLE females and males, respectively, are illustrated on either side of the mean f SE of the group
as a whole.
HOFFMAN
32
Table 2. Effect of removing Fc receptor-bearing cells on NK activity
% 5’Crreleased
from cell lines:
Population (E/T
= 100 I )
Experiment 1
Peripheral blood lymphocytes
(whole)
-Fc*
+Fct
Experiment 2
T cells (whole)
-Fc*
+Fct
1301
Raji
K562
37.0
1.6
16.0
7.4
3.3
3.0
28.2
8.7
12.7
55.4
7.3
20.6
46.7
4.1
7.8
66.5
4.5
20.2
* Peripheral blood lymphocytes found at interphase of Ficoll-Hypaque gradient after rosette formation with EAG, thereby depleted (<
I%) of Fc receptor positive cells.
t Peripheral blood lymphocytes rosetting with EAG (> 95%) pelleted through a Ficoll-Hypaque gradient.
cytotoxic capacity for all three cell lines tested, as evidenced by the wide standard deviations observed in
Table 1 and Figure 1. However, individuals tested on
different days consistently displayed characteristic high
or low cytotoxicity versus all cell lines tested.
As a group, patients with systemic lupus erythematosus, studied in parallel with normals, demonstrated significantly reduced cytotoxicity against all
three cell lines (Table 1). Six of 31 patients unequivocally classified as having active disease based on criteria
outlined in Materials and Methods had among the lowest levels of NK cytotoxicity measured, as seen from
data for cell line 1301 (Figure 1).
Male SLE patients were particularly deficient in
NK activity compared to normal males; the disparity
was somewhat less marked in a comparison between the
female groups (Figure l), as seen from data presented
for the 1301 cell line. The data also suggest a statistical
difference (P < 0.01) between normal males and females in NK function against the cell line 1301 (shown
in the figure). Studies in the K562 system also suggested
this difference.
Although certain patients classified as having
“inactive” disease demonstrated impaired NK activity
to a degree similar to the 6 active patients, corroborating laboratory findings or clinical signs of overt activity
were lacking. Attempts to find a single predictor of low
NK function were unrevealing. Examples could be
found of selected patients with relatively normal lymphocyte counts, ESR, and CH50 (and normal markers
for T, B, and total Fc receptor cells) who had natural
cytotoxicity in a low range similar to the “active” patients. Conversely, certain patients considered inactive
clinically but with lymphopenia and elevated sedimentation rate, but generally not those with low complement (unless due to an inherited complement abnormality), had close to normal natural cytotoxicity.
Initially SLE patients on pharmacologic doses of
steroids were avoided because of problems of interpreting the effects of the drug on NK function. Evidence in the literature (12) supports the concept that
steroids may impair many cellular functions and some
cytotoxic functions as well. However, it was observed
that as initially active patients were treated with steroids
in high dosage (60 mg/day), thereby effecting improvement in their clinical status, cytotoxicity against cell line
targets increased. A comparison of cytotoxicity by lymphocytes of SLE patients on various regimens of steroids showed no significant difference to those on no
therapy. Indeed, of 4 patients on the highest steroid dosages, 2 had normal cytotoxicity.
Possible role for immune complexes in inhibition
of NK activity. Preliminary experiments on the nature
of effector cells in our NK system showed its dependence on free Fc receptor-bearing lymphocytes for activity. As seen in representative experiments in Table 2,
removal of Fc receptor-bearing cells by centrifugation
through Ficoll-Hypaque of those cells rosetting with
antibody-coated bovine erythrocytes (EAG), resulted in
profound reduction of NK activity in the residual Fc(interphase) population. This was true whether whole
(Experiment 1) or purified E-rosette forming populations (Experiment 2) were used. Minor residual cytotoxic capacity could be detected in Fc’ (pelleted) fractions, but no enrichment was observed. Inhibition of
natural cytotoxicity could also be effected by the graded
addition of preformed antigen-antibody complexes
(EAG) directly to the assay system (Table 3).
Documentation of inhibition of natural killer activity by circulating immune complexes was precluded
by technical considerations in assaying the effects of
SLE sera on the NK system, including the prevalence of
antibodies against peripheral blood cells and (espeTable 3. Effect of EAG immune complexes on natural killing
% ”Cr released
from cell lines:
Peripheral blood
lymphocytes + 0
1301
Raji
K562
+ I%OxRBC
+ I%EAG
+ 0. I% EAG
+ 0.01%EAG
46.0
60.2
3.1
2.2
10.4
51.9
57.3
6.2
8.5
39.4
31.9
58.2
1.6
2.8
31.5
NATURAL KILLER FUNCTION IN SLE
33
Table 4. Natural cytotoxicity against lymphoblastoid cell line targets
by normal or SLE peripheral blood mononuclear cells before and
after culture in fetal calf serum
toxicity could be observed (data not shown in the table).
Culture in AB serum invariably resulted in a persistent
loss of measurable cytotoxic function.
As evidenced in Table 5, cytotoxicity against cell
lines after culturing peripheral blood lymphocytes was
much less dependent on Fc receptor-bearing cells. Representative experiments summarized in the table demonstrate removal on a Ficoll-Hypaque gradient of Fcrosette forming cells or addition of EAG complexes
having relatively minor effect on cytotoxicity against
LCL. Furthermore, purified (prior to initiation in culture) Fc- peripheral blood lymphocytes or Fc- T populations showed significant cytotoxicity on day 6 despite
the failure to express Fc receptors (data not illustrated
in the table).
As observed for cytotoxicity against LCL measured prior to initiation in culture, SLE patients showed
significantly impaired NK activity (Pc 0.001) after culture in FCS compared to normal controls (Table 4).
Certain individual SLE patients’ cells occasionally were
seen to develop significantly augmented NK function
after culture in fetal calf serum (5/11), but in general,
most cases failed to show an increase, including 4/5 additional patients not included in Table 6 (10/15 total).
Of the 6 “active” cases studied in this fashion, none
showed enhanced cytotoxicity.
Results employing the Raji cell (B) line as targets
before and after culture gave results similar to those described for 1301 (T).
Failure to establish a role for suppressor cells in
the diminished cytotoxic function of SLE peripheral
blood lymphocytes. In those patients who developed
cytotoxic capacity after culture, the possibility existed
that suppressor cells present in vivo could be inactivated
Cell line (1301)
Normal
A
B
i=
D
E
F
G
H
I
J
K
(mean f SD)
SLE
A
B
C
D
E
F
G
H
I
J
K
(mean f SD)
Day 0
Day 6
20.2
47.8
34.7
65.7
48.6
61.4
7.7
25.6
68.7
40.4
42.8 f 20.3
64. I
66.8
46.3
79.8
45.8
68.0
45.0
71.9
88.0
68.0
56.6
63.6 f 14.1
9.5
3.5
0
15.0
2.9
21.0
6.7
23.7
11.0
23.5
35.0
13.8 f 10.9
61.0
18.1
11.0
15.3
2.7
61.6
63.3
83.7
13.9
26.5
50.3
37.6 f 28. I
P < 0.001
P < 0.001
cially) lymphoblastoid cell lines in the sera of most SLE
patients. Since indirect evidence did exist that immune
complexes blocking Fc receptors might play a role in
decreased NK function, attempts were made at augmenting this activity by removing immune complexes.
Overnight culture of SLE lymphocytes at 4” or 37°C in
FCS-containing or serum-free medium with or without
prior protease treatment or repeated (5-10) washes did
not alter the activity.
Cytotoxicity after &day culture in FCS. Since
short-term (24-48 hours) culture failed to result in improved NK cell function, longer incubations were attempted. When normal peripheral blood mononuclear
cells were cultured in medium supplemented with fetal
calf serum, an augmentation of NK activity was usually
observed (cf. Table 4). This effect, independent of the
lot of serum tested or the geometry of the culture vessel
employed, was maximal after 6-7 days of culture and
was relatively independent of the concentration of FCS
(2-20%) used. At higher effector cell concentrations individuals with high levels of cytotoxicity showed less
dramatic improvement than those who were low to
start, but at lower E/T ratios tenfold increase in cyto-
Table 5. Effect of removing Fc receptor bearing cells or addition of
EAG immune complexes on cytotoxicity after culture for 6 days in
fetal calf serum
% 51Crreleased from
1301
Raji
Whole
-Fc*
+Fct
46.3
49.2
26.6
20.5
20.6
7.0
+O
54.1
62.3
40.7
38.5
37.7
30. I
Peripheral blood lymphocytes
+ 1% Ox RBC
+ I%EAG
* Cells found at interphase after EAG-rosette formation with cultured peripheral blood lymphocytes and centrifugation through a Ficoll-Hypaque gradient.
t Cells found in the pellet after EAG-rosette formation with cultured peripheral blood lymphocytes and centrifugation through a Ficoll-Hypaque gradient.
HOFFMAN
34
or lost in vitro. However, significant suppression of normal cytotoxicity was only rarely (2/ 15) demonstrable by
addition of SLE mononuclear cells to those of normal
individuals for 24 hours before assay (on either day 1 or
day 6). Incubating normal cells on monolayers of cultured SLE cells for 24 hours, or direct addition of SLE
lyaphocytes to the cytotoxic assay, did not demonstrate
a sbppressive effect. Furthermore, x-irradiation of SLE
cells in graded doses from 120R to 1200R similarly had
no effect on augmenting cytotoxicity.
DISCUSSION
This study demonstrates abnormal natural cytotoxicity on the part of patients with systemic lupus erythematosus. SLE patients, as a group, failed to lyse a variety of lyinphoblastoid cell line targets (in the absehce
of exogenous antibody) compared with normal individuals.
One form of spontaneous cytotoxicity, so-called
natural killer activity, detectable in freshly isolated lymphocyte preparations is dependent on lymphocytes
bearing free Fc receptors, including those cells with the
property of forming low affinity E rosettes. As evidenced from experiment5 employing ox erythrocytes
coated with rabbit 7s antibody, and examples from the
literature using aggregated gamma globulin or sheep
EA (12,13), immune complexes may interfere with natural killing function in vitro. SLE patients with circulating immune complexes and defective NK function may
represent the in vivo correlate of this phenomenon.
Unlike the interference with ADCC by direct
competition for Fc receptors, immune complex impairment of natural cytotoxicity may take place via steric
inhibition of other specific cell surface receptors that
recognize the target. Fc interaction with immune complexes may also trigger events usually associated with
lysis from which the cell is unable to recover. We favor
this latter interpretation based on the inability to restore
NK activity of SLE lymphocytes upon incubation under conditions known to favor shedding of formed immune complexes, even after enzymatic treatment.
Other explanations for impaired natural killing
function may reside in an absence of cells capable of
NK activity and failure of binding or lytic function. Although Fc receptor cells are detectable in the peripheral
blood of SLE patients, relative numbers are generally
lower (14), possibly reflecting a loss of subpopulations
of these cells, including those functional in natural killing.
Decreased NK was observed to correlate with
disease activity in certain SLE patients. However, instances of markedly depressed natural killing were also
observed in selected inactive cases, precluding the assay’s general use as a laboratory indicator of clinical
status.
Lymphocytes from certain SLE patients fail to
develop increased cytotoxicity toward LCL after culture
in fetal calf serum. This property of normal lymphocytes, as desdibed by Zielski and Golub (15) and Ortaldo (16), probably differs from standard natural killer
function in not being dependent on cells bearing Fc
receptors. Data presented here support the contention
that at least two functionally different populations capable of lysing LCL targets exist or that some cooperation between different (Fc- and Fc’) cell types may be
initially necessary in this system. This phenomenon
may be a form of mitogen-induced cytotoxicity whereby
special cytotoxic cells are activated during culture or removed from controlling factors operating on circulating
cells. Our observations on persistent low NK activity
versus cell lines on the part of certain SLE patients’
lymphocytes after 6 days of culture suggest that some
patients are deficient in recognition or lytic functions
other than those associated with Fc receptor-bearing
cells exclusively.
In an extensive review of the literature, only one
report citing a study of natural cytotoxicity by patients
with SLE was encountered. Skurkovich et a1 (17) found
increased spontaneous cytotoxicity toward a certain
lymphoblastoid cell line by 4 of 5 patients with SLE.
This activity could be abrogated by the in vivo administration or in vitro addition of anti-interferon immune
globulin. Although the study is small and their system
less well characterized than our own, their observations
suggest variation in NK activity toward certain targets
in SLE Patients as well as in nortnal individuals.
The differences in NK against two cell lines observed in males and females along with especially low
function in SLE males raises implications regarding the
tole of genetic factors unique to the sexes, or hormonal
interplay in modulating natural cytotoxicity responses.
The greater susceptibility to SLE in females compared
with males, the observed occurrence of SLE in some patients with Klinefelter’s syndrome (18), and the ability
to modify the course of autoimmune disease in NZB/
NZW mice by sex hormone manipulation (19) may be
related to differences in immune capabilities partly reflected in NK activity.
Presently it remains unclear whether the defects
in cytotoxic activity observed in SLE are primary or
secondary. It would be attractive to consider a geneti-
NATURAL KILLER FUNCTION IN SLE
35
cally determined lack of recognition or effector function
underlying an increased susceptibility to the inciting
pathogenetic event (possibly virus infection) in SLE.
Mice with high or low natural cytotoxic capability (20)
based on genetic control of cell binding specificities (21)
have been described which show correlation with susceptibility to tumors or virus infection. Furthermore,
lower levels of NK against xenogenic or allogeneic targets have been observed in individuals with the specific
HLA type A3,B7 (22,23). What role, if any, diminished
NK function plays. in promoting the “autoimmune”
phenomena observed in SLE remains to be elucidated.
At present, these observations provide a basis for studying the complex alterations in recognition and lytic
function manifested in this disease, while illustrating the
vaned mechanisms responsible for cytotoxic phenomena in normal individuals.
9. Hoffman T, Kunkel HG: The E-rosette test, In Vitro
Methods in Cell-Mediated and Tumor Immunity. Edited
by BR Bloom, JR David. New York, Academic Press,
1976, pp 71-81
10. Knowles DM, Hoffman T, Ferrarini M, Kunkel HG: The
demonstration of acid a-naphthyl acetate esterase activity
in human lymphocytes: usefulness as a T-cell marker.
Cell Immunol35:112-123, 1978
11. Ferrarini M, Hoffman T, Fu SM, Winchester RJ, Kunkel
HG: Receptors for IgM on certain human B lymphocytes.
J Immunol 119:1525-1529, 1977
12. Parillo JE, Fauci AS: Comparison of the effector cells in
human spontaneous cellular cytotoxicity and antibodydependent cellular cytotoxicity: differential sensitivity of
effector cells to in vivo and in vitro corticosteroids. Scand
J Immunol8:99-108, 1978
13. West WH, Cannon GB, Kay HD, Bonnard GD, Herberman RB: Natural cytotoxic reactivity of human lymphocytes against a myeloid cell line: characterization of
effector cells. J Immunol 118:355-361, 1977
14. Fauci AS, Steinberg AD, Haynes BF, Whalen G: Immunoregulatory aberrations in systemic lupus erythematosus.
J Immunol 121:1473-1479, 1978
15. Zielskie JV, Golub SH: Fetal calf serum induced blastogenic and cytotoxic responses of human lymphocytes.
Cancer Res 36:3842-3846, 1976
16. Ortaldo JR, Bonnard GD, Herberman R: Cytotoxic reactivity of human lymphocytes cultured in vitro. J Immunol
119:1351-1357, 1977
17. Skurkovich SV, Skorikova AS, Kubrovina NA, Riabova
TV, Eremkina EF, Golodnenkova VN, Klinova EG, 01shanski AJ, Shurlop NF: Lymphocytes cytotoxicity toward cells of human lymphoblastoid lines in patients with
rheumatoid arthritis and systemic lupus erythematosus.
Ann Allergy 39:344-350, 1977
18. Stern R, Fishman J, Brusman H, Kunkel HG: Systemic
lupus erythematosus associated with Klinefelter’s syndrome. Arthritis Rheum 20: 18-29, 1977
19. Roubinian JR, Papoian R, Talal N: Androgenic hormones modulate autoantibody responses and improve
survival in marine lupus. J Clin Invest 59:1066-1070, 1977
20. Haller 0, Hansson M, Kiessling R, Wigzell H: Role of
nonconventional natural killer cells in resistance against
syngeneic tumour cells in vitro. Nature (London)
270609-6 1 1, 1977
21. Roder JC, Kiessling R: Target-effector interaction in the
natural killer cell system. I. Covariance and genetic control of cytolytic and target cell binding subpopulations in
the mouse. Scand J Immunol8:135-144, 1978
22. Petranyi GyG, Ivany P, Hollan SR: Relation of HL-A
and Rh systems to immune reactivity. Vox Sang 27:470482, 1974
23. Santouli D, Trinchieri G, Zmijewski CM, Koprowski H:
HLA-related control of spontaneous and antibody-dependent cell-mediated cytotoxic activity in humans. J Immuno1 117:765-770, 1976
ACKNOWLEDGMENTS
Many thanks to Dr. M. Ferrarini for his critical reading of the manuscript. The excellent technical contribution of
Dennis Brinkmann is greatly appreciated. Drs. R. Lahita, H.
S. KO, N. Chiorazzi, and A. Gibofsky provided clinical material for study. Lymphoblastoid cell lines were provided by J.
Hurley.
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Engelhard M, Hoffman T: Dissociation of antibody-dependent cell cytotoxicity from serum inhibition in systemic lupus erythematosus. In preparation
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