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Monoclonal anticardiolipin autoantibodies established from the new zealand white x bxsbf1 mouse model of antiphospholipid syndrome cross-react with oxidized low-density lipoprotein.

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ARTHRITIS & RHEUMATISM
Vol. 38, No. 10, October 1995, pp 1382-1388
0 1995, American College of Rheumatology
1382
MONOCLONAL ANTICARDIOLIPIN AUTOANTIBODIES ESTABLISHED
FROM THE (NEW ZEALAND WHITE x BXSB)FI MOUSE MODEL OF
ANTIPHOSPHOLIPID SYNDROME CROSS-REACT WITH
OXIDIZED LOW-DENSITY LIPOPROTEIN
HAJIME MIZUTANI, YOSHIYUKI KURATA, SATORU KOSUGI, MASAMICHI SHIRAGA,
HIROKAZU KASHIWAGI, YOSHIAKI TOMIYAMA, YUZURU KANAKURA,
ROBERT A. GOOD, and YUJI MATSUZAWA
Objective. Autoimmunity-prone (New Zealand
white X BXSB)F, ([NZW X BXSBIF,) mice have been
shown to be useful as a model of antiphospholipid
syndrome with myocardial infarction. The aim of this
study was to examine the cross-reactivity of anticardiolipin antibody (aCL) derived from (NZW X BXSB)F,
mice with oxidized low-density lipoprotein (ox-LDL),
which is closely associated with atherosclerosis.
Methods. Six monoclonal antibodies (MAb)
against CL were established from (NZW X BXSB)F,
mice, and reactivity of aCL with ox-LDL was examined
by micro-enzyme-linked immunosorbent assay.
Results. Higher titers of anti-ox-LDL autoantibodies were found in adult (NZW X BXSB)F, mice
compared with other autoimmunity-prone mouse
strains (P< 0.01) or a control strain (I' < 0.005). There
was a significant positive correlation between titers of
aCL and those of anti-ox-LDL in (NZW X BXSB)F,
mice (r = 0.79, P < 0.001). Of the 6 MAb against CL,
2 clones that showed &-glycoprotein l-dependent reactivity also cross-reacted with ox-LDL. Binding of monoclonal aCL to solid-phase cardiolipin was inhibited by
ox-LDL, but not by native LDL.
Conclusion. We confirmed that aCL derived
from (NZW x BXSB)F, mice can cross-react with
Hajime Mizutani, MD, PhD, Satoru Kosugi, MD, Masamichi Shiraga, MD, Hirokazu Kashiwagi, MD, Yoshiaki Tomiyama,
MD, PhD, Yuzuru Kanakura, MD, PhD, Yuji Matsuzawa, MD,
PhD: Osaka University Medical School, Osaka, Japan; Yoshiyuki
Kurata, MD, .PhD: Osaka University Hospital, Osaka, Japan; Robert A. Good, MD, PhD, DSc, FACP: University of South Florida,
All Children's Hospital, St. Petersburg, Florida.
Address reprint requests to Hajime Mizutani, MD, The
Second Department of Internal Medicine, Osaka University Medical
School, 2-2 Yamadaoka, Suite 565 Japan.
Submitted for publication December 22, 1994; accepted in
revised form May 23, 1995.
ox-LDL. This result suggests that a c t , which is closely
associated with lupus-associated thrombosis, may also
play an important role in atherosclerotic complications
in patients with systemic lupus erythematosus.
Antibodies recognizing anionic phospholipids,
especially anticardiolipin antibodies (aCL), have been
found in patients with systemic lupus erythematosus
(SLE), antiphospholipid syndrome (APS), and other
autoimmune disorders (1,2). These diseases have been
associated with important clinical manifestations, such
as thrombosis, thrombocytopenia, and fetal loss, and
aCL have been reported to have a pathogenetic
role (3,4).
Recently, an animal model of APS has been
identified, i.e., (New Zealand white x BXSB)F,
([NZW X BXSBIF,) mice, which develop immune
thrombocytopenia and occlusive coronary vascular
disease (CVD) with age (3-10). Beginning at 10 weeks
of age, these mice develop systemic autoimmunity that
involves multiple autoantibodies to DNA, cardiolipin,
and platelets, and manifests as progressive thrombocytopenia, lupus nephritis, and CVD (5,6,8). By reciprocal bone marrow transplantation between (NZW x
BXSB)F, mice and normal mice, we have shown that
aCL-mediated thrombogenic mechanisms may contribute to lupus-associated CVD in these animals (10).
The surface structure of low-density lipoproteins (LDL) comprises apolipoprotein B and a mixed
phospholipid and cholesterol monolayer, and its oxidative form (ox-LDL) is closely associated with the
pathophysiology of atherosclerosis (1 1). Ox-LDL may
act as a target for aCL, since aCL in SLE appear to be
directed to a phospholipid-apolipoprotein H (&glycoprotein 1 [&GPl]) complex, which structurally
CROSS-REACTION OF aCL WITH OXIDIZED LDL
resembles the LDL molecules (12). Vaarala e t a1
reported that antibodies against ox-LDL were often
found in patients with SLE and suggested that crossreactivity between aCL and ox-LDL occurs (13). We
have succeeded in establishing several monoclonal
antibodies (MAb) t o CL and platelets from (NZW x
BXSB)F, mice (14). In the present study, we used
these MAb t o detect circulating antibodies t o ox-LDL
in (NZW x BXSB)F, mice and demonstrate crossreactivity between aCL and ox-LDL.
MATERIALS AND METHODS
Animals. Male (NZW x BXSB)F, mice (hybrids of
female NZW and male BXSB) were raised under specific
pathogen-free conditions in the animal facility of Kiwa
Experimental Animal Laboratories (Wakayama, Japan).
Male BXSB and (New Zealand black x New Zealand
white)F, ([NZB X NZWIF,) mice were originally purchased
from Jackson Laboratories (Bar Harbor, ME).
Monoclonal antibodies. Murine MAb against cardiolipin, 2A12 (IgM), 4-13 (IgM), 2E7 (IgG2a), 1H6 (IgGl), 1B9
(IgG31, and 6B6 (IgG2a) were established previously, by
fusing splenic mononuclear cells of (NZW x BXSB)F, mice
with SpZO murine myeloma cells according to standard
methods (14). Hybridoma cells from cultures producing aCL
antibodies were cloned twice by limiting dilution. MAb from
nonreactive clone 3H6 (IgG1) or 2ElO (IgM), which did not
bind to CL, platelets, sihgle-stranded DNA, or doublestranded DNA (dsDNA), were used as negative controls to
evaluate nonspecific binding. Purification of MAb was performed as described elsewhere (14).
Enzyme immunoassay for cardiolipin. Reactivity with
CL was determined by enzyme-linked immunosorbent assay
(ELISA) as previously described (lo), with minor modifications. Briefly, flat-bottomed microtiter plates (Greiner,
Frickhausen, Germany) were filled with 50 pl of CL solution
(50 pg/ml CL in methanol; Sigma St. Louis, MO) and left for
16 hours at 4°C to evaporate methanol. To block nonspecific
binding of immunoglobulin, 200 pl of 10% fetal calf serum
(FCS) was added to each well, followed by incubation for 1
hour at 37°C and 3 washings with phosphate buffered saline
(PBS), pH 7.4. In some experiments, another blocking
reagent was applied instead of 10% FCS, i.e., 0.5% bactogelatin (Difco, Detroit, MI) supplemented with affinitypurified &GP1 (Serbio Laboratories, Gennevilliers, France).
Diluted serum samples (1:lOO) or purified MAb (50 pl) were
added to each well, incubated for 1 hour at room temperature, and washed 3 times with PBS. Alkaline phosphataseconjugated goat anti-mouse IgC or IgM (100 pl, diluted
1: 1,000-1:3000; Sigma) was added to each well, the alkaline
phosphatase reaction was developed, and absorbance using
optical density (OD) measurement was determined as described previously (10).
Enzyme immunoassay for dsDNA and platelets. Enzyme irnmunoassay for double-stranded DNA (dsDNA) or
platelets was examined by micro-ELISA, as described previously (10).
1383
Oxidation of low-density lipoprotein. Oxidized LDL
was prepared from human LDL purchased from Sigma. To
remove EDTA from this preparation, LDL was dialyzed
against PBS for 24 hours. Malondialdehyde-modified LDL
(MDA-LDL) was prepared by incubating LDL (10 mg/ml in
0.5M MDA) for 3 hours at 37°C. Details of the methods have
been described elsewhere (15). Copper-oxidized LDL was
prepared by incubating 500 pg LDLiml in PBS containing 10
pmoles/liter CuSO, for 24 hours at 37°C. At the end of the
incubation, 1 mM EDTA was added to stop further oxidation. To confirm the oxidation, the electrophoretic mobility
of the modified lipoproteins was compared with that of
native LDL by electrophoresis using 1% agarose gel in
borate buffer (pH 8.6).
Enzyme immunoassay for oxidized LDL. For the
detection of antibodies to ox-LDL, a micro-ELISA was used
as previously described by Palinski et a1 (15). Briefly, half of
a 96-well microtiter plate (Greiner) was coated with native
LDL and the other half was coated with MDA-LDL or Cuf+oxidized LDL, both at 5 pg/ml (50 pl) in PBS containing 2
mM EDTA and 20 pM butylated hydroxytoluene (Sigma).
The plates were incubated for 2 hours at 37°C and then
overnight at 4°C. After washing 3 times with PBS containing
0.05% Tween 20 (PBS-Tween), plates were blocked with
0.5% gelatin in PBS for 2 hours at room temperature. Diluted
MAb or serum samples were incubated for 2 hours at room
temperature. After washing with PBS-Tween, alkaline
phosphatase-conjugated goat anti-mouse IgG or IgM was
added to each well, and the enzyme reaction was developed
as described above. Results were expressed as OD, and the
level of binding to ox-LDL was determined by subtracting
the level of binding to native LDL.
Statistical analysis. Data are presented as the mean k
SD. Statistical analyses were performed using the Wilcoxon
rank sum test. Correlation coefficients were calculated by
linear regression analysis. P values less than 0.05 were
considered significant.
RESULTS
Circulating autoantibodies against oxidized LDL
in (NZW X BXSB)FI mice. Anti-ox-LDL and aCL in
(NZW X BXSB)FI and other strains of mice were
examined by micro-ELISA. In our preliminary experiments, there was no significant difference in OD levels
between anti-ox-LDL antibodies and anti-MDA-LDL
antibodies, although higher background OD levels
were observed with MDA-LDL antibodies. Therefore,
only the results with anti-ox-LDL antibodies are
shown. As seen in Figure lA, anti-ox-LDL antibody
levels were negligible in all (NZW x BXSB)F, mice
under 10 weeks of age (mean 2 SD OD 0.151 ? 0.069).
By age 18 weeks, 80% of sera from (NZW X BXSB)F,
mice had become positive for IgG anti-ox-LDL (OD
0.533 k 0.348). Significantly increased OD levels were
observed in (NZW x BXSB)F, mice compared with
other autoimmune mouse strains (BXSB: 0.206 +-
MIZUTANI ET AL
1384
l"i
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Strain
Age (wk)
WlBF1 W l B F l
10-18
6-10
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BXSB BALBlc
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Strain
Age (wk)
I
WlBFl
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----t
0.20.1
0.2-
WIBF1-nLDL
WlBFl -oxLDL
BALBk-nLDL
BALBk-OXLDL
Z
0.3-
-
1
Inhibitor (pglml)
OX-LDL (O.D.)
Figure 1. A, Circulating anti-oxidized low-density lipoprotein antibodies (anti-ox-LDL) in (New Zealand white X BXSB)F, (WIBFl) mice and
other mouse strains. Antibodies were measured by micro-enzyme-linked immunosorbent assay (micro-ELISA). Bars represent the mean
values. * = Significantly different from levels in other autoimmunity-prone strains (P < 0.01 versus [New Zealand black X New Zealand
white]F, [B/WFl] mice and versus BXSB mice) and in control mice (BALB/c; P < 0.005). B, Circulating anticardiolipin antibodies (aCL) in
W/BFl mice and other mouse strains. Bars represent the mean values. * = Significantly different from levels in BXSB mice (P< 0.01) and in
control mice (P < 0.005). C, Correlation between anti-ox-LDL and aCL levels in W/BFl mice. A significant positive correlation was
demonstrated (r = 0.79, P < 0.001). D, Competitive CL binding with LDL. Anticardiolipin antibodies were evaluated by micro-ELISA for their
ability to bind competitively to CL-coated wells with LDL. The binding of W/BFl serum was decreased in the presence of increasing
concentrations of ox-LDL, but not in the presence of native LDL (nLDL). O.D. = optical density.
*
0.097 [P < 0.011, [NZB X NZWIF, 0.182 0.104 [P <
0.011) or the control strain (BALBk: 0.112 k 0.044
[ P < 0.0051). However, no significant difference in
IgM antibody levels was detected between (NZW x
BXSB)F1 mice and other strains (data not shown).
Significantly high OD levels for aCL were also observed in adult (NZW x BXSB)F, mice compared
with other strains (Figure 1B). Figure 1C shows the
correlation between circulating aCL and anti-ox-LDL
antibodies in adult (NZW X BXSB)F, mice (10-18
weeks old). There was a significant positive correlation between the OD levels of the 2 autoantibodies (r =
0.79, P < 0.001).
Competitive CL binding with LDL. To examine
possible cross-reactivity between circulating aCL and
anti-ox-LDL, inhibition experiments were performed
using CL-coated plates. In (NZW x BXSB)F, serum,
significant inhibition in binding of IgG to solid-phase
CL was achieved by ox-LDL, whereas no inhibition
was observed with native LDL (n-LDL) (Figure 1D).
When liquid-phase CL was used as an inhibitor, no
inhibition was observed in binding of antibody to
solid-phase ox-LDL (data not shown).
Characterization of MAb against cardiolipin. We
have established 6 MAb against CL from (NZW x
BXSB)Fl mice. Their characteristics are summarized
1385
CROSS-REACTION OF aCL WITH OXIDIZED LDL
Table 1. Characterization of anticardiolipin monoclonal antibodies
Binds to*
Clone
Isotype
CL
Plts
dsDNA
n-LDL
MDA-LDL
ox-LDL
dependency?
* Binding to cardiolipin (CL), murine platelets (Plts), double-stranded DNA (dsDNA), native
low-density lipoprotein (n-LDL), malondialdehyde-modified LDL (MDA-LDL), and copper-oxidized
LDL (ox-LDL) was determined by. micro-enzyme-linked immunosorbent assay (micro-ELISA).
t&glycoprotein 1 (p,GPI) dependency was determined by micro-ELISA using affinity-purified P,GPI
(see Materials and Methods).
in Table 1. Two of them are of IgM isotype, and the
others IgG. Four clones (2A12, 4-13, 2E7, and 6B6)
reacted with murine platelets, and 2 (2A12 and 4-13)
reacted with dsDNA. To determine the P,GPl dependency of monoclonal aCL from the (NZW x BXSB)F,
mice, we carried out the ELISA using affinity-purified
P,GPl. T o avoid the influence of &GPl in ascites or
bovine serum albumin, we used an affinity purified
monoclonal aCL and 0.5% gelatin. Representative
results from experiments using 1H6 are shown in
Figure 2. The CL binding activity was elevated in a
dose-dependent manner by the addition of increasing
amounts of purified &GPI, and reached a plateau at a
concentration of 5 pg/ml of PzGP1. Another MAb,
4-13, showed the same P,GP1 dependency for C L
binding. However, the remaining 4 MAb showed
P,GPl-independent C L binding (Table 1).
Reactivity of MAb to LDL. The cross-reactivity
of these MAb with L D L was examined by microELISA. Clones 4-13 and 1H6, which showed P,GPldependent C L binding, also reacted with ox-LDL, but
failed to react with n-LDL (Figure 3). In contrast,
clone 2E7 bound to neither ox-LDL nor n-LDL, and
the remaining MAb (2A12, 1B9, and 6B6) also showed
low or no ox-LDL binding activity. Interestingly,
these 4 MAb showed P,GPl-independent C L binding.
--+-
1.4-
Clone 1H6
-:
cu
1 H6-oxLDL
1 H6-nLDL
4-13-oxLDL
4-13-nLDL
2E7-oxLDL
2E7-nLDL
0.8
a
J
s
ri
0.6
0 0.4
0.2
+
0
0.0
+
+
+
+
0
0.63
1.25
5.0
Figure 2. Effect of increasing concentrations of &-glycoprotein 1
(/32GPI) concentrations on the binding of clone 1H6 to solid-phase
cardiolipin as measured by micro-ELISA. BSA = bovine serum
albumin; see Figure I for other definitions.
1
2
4
8
16
32 64
Dilution
Figure 3. Reactivity of anticardiolipin monoclonal antibodies
(MAb) to oxLDL or nLDL. Clones 4-13 and 1H6 (&-glycoprotein 1
[/32GPI]-dependent MAb) showed high reactivity with oxLDL, but
low reactivity with nLDL. Clone 2E7 (&GPI-independent MAb) did
not bind to either oxLDL or nLDL. See Figure I for other
definitions.
MIZUTANI ET AL
1386
To determine whether monoclonal aCL cross-react
with oxidized LDL, a competitive inhibition assay was
performed. Binding of MAb 4-13 and 1H6 to solidphase CL was inhibited by ox-LDL (at concentrations
of 1-100 pg/ml), whereas no inhibition was seen with
n-LDL (Figure 4).
' . O - I
P
0.8
h
E
C
a 0.6
a,
d
DISCUSSION
In this study, we have found circulating antiox-LDL autoantibodies in (NZW X BXSB)F, mice
and a significant correlation between aCL and anti-oxLDL in these mice. Furthermore, we have confirmed
the P,GPI-dependent binding in 2 of 6 monoclonal
aCL derived from (NZW X BXSB)F, mice and have
obtained evidence that these MAb bind to ox-LDL.
These findings may be explained by the structural
similarity between ox-LDL and CL-P,GPl complexes. The surface structure of LDL comprises apolipoprotein B (Apo B) and a mixed phospholipid/
cholesterol monolayer. Therefore, LDL resembles the
target antigen of aCL, which consists of anionic phospholipids and apolipoprotein H (&GPl). In view of
this structural similarity, it is not unexpected that
p,GPl-dependent monoclonal aCL could cross-react
with ox-LDL. However, it is still unclear why these
aCL do not bind to n-LDL. We speculate that the
epitope recognized by aCL is on a structurally altered
Apo B and phospholipid complex during the oxidative
modification. The other 4 MAb that we have established were &GPl independent, and other investigators have also reported the existence of such MAb
(8,16,17). These &GPl-independent MAb did not bind
to ox-LDL, suggesting that they recognize CL directly
and may have different pathogenetic significance.
Vaarala et a1 first reported that antibodies to
ox-LDL were often found in patients with SLE, although they could not find the correlation between
aCL and anti-ox-LDL antibodies (13). More recently,
there have been several reports supporting this association (18,19). In our animal model, because of its
simplicity and purity, we have been able to show a
significant correlation between the antibodies as well
as cross-reactivity , using polyclonal mouse sera and
monoclonal antibodies. We used human LDL as an
antigen for ELISA in this study since it is difficult to
obtain sufficient amounts of murine LDL. Although
the difference in antigenicity of LDL between humans
and mice requires further study, our results demonstrating cross-reactivity between aCL and anti-oxLDL in a murine model could be applied to the
d
0
0.4
v
-r
%
0.2
0.0
1
1;-3
1;-2
1 I0 - 1 1 I0 0
l oI 1
l oI 2
Inhibitor ( p g / m l )
Figure 4. Competitive CL binding with LDL. Monoclonal aCL
were evaluated by micro-ELISA for their ability to bind competitively to CL-coated wells with LDL. The binding of &-glycoprotein
l-dependent monoclonal antibodies against CL (4-13 and 1H6) was
reduced in the presence of increasing concentrations of oxLDL, but
not in the presence of nLDL. See Figure 1 for definitions.
relationship between human aCL and anti-ox-LDL.
We hypothesize that a subpopulation of human aCL
has the capacity to bind to ox-LDL in vivo.
(NZW x BXSB)F, mice are known to have
very short life spans, and they die of myocardial
infarction due to arterial thrombi prior to the development of typical atherosclerosis (5,lO). Although the
major epicardial coronary arteries of (NZW X
BXSB)F, mice remain largely unaffected, multiple
small, intramyocardial arterioles develop endothelial
and intimal proliferative thickening, become stenotic,
and often develop occlusive thrombi (10). Therefore,
the influence of ox-LDL on the development of atherosclerosis in these mice should be investigated further.
Although we have shown that autoantibodies
against CL cross-react with ox-LDL, their pathogenetic role is still unclear. Modified LDL are believed to
induce the transformation of macrophages into foam
cells and, in some cases, to cause endothelial cell
damage (1 1,20).In addition, modified LDL are immunogenic, leading to the formation of antibodies and subsequently to the formation of LDL-containing immune
complexes (21,22). These findings may be particularly
important in that antibody-coated ox-LDL would be
taken up rapidly by macrophages via Fc receptors,
resulting in foam cell formation. In fact, several antibodies specific for LDL have been found to enhance the
CROSS-REACTION OF aCL WITH OXIDIZED LDL
uptake of LDL aggregates by macrophages, and this
enhanced uptake was abolished when the F(ab’), fragment of antibodies was substituted for intact antibody
(23,24). Therefore, it is speculated that aCL may further
enhance the atherosclerotic changes in patients with
SLE by reacting with ox-LDL. Furthermore, increased
titers of anti-ox-LDL antibodies have been found in
patients with coronary or carotid atherosclerosis (25-27),
implying that a part of these antibodies might be derived
from aCL.
Another possible role of aCL in the development of atherosclerosis is that they may directly bind
to endothelial cells as anti-endothelial cell antibody,
with consequent vascular damage. Several reports
also indicate cross-reactivities between aCL and antiendothelial antibodies, suggesting that aCL interfere
with endothelial cell function (28,29).
CVD is one of the major causes of mortality in
patients with SLE, and coronary atherosclerosis has
been found in many autopsied patients despite relative
youth (30,31). The incidence of CVD in SLE patients
is 9-fold greater than expected in the general population (32). The pathogenesis of premature, accelerated
atherosclerotic changes is likely to be multifactorial,
with disease-related factors (coronary vasculitis and
immune complex-mediated vascular injury), treatmentrelated factors (steroid-induced hyperlipidemia, obesity, and hypertension), and typical CVD risk factors
all playing roles (33). The presence of aCL in these
patients may be another independent risk factor, and
several reports also indicate that aCL may be associated with progression of preexisting atherosclerotic
vascular disease, in particular, CVD (34-36). A recent
prospective cohort study in initially healthy middleaged men indicates that the presence of a high level of
anti-ox-LDL is an independent risk factor for myocardial infarction (37).
In summary, we have confirmed that aCL can
cross-react with ox-LDL. Although the association
between aCL and atherosclerosis requires further clinical investigation, our results lead us to hypothesize
that aCL plays an important role in atherosclerotic
complications in patients with SLE.
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reac, established, mode, oxidizer, autoantibodies, syndrome, low, mouse, white, cross, new, density, lipoprotein, monoclonal, bxsbf1, anticardiolipin, antiphospholipid, zealand
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