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IMMUNOBIOLOGY
Exacerbation of autoantibody-mediated thrombocytopenic purpura by
infection with mouse viruses
Andrei Musaji, Françoise Cormont, Gaëtan Thirion, César L. Cambiaso, and Jean-Paul Coutelier
Antigenic mimicry has been proposed as
a major mechanism by which viruses
could trigger the development of immune
thrombocytopenic purpura (ITP). However, because antigenic mimicry implies
epitope similarities between viral and self
antigens, it is difficult to understand how
widely different viruses can be involved
by this sole mechanism in the pathogenesis of ITP. Here, we report that in mice
treated with antiplatelet antibodies at a
dose insufficient to induce clinical disease by themselves, infection with lactate
dehydrogenase-elevating virus (LDV) was
followed by severe thrombocytopenia and
by the appearance of petechiae similar to
those observed in patients with ITP. A
similar exacerbation of antiplateletmediated thrombocytopenia was induced
by mouse hepatitis virus. This enhancement of antiplatelet antibody pathogenicity by LDV was not observed with F(abⴕ)2
fragments, suggesting that phagocytosis
was involved in platelet destruction. Treatment of mice with clodronate-containing
liposomes and with total immunoglobulin
G (IgG) indicated that platelets were
cleared by macrophages. The increase of
thrombocytopenia triggered by LDV after
administration of antiplatelet antibodies was
largely suppressed in animals deficient for
␥-interferon receptor. Together, these results suggest that viruses may exacerbate autoantibody-mediated ITP by activating macrophages through ␥-interferon
production, a mechanism that may account for the pathogenic similarities of
multiple infectious agents. (Blood. 2004;
104:2102-2106)
© 2004 by The American Society of Hematology
Introduction
Acute immune thrombocytopenic purpura (ITP) is a common
disease of suspected autoimmune origin that often develops in the
course of a viral infection, especially in children.1 In affected
patients, platelets opsonized with autoantibodies are destroyed
through phagocytosis by cells of the reticuloendothelial system,
leading to clinical symptoms such as petechiae or, in more severe
cases, bleedings. Widely different viruses, including Epstein-Barr
virus, influenza, varicella zoster virus, cytomegalovirus, mumps,
parvovirus, and rubella virus have been suspected as potential
triggers of the disease.1 Molecular mimicry between epitopes
shared by infectious agents and platelets, followed by spreading of
the autoimmune response to new determinants, has been proposed
as an explanation for the etiologic role of viruses in ITP.2,3
Interestingly, proinflammatory cytokines, such as ␥-interferon
(IFN-␥) have been found at higher levels in patients with ITP when
compared with healthy individuals.2,3 Although the role of viruses
in the pathogenesis of ITP is not disputable, it is, however, unclear
how viruses with very divergent antigenic determinants can induce
a similar autoimmune response focused to platelet epitopes through
molecular mimicry.
So far, very few animal models have been developed that allow
for an experimental approach of ITP. Mechanisms of platelet
destruction may be analyzed in mice by using polyclonal antiplatelet xenoimmune antibodies or monoclonal antibodies elicited in
rats or in mice.4 (NZW ⫻ BXSB)F1 mice spontaneously produce
antiplatelet autoantibodies, leading to thrombocytopenia in the
context of a complex autoimmune syndrome dissimilar to organspecific ITP.5 Production of antiplatelet autoantibodies through
molecular mimicry may be studied by immunizing mice with rat
platelets, but the resulting thrombocytopenia is at best moderate
and very transient in normal mice.6 Here, we report on the effect of
infection with the common mouse viruses lactate dehydrogenaseelevating virus (LDV) and mouse hepatitis virus (MHV), on
platelet counts in mice with preexisting antiplatelet autoantibodies.
Infection triggers a clinical disease similar to childhood acute ITP
through mechanisms that do not rely on autoantibody production
by molecular mimicry but rather on activation of phagocytic cells
after secretion of IFN-␥.
From the Unit of Experimental Medicine and the Ludwig Institute for Cancer
Research, the Institute for Cellular Pathology, Université catholique de
Louvain, Brussels, Belgium.
the FNRS.
Submitted January 28, 2004; accepted May 6, 2004. Prepublished online as
Blood First Edition Paper, June 17, 2004; DOI 10.1182/blood-2004-01-0310.
Supported by the Fonds National de la Recherche Scientifique (FNRS), Fonds
de la Recherche Scientifique Médicale (FRSM), Loterie Nationale, Fonds de
Développement Scientifique, and the State-Prime Minister’s Office-SSTC
(Interuniversity Attraction Poles, grant no. 44) and the French Community
(Concerted Actions, grant no. 88/93-122). J.-P.C. is a research director with
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Materials and methods
Animals
Specific pathogen-free CBA/Ht, BALB/c nu/nu female and 129/Sv female
mice were bred at the Ludwig Institute for Cancer Research by G. Warnier
and used when 8 to 12 weeks old. IFN-␥ receptor–deficient mice (G129),
received courtesy of F. Brombacher (Max Planck Institute for Immunobiology, Freiburg, Germany), were reared in the same manner as the 129/Sv
An Inside Blood analysis of this article appears in the front of this issue.
Reprints: Jean-Paul Coutelier, Unit of Experimental Medicine, ICP, UCL, Av
Hippocrate 7430, B-1200 Bruxelles, Belgium; e-mail: coutelier@mexp.
ucl.ac.be.
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.
© 2004 by The American Society of Hematology
BLOOD, 1 OCTOBER 2004 䡠 VOLUME 104, NUMBER 7
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BLOOD, 1 OCTOBER 2004 䡠 VOLUME 104, NUMBER 7
VIRALLY ENHANCED EXPERIMENTAL THROMBOCYTOPENIA
mice, from which they were initially derived by S. Huang and M. Aguet.7
Some mice were purchased from B&K Universal (Hull, United Kingdom).
Spleens were surgically removed after anesthesia with intraperitoneal
administration of ketamine hydrochloride (Imalgene 500; 1.25 mg/mouse;
Merial Toulouse, France) and medetomidine hydrochloride (Domitor; 25
␮g/mouse; Orion Pharma, Espoo, Finland), followed by atipamezole
hydrochloride (Antisedan; 125 ␮g/mouse; Orion Pharma).
Virus
Mice were infected by intraperitoneal injection of approximatively 2 ⫻
50% infectious doses (ID50) of LDV (Riley strain; ATCC, Rockville, MD)
in 200 ␮L saline or of approximately 1 ⫻ 104 50% tissue culture infectious
doses (TCID50) of MHV-A59 grown in NCTC 1469 cells.
107
Platelet counts
Blood was collected from the retroorbital plexus of ether-anesthetized
mice with the use of Unopette pipettes and kits (Unopette microcollection system; Becton Dickinson, Franklin Lakes, NJ). Platelets were
counted by microscopy with an improved Neubauer hemacytometer
(Marienfeld, Germany).
Antibodies
Polyclonal antiplatelet antibodies were obtained after subcutaneous immunizations of a rabbit every 2 weeks with approximately 109 BALB/C mouse
platelets, once with complete Freund adjuvant, then with incomplete
Freund adjuvant. Immunoglobulin G (IgG) was isolated by treatment with
acridine lactate (Rivanol; Chinosol, Seelze, Germany) and precipitation
with half-saturated ammonium sulfate. F(ab⬘)2 fragments were prepared by
peptic digestion, followed by purification by chromatography on Ultrogel
AcA 4-4 and precipitation with ammonium sulfate.8 Rat anti–mouse CD41
(integrin ␣IIb chain) monoclonal antibody9 was obtained from BD PharMingen (San Diego, CA). F96A9K1 is a monoclonal antiplatelet IgM autoantibody and N1 a monoclonal antiplatelet IgG2a autoantibody derived from
(NZW ⫻ BXSB)F1 mice. Control monoclonal antibodies were rat IgG1
(LO-DNP1 from LO/IMEX; Université catholique de Louvain, Brussels,
Belgium), mouse IgG2a (A6202F4), and mouse IgM (M444) of irrelevant
specificity. Human IgG was Gammagard (Baxter, Lessines, Belgium). In
vivo administration of antibodies was by the intraperitoneal route.
Liposome preparation
Clodronate-containing liposomes were prepared following the method
described by Van Rooijen.10 Briefly, 86 mg phosphatidylcholine (Sigma,
Bornem, Belgium) at 100 mg/mL in chloroform was added to 8 mg
cholesterol (Sigma) in 10 mL chloroform. After evaporation, the lipidic film
was dispersed by rotation for 10 to 15 minutes in 10 mL phosphate-buffered
saline (PBS) alone or containing 2.5 g clodronate (dichloromethylenebisphosphonate; kindly given by Boehringer Mannheim GmbH, now Roche
Diagnostics GmbH, Germany). Liposomes were sonicated for 3 minutes at
50 W, then washed with PBS, and resuspended in 4 mL PBS. Mice were
treated by intravenous injection with 200 ␮L liposomes.
Figure 1. Exacerbation by viral infection of thrombocytopenia induced by polyclonal antibodies. (A) IgG
(3 ␮g) purified from polyclonal anti–mouse platelet rabbit
serum (anti-plt Ab) or control rabbit IgG was injected into
groups of 4 CBA/Ht mice 1 day after LDV infection or
administration of saline. Platelets were counted 2 days
after antibody administration (E represents each individual datum; F, means ⫾ SEM). (B) Similar experiment
performed in groups of 5 CBA/Ht mice after infection with
MHV 1 day before administration of polyclonal antiplatelet or control antibodies.
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Statistical analysis
Statistical analysis was performed by using nonparametric unpaired MannWhitney test.
Results
Exacerbation of antibody-mediated thrombocytopenia
by viral infection
To determine the effect of a viral infection on experimental ITP, we
administered LDV and rabbit anti–mouse platelet polyclonal
antibodies to normal mice. As shown in Figure 1A, when administered alone, both the virus and the antibody, at the selected dose,
induced a moderate thrombocytopenia in CBA/Ht animals, whereas
in mice with other genetic backgrounds, such as BALB/C, there
were no consequences (not shown). In contrast, a sharp drop in
platelet counts was observed in mice that received both the virus
and the antiplatelet antibody (P ⫽ .0286 for mice treated with
antiplatelet antibody and LDV versus antibody or virus alone). A
similar exacerbation of antiplatelet antibody–mediated thrombocytopenia was observed in mice infected with MHV 1 day before
antiplatelet antibody administration (P ⫽ .0079 for mice treated
with antiplatelet antibody and MHV versus antibody or virus alone;
Figure 1B). Analysis of this effect of viral infection was performed
after LDV inoculation in all subsequent experiments. LDV infection was also found to enhance antiplatelet antibody–mediated
thrombocytopenia in BALB/c nu/nu mice (P ⫽ .0286 for mice
treated with antiplatelet antibody and LDV versus antibody or virus
alone; Figure 2B). This effect of the virus led to a clinical picture
reminiscent of purpura developing in patients (Figure 2A). Numerous petechiae could indeed be detected on mice that had received
both the virus and the antiplatelet antibody but not in animals that
were only infected or that were treated with the antibody alone.
LDV similarly worsened the thrombocytopenia induced by a rat
monoclonal antibody recognizing mouse CD419 (platelet glycoprotein IIb; BD PharMingen, San Diego, CA) and by an IgG2a (N1)
and an IgM (F96A9K1) monoclonal autoantibodies derived from
(NZW ⫻ BXSB)F1 mice that spontaneously develop autoantibodymediated thrombocytopenia (as shown for typical experiments in
Figure 3A). Moreover, kinetics experiments indicated that the
effect of LDV was transient (Figure 3B). A sharp enhancement of
autoantibody-mediated thrombocytopenia was indeed observed in
mice that had been infected the same day, and 1 or 2 days before
antiplatelet antibody inoculation (P ⫽ .0079), but not in animals
that were infected for 4 days or more. Infection 1 or 2 days after
antiplatelet antibody administration also resulted in an increase of
thrombocytopenia (data not shown).
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2104
MUSAJI et al
Figure 2. Thrombocytopenic purpura induced by LDV infection in nude mice.
(A) Global clinical picture and skin detail of BALB/c nu/nu mice 1 day after
administration of IgG from polyclonal anti–mouse platelet rabbit serum (anti-plt Ab) (3
␮g; iii-iv) or control rabbit IgG (i-ii) and of LDV (ii, iv) or saline (i, iii). Photographs were
taken with a Nikon Coolpix 4500 (Nikon, Tokyo, Japan). (B) IgG (3 ␮g) from polyclonal
anti–mouse platelet rabbit serum or control rabbit IgG was injected into groups of 4
BALB/c nu/nu mice with LDV infection or administration of saline. Platelets were
counted 2 days later (E represents each individual datum; F, means ⫾ SEM). Panels
A and B represent independent experiments.
Mechanisms involved in LDV-enhanced antibodymediated thrombocytopenia
To further analyze the mechanisms by which a viral infection may
exacerbate antibody-mediated thrombocytopenia, we first determined which part of the immunoglobulin was required in this
BLOOD, 1 OCTOBER 2004 䡠 VOLUME 104, NUMBER 7
phenomenon. Administration of F(ab⬘)2 fragments of antiplatelet
polyclonal antibody was not followed by the development of
disease, even in infected animals, in contrast to intact immunoglobulin (significant difference between infected mice that received
antiplatelet IgG or F(ab⬘)2: P ⫽ .0286; Figure 4). This suggests that
phagocytosis is involved in LDV-enhanced thrombocytopenia.
This hypothesis was tested by administration of clodronatecontaining liposomes to LDV-infected mice, a treatment known to
suppress macrophages with phagocytic activity10 and, therefore, to
cure experimental autoantibody-mediated blood autoimmune diseases that are mediated by phagocytosis.6,11,12 Administration of
these clodronate-containing liposomes resulted in a complete
prevention of the increased pathogenicity of both polyclonal and
monoclonal antiplatelet antibodies observed in LDV-infected mice
(significant difference for all antibodies between mice treated with
PBS- and clodronate-containing liposomes: P ⫽ .0286; Figure
5A). The hypothesis that LDV enhances thrombocytopenia through
Fc receptor–mediated phagocytosis was further supported by
administration of total human IgG to mice. This treatment has
previously been shown to inhibit in vivo Fc receptor–mediated
phagocytosis of autoantibody-coated red blood cells and to subsequently decrease the resulting hemolytic anemia.13 Similarly,
LDV-enhanced antibody-mediated thrombocytopenia was largely
suppressed by administration of total human IgG (significant
difference between infected mice that received antiplatelet antibody and treated with total human IgG, or untreated: P ⫽ .0286;
Figure 5B). However, the major site of this increased phagocytosis
of antibody-coated platelets was not the spleen, because administration of antiplatelet antibodies to LDV-infected splenectomized
mice and mock-operated animals induced a thrombocytopenia that
was not quite significantly different (P ⫽ .0571; Figure 6).
Because IFN-␥ is a potent activator of macrophage function, a
possible role for this cytokine in LDV-induced enhancement of
antibody-mediated thrombocytopenia was investigated by infecting mice deficient for the receptor of this cytokine (G129).
Although the thrombocytopenia induced by the virus alone was not
significantly different in these animals and in their normal counterparts, the aggravating effect of LDV on the pathogenicity of
antiplatelet antibodies was largely decreased in mice unable to
respond to IFN-␥. This suppression of LDV-enhanced thrombocytopenia in mice deficient for IFN-␥ receptor was observed after
administration of both polyclonal anti–mouse platelet rabbit IgG
(Figure 7A) and monoclonal rat anti–mouse CD41 antibody
(Figure 7B).
Figure 3. Exacerbation by LDV infection of thrombocytopenia induced by monoclonal antiplatelet antibodies. (A) Control and anti–mouse platelet monoclonal
antibodies were injected into groups of 3 to 4 CBA/Ht
mice 1 day after (anti-CD41; 3 ␮g/mouse) or the same
day (N1, 100 ␮g/mouse; F96A9K1, 300 ␮g/mouse) as
LDV infection or administration of saline. Platelets were
counted 1 day (anti-CD41) or 2 days (N1 and F96A9K1)
after antibody administration. Results are shown as
means ⫾ SEM for independent experiments. (B) Antimouse platelet monoclonal antibody (N1, 100 ␮g/mouse)
was administered at different times after LDV infection,
as indicated, into groups of 5 CBA/Ht mice. Platelets
were counted 2 days after antibody administration (E
represents each individual datum; F, means ⫾ SEM).
Control groups received neither virus nor antibody (control); virus alone 3 days before platelet count (LDV) or
antibody alone 2 days before platelet counts (Ab).
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BLOOD, 1 OCTOBER 2004 䡠 VOLUME 104, NUMBER 7
Figure 4. Requirement of immunoglobulin Fc portion in LDV-enhanced antibodymediated thrombocytopenia. Groups of 4 BALB/c mice received either 3 ␮g control
or anti–mouse platelet (anti-plt) rabbit polyclonal IgG or 6 ␮g anti–mouse platelet
rabbit polyclonal F(ab⬘)2 1 day after LDV infection or administration of saline.
Platelets were counted 2 days after antibody administration. E represents each
individual datum; F, means ⫾ SEM.
Discussion
Our results indicate that LDV, in addition to inducing a transient
thrombocytopenia by itself, can dramatically enhance thrombocytopenia that is triggered concomitantly to the infection by antiplatelet
antibodies. This effect of the virus on antiplatelet antibody–induced
thrombocytopenia does not require T lymphocytes, because it is
observed in nude mice. Therefore, it is not caused by new antibody
production in response to infection, because such antibody responses are T-cell dependent and do not start before 4 days after
infection,14 and antigenic mimicry cannot explain this virally
induced platelet drop. Because LDV may enhance phagocytosis,15
it could be postulated that the virus induces thrombocytopenia by
this mechanism. Indeed, treatment with clodronate-containing
liposomes indicated that the enhancing effect of LDV on autoantibody-dependent thrombocytopenia involves phagocytosis exclusively. Moreover, inhibition of this thrombocytopenia with total
IgG indicated that LDV-enhanced phagocytosis of opsonized
platelets was at least partly mediated by Fc receptors expressed on
activated macrophages. Which type of receptors is involved and
VIRALLY ENHANCED EXPERIMENTAL THROMBOCYTOPENIA
2105
Figure 6. Role of the spleen in LDV-enhancement of antibody-mediated
thrombocytopenia. Control and anti–mouse platelet rabbit polyclonal antibodies (3
␮g) were injected 1 day after LDV infection or administration of saline into groups of 4
CBA/Ht mice that had been either splenectomized or mock-operated 2 weeks
previously. Platelets were counted 2 days after antibody administration. Results are
shown as means ⫾ SEM.
whether infection leads to an increase of the expression of these
receptors remains to be determined. Interestingly, the moderate and
transient thrombocytopenia induced by LDV infection in the
absence of antiplatelet antibody administration was only partially
prevented by treatment with clodronate-containing liposomes (data
not shown). This suggests that different mechanisms may be
involved in the thrombocytopenia induced by the virus alone or in
the presence of antiplatelet antibodies.
Because macrophage functions, and especially phagocytosis,
are enhanced by IFN-␥, a cytokine produced in the course of LDV
infection,16 this cytokine was suspected as a mediator of LDVinduced enhancement of antiplatelet antibody pathogenicity. The
causative role of IFN-␥ was shown in mice genetically unable to
respond to this cytokine. The transient effect of LDV on antiplatelet
antibody pathogenicity may thus be explained by the peculiar
kinetics of immune modulation observed after infection with this
virus. Indeed, IFN-␥ production after LDV infection reaches a peak
18 hours after virus inoculation, and then rapidly decreases.16 In
addition to IFN-␥, we cannot exclude that other cytokines,
including interleukins 2 and 12 and macrophage colony-stimulating factor (M-CSF) may also be involved in this virally induced
activation of macrophage functions.
Figure 5. Role of phagocytosis in LDV-mediated thrombocytopenia. (A) Antiplatelet antibodies (polyclonal rabbit IgG, 1 ␮g/mouse; monoclonal N1 IgG2a and F96A9K1,
100 ␮g/mouse) were administered 1 day after LDV infection in groups of 4 CBA/Ht mice. Animals were treated with PBS-containing or clodronate-containing liposomes (200
␮L) as indicated 36 hours before antibody administration. Control mice were infected but received saline instead of antiplatelet antibody. Platelets were counted 2 days after
antibody administration (results shown as means ⫾ SEM). Experiment with polyclonal antibody was independent from experiment with monoclonal antibodies. (B) IgG (3 ␮g)
purified from polyclonal anti–mouse platelet rabbit serum (anti-plt Ab) or control rabbit IgG was administered 1 day after LDV infection in groups of 4 CBA/Ht mice. Animals were
treated with 5 daily doses of 4 mg total human IgG, where indicated, starting 3 days before antibody administration. Platelets were counted 1 day after antibody administration.
E represents each individual datum; F, means ⫾ SEM.
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2106
BLOOD, 1 OCTOBER 2004 䡠 VOLUME 104, NUMBER 7
MUSAJI et al
Figure 7. Role of IFN-␥ in LDV-enhanced antibodymediated thrombocytopenia. (A) Control or antiplatelet
polyclonal rabbit IgG (anti-plt, 3 ␮g/mouse) was administered 1 day after LDV infection in groups of 3 129/Sv or
G129 mice. Platelets were counted 1 day after antibody
administration. Individual datum is shown as open dots
and means as black dots ⫾ SEM. (B) Control or anti–
mouse CD41 monoclonal rat antibody (3 ␮g/mouse) was
administered 1 day after LDV infection in groups of 3
129/Sv or G129 mice. Platelets were counted 1 day after
antibody administration. E represents each individual
datum; F, means ⫾ SEM.
It is not easy to understand how the antigenically different
pathogens that have been suspected to trigger childhood acute ITP
may lead to autoantibody-mediated thrombocytopenia through
antigenic mimicry. However, because macrophage activation and
IFN-␥ production may be induced by distinct viruses, with diverse
kinetics, exacerbation of antibody-mediated thrombocytopenia
through enhanced phagocytosis may explain the similar consequences on platelet counts observed after infection of patients with
widely different pathogens. This hypothesis is further supported by
our observation that MHV, which also triggers IFN-␥ production,17
has an enhancing effect on antiplatelet pathogenicity similar to that
found after LDV infection. We can thus hypothesize that the
development of childhood acute ITP requires 2 successive events:
first, a modification of the potential recognition of platelets by
phagocytic cells that might be due to autoantibody production
following a common, but still unrecognized cause, and that remains
clinically silent, and then a triggering of thrombocytopenia as a
consequence of IFN-␥–enhanced phagocytosis by macrophages in
the course of infection with one of many different viruses.
Therefore, targeting this cytokine-induced macrophage activation
might be an alternative for new treatments of autoimmune blood
diseases that follow viral infections.
Acknowledgments
We thank J. Van Snick, P.L. Masson, and B. McIntyre for critical
reading of this manuscript; V. Préat and C. Lombry for very kind
help in the preparation of liposomes; J-P. Dehoux for immunizing
rabbits; M.D. Gonzalez and T. Briet for expert technical assistance;
and Roche Diagnostics GmbH, Germany for the gift of clodronate.
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2004 104: 2102-2106
doi:10.1182/blood-2004-01-0310 originally published online
June 17, 2004
Exacerbation of autoantibody-mediated thrombocytopenic purpura by
infection with mouse viruses
Andrei Musaji, Françoise Cormont, Gaëtan Thirion, César L. Cambiaso and Jean-Paul Coutelier
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