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Pathogenesis of the Antiphospholipid
Syndrome
Yaniv Sherer, Yackov Berkun#, Miri Blank,
Yehuda Shoenfeld*
Department
of Medicine 'B' and #Department of Pediatrics, The Center for Autoimmune
Diseases, Sheba Medical Center, Tel-Hashomer,
and Sackler Faculty of Medicine, Tel-Aviv University, Israel
* Incumbent
of the Laura Schwarz-Kipp Chair for Autoimmunity,
Tel-Aviv University, Israel.
Correspondence: Y. Shoenfeld M.D., Department of Medicine ‘B’, Sheba Medical
Center, Tel-Hashomer, 52621, Israel. Tel:
972-3-5302652. Fax: 972-3-5352855. E-mail: Shoenfel@post.tau.ac.il
Abstract
Antiphospholipid syndrome (APS) is characterized by the presence
of pathogenic autoantibodies against b2-glycoprotein-I (b2GPI). Studies of experimental APS
models emphasized that molecular mimicry between b2GPI related synthetic peptides and
structures within bacteria, viruses (cytomegalovirus) and tetanus toxoid could explain APS. In this review we discuss the association
of antiphospholipid antibodies with infectious
agents.
_________________
Autoimmune diseases have a multifactorial etiology influenced by both genetic and environmental
factors. Infectious agents can induce autoimmune diseases by a variety
of mechanisms
(1-2)
Antiphospholipid syndrome (APS) is a multisystem
autoimmune disease, characterized by vascular thrombosis, recurrent
fetal loss, thrombocytopenia and other clinical manifestations in the
presence of persistent circulating antiphospholipid
antibodies (aPL), such as lupus anticoagulant and anticardiolipin
antibodies. aPL antibodies
target phospholipid molecules, mainly via
β2-glycoprotein-I (β2GPI) (3-5).
Human β2GPI molecule
is a heavily glycosylated membrane-adhesion
glycoprotein, present in blood plasma at a concentration of ~150-300
µg/ml (6). b2GPI exhibits several anticoagulant
properties in vitro (7-8) and was found to be immunogenic in vivo: immunization
of BALB/c, PL/J mice, or New
Zealand white rabbits with b2GPI resulted in generation of anti-ß2GPI
Abs (9-12). b2GPI-immunized
mice developed high titers of ß2GPI-dependent anticardiolipin
antibodies (aCL) associated with increased
fetal resorption (the equivalent of fetal loss in human APS), thrombocytopenia,
and prolonged activated partial thromboplastin
time (aPTT) indicating the presence of lupus
anticoagulant (11). In addition, tolerance was induced in b2GPI orally fed mice, and APS was prevented
(13). Anti-b2GPI antibodies
exert direct pathogenic effect by interfering with homeostatic reactions
occurring on the surface of monocytes, platelets
and vascular endothelial cells (14-16). They activate monocytes leading to tissue factor release (15-16) and activate
endothelial cells via induction of adhesion molecule expression including
E-selectin, ICAM-I, and VCAM-I, NFkB expression (17-19). In an ex-vivo model of thrombosis
these antibodies induce thrombus formation (20-21).
APL antibodies are found in 5% - 8%
of healthy control subjects, and the level increases with age and coexistent
chronic diseases (22). Most antibodies do not have any clinical significance
and disappear within 1.9 years. In a study from Europe,
low titer anticardiolipin and anti-β2GPI
antibodies were found in 11% and 7% of healthy children respectively
(23). Most antibodies are transient and non pathogenic. The levels of
IgA anticardiolipins
are lower in children than in adults, while IgG
anti-β2GPI levels are highest in preschool children (23). Similar
findings were also observed in a large Mexican study, where higher levels
of anti-β2GPI were found in a group of 360 healthy Mexican children
aged from 1 month through 8 years compared to Mexican adults (24). Correlation
between the prevalence of aPL antibodies and history of previous infections and
vaccinations was documented.
Several infectious states may cause
aPL titer elevation, but only rarely
cause APS. In a study of infection-related APS, the main "triggering"
factors were found to be skin infections (18%), Human immunodeficiency
virus infection (HIV) (17%), pneumonia (14%), Hepatitis C Virus (HCV)
(13%) and urinary tract infections.. Other
infections less frequently associated with APS are pulmonary tuberculosis,
mycoplasma, malaria, P. carinii
and leptospirosis.
Catastrophic APS, a
rare form of APS, is an acute widespread small vessel coagulopathy
resulting in almost simultaneous multiorgan
disease (most common renal pulmonary, CNS, cardiac) with mortality in
a half of cases. In this disease, “triggering” factors have become increasingly
apparent and were present in 51% of cases in the latest analysis (25).
These triggering factors include trauma, anticoagulant withdrawal, malignancy
and most commonly infections, which were identified in 24% of catastrophic
APS patients. These infections included urinary tract infections (4%),
respiratory (10%), cutaneous (including infected
leg ulcers) (4%), gastrointestinal (2%), sepsis (1%) and other infections
(3%). Molecular “mimicry” has been proposed as one of the major mechanisms
responsible for the development of catastrophic APS following infections
(26) but there may be an interplay of other mechanisms.
Passive transfer of anti-b2GPI related synthetic peptides with
homology to common bacteria to naive mice resulted in an induction of
APS (27-28). Exchanging heavy and light chains between pathogenic and
non-pathogenic anti-b2GPI single
chain Fv, demonstrated that the pathogenic part of the anti-b2GPI molecule is located on the CDR3
of the heavy chain of the immunoglobulin (29). Molecular mimicry between
common pathogen and anti-b2GPI peptide
epitopes is a possible origin for anti-b2GPI antibodies. This assumption is
based on the fact that there is a correlation between APS clinical manifestations
and infectious agents in human, also supported by the homology found
between b2GPI related
peptides (target epitopes for anti-b2GPI Abs) and different common pathogens,
as demonstrated in the protein data bases.
We have previously identified several synthetic peptides as target
epitopes for anti-b2GPI Abs. These b2GPI related
peptides were found to be located on domain I-II (mimotope),
domain-III and domain-IV (both linear sequences) of b2GPI molecule. All 3 synthetic peptides
inhibited activation of endothelial cell in-vitro and induce APS in
naïve mice via neutralizing of the pathogenic anti-b2GPI Abs (18). Moreover, the prevalence
of circulating autoantibodies against these
peptides in a sera of 295 APS patients ranged
between 18% to 47.5% (30). In addition, homology exists between these
peptides and common infectious agents. Following immunization of naive
mice with microbial pathogens (which share structural homology with
the TLRVYK hexapeptide), mouse anti-TLRVYK were affinity purified from
the immunized mice on a TLRVYK-column and then passively infused into
naive mice at day 0 of pregnancy. Following this latter immunization,
various levels of mouse anti-b2GPI Abs were
observed. The highest was detected
in those mice immunized with Haemophilus influenzae, Neisseria gonorrhoeae or Tetanus toxoid. Mice
infused with these anti-b2GPI Abs had significant thrombocytopenia, prolonged
aPTT and increased fetal loss, similarly to
a control group of mice given pathogenic anti-b2GPI monoclonal antibody (31). Hence,
this established a mechanism of molecular mimicry in experimental APS,
demonstrating that b2GPI-structure
homologous bacteria are able to induce the generation of pathogenic
anti-b2GPI Abs along with APS manifestations
(31).
There is structural similarity between
various common pathogens, including Helicobacter pylori, Streptococcus
pyogenus, Borrelia burgdorferi, Saccharomyces cerevisiae, Vaccinia virus, Epstein-Barr
virus and b2GPI and b2GPI related peptides. One theory is that pathogen particles are phagocytized and digested by antigen presenting cells (macrophages,
dendritic cells or B cells). After presentation to T cells with appropriate
HLA molecules and cytokine milieu, plasma cells are generated and secrete
anti-b2GPI Abs which
are directed against the pathogen particles
with structural homology (molecular mimicry) with the b2GPI molecule. Whether an individual will develop APS will
depend mainly on his genetic predisposition. Therefore, a mimicking
antigen, similar in only one epitope, may
initiate a primary cross-reactive response to that epitope
that subsequently results in recognition of numerous epitopes
on the host b2GPI. Mimicry
may be one of the mechanisms for breaking the tolerance and triggering
the autoimmune response. Yet, the mere presence of
a self-determinants on a virus or bacteria, will not necessarily
result in disease. The full-blown APS will emerge only if appropriate
genetic predisposition exists.
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