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MULTICENTRE
STUDIES
AVIDITY OF ANTI-BETA2-GLYCOPROTEIN I
ANTIBODIES IN PATIENTS WITH ANTIPHOSPHOLIPID SYNDROME
COORDINATORS
Prof. Božič Borut, PhD, Čučnik Saša, PhD, Kveder Tanja,
PhD, Prof. Blaž Rozman, MD, PhD (project coordinator)
University Medical
Centre, Department of Rheumatology, Vodnikova 62, SI-1000 Ljubljana
PROJECT
Background:
A large part of autoantibodies in patients with the antiphospholipid
syndrome (APS) are directed against β2GPI and therefore represent one of
the main subgroups of antiphospholipid antibodies. There is an enormous
heterogeneity among them due to:
1/ Epitopic specificity:
The exact epitopic sites for anti-β2GPI antibodies have not been
revealed yet, but for the binding of anti-β2GPI from APS patients domains
I and IV seem dominant (1-5).
2/ The heterogeneity of anti-β2GPI has been recognized through
different pathogenic mechanisms in which they are involved (6,7)
3/ The avidity of anti-β2GPI (8, 9,10, 11).
Although the avidity of anti-β2GPI has not been extensively
studied; these antibodies are generally believed to be of low avidity.
Nevertheless, in our recent study the results clearly showed (7):
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That high avidity anti-β2GPI
were not rare in patients with APS despite great heterogeneity in the avidity
of anti-β2GPI among samples.
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Significantly more APS patients were
found in the group with high avidity anti-β2GPI than in that of low
avidity, while, the opposite was true for patients with SLE in the absence of
APS.
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Thrombosis, predominantly venous,
was the main clinical feature associated with high avidity anti-β2GPI.
Aim:
To extend the study by measuring the avidity of anti-β2GPI
antibodies on a large group of anti-β2GPI positive patients:
1. To find whether high avidity anti-β2GPI could be an independent
risk factor for thrombosis and/or miscarriages.
2. To evaluate the association of high avidity anti-β2GPI with a
thrombotic event and/or pregnancy complications.
3. To study the possible association of high avidity anti-β2GPI with
other clinical manifestations of primary and secondary APS.
Inclusion criteria:
The expected number of samples:
1. 200 samples from 100 patients with primary or secondary APS at the time
of thrombotic event and at least one month after the event (two samples from
each patient)
2. 100 samples from 50 anti-β2GPI positive patients without APS (two
samples from each patient at least 6 weeks apart).
Outlines:
1. We expect each of the participating centres to select at least 10 sera
with corresponding clinical and laboratory data (the questionnaire will be
presented)
2. 1ml of each serum should be sent to University Medical Centre,
Ljubljana, where anti-β2GPI will be measured simultaneously with the
measurements of the avidity to overcome a possible inter-laboratory
variability.
3. Before final conclusions all discrepancies and/or misunderstanding will
be discussed in order to achieve a consensus among participants.
4. The avidity of anti-β2GPI will be measured by an in-house
chaotropic ELISA (7) and the results adequately evaluated. Statistical analysis
will be performed with computerised software, using parametric and
nonparametric tests, as appropriate.
Time schedule:
In the case of the approval of aPL Forum chair persons the project will
be presented in details in Barcelona together with the questionnaire and
instructions to those willing to participate.
It should be an open-type project with the inclusion time till the
proposed number of patients/samples was obtained with the possibility of
inclusion additional centres in later stages of the project.
The dynamics of analyses will depend on the number of sera/participating
centres.
A full report will be presented/published with the agreement of the
participating centres.
Literature:
1.
George J, Gilburd B, Hojnik M, Levy Y, Langevitz
P, Matsuura E, Koike T, Shoenfeld Y. Target recognition of beta2-glycoprotein I
(beta2GPI)-dependent anticardiolipin antibodies: evidence for involvement of
the fourth domain of beta2GPI in antibody binding. J Immunol 1998;160:3917-3923.
2.
Iverson GM, Victoria EJ, Marquis DM. Anti-β2
glycoprotein I (β2GPI) autoantibodies recognize an epitope on the first
domain of β2GPI. Proc Natl Acad Sci USA 1998; 95:15542-6.
3.
McNeeley PA, Dlott JS, Furie RA et al. β2-glycoprotein
I-dependent anticardiolipin antibodies preferentially bind the amino terminal
domain of β2-glycoprotein I. Thromb Haemost 2001; 86:595.
4.
J Reddel SW, Wang
YX, Sheng YH, Krilis SA. Epitope studies with
anti-β2-glycoprotein I antibodies from autoantibody and immunized sources.
J Autoimmun 2000;15:91-6.
5.
Ambrozic A, Avcin T, Ichikawa K, Kveder T,
Matsuura E, Hojnik M, Atsumi T, Rozman B, Koike T. Anti-beta2-glycoprotein I
antibodies in children with atopic diseases. Int Immunol 2002; 14: 823-830.
6.
Espinosa G, Cervera R, Font J, Shoenfeld Y.
Antiphospholipid syndrome: pathogenic mechanisms. Autoimmun Rev 2003; 2:86-93.
7.
Ambrožič A, Božič B, Kveder T, Majhenc J,
Arrigler V, Svetina S, Rozman B. Budding, vesiculation, permeabilization of
phospholipids membranes-evidence for a feasible.physiologic role of
β2-glycoprotein I and pathogenic action of anti- β2-glycoprotein I
antibodies. Biochim Biophys Acta 2005;1740:38-44.
8.
Cucnik S, Kveder T, Krizaj I. Rozman B,
Bozic B. High avidity anti-β2-glycoprotein I antibodies in patients with antiphospholipid syndrome.
Ann. Rheum. Dis 2004; 63:1478-1482.
9.
Čučnik S, Kveder T, Rozman B, Božič B. Binding of
high-avidity anti-beta2-glycoprotein I antibodies. Rheumatology 2004;
43:1353-6.
10. Cucnik S, Bozic B, Kveder T, Tomsic M, Rozman B. Avidity of anti-β2-glycoprotein
I and thrombosis or pregnancy loss in patients with antiphospholipid syndrome. New
York Academy of Science 2005, in press.
11. Božič B, Čučnik S, Kveder T, Rozman B. Avidity of
anti-beta-2-glycoprotein I antibodies. Autoimmunity revews 2005, in press.
For additional
information and applications, please e-mail: kc.lj.rozman@siol.net
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Last updated: 17 November 2005 |
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