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MULTICENTRE
STUDIES
THE ROLE OF FCgRIIA
POLYMORPHISMS IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE), ANTI-PHOSPHOLIPID SYNDROME
(APS), AND CATASTROPHIC-APS (CAPS)
COORDINATORS
Martin Herrmann, PhD MD, Udo S.Gaipl, PhD, Ahmed Sheriff, PhD, and Joachim
R. Kalden, MD
Institute for Clinical Immunology, Department
of Internal Medicine III, Friedrich-Alexander-University of Erlangen-Nuremberg,
Glückstrasse 4a, D-91054 Erlangen, Germany
Collaborators
Dorette Raaz, MD, Christian Stumpf, MD, and Christoph Garlichs, MD
Laboratory for Molecular Cardiology, Medical
Clinic II with Policlinic, Friedrich-Alexander-University of
Erlangen-Nuremberg, Schwabachanlage 10, D-91054 Erlangen, Germany
PROJECT
Our
knowledge about the role of human Fc receptors for IgG (FcgR)
has increased considerably within the last several years. These receptors vary
in their affinity for IgG, their preferences for IgG subclasses, the cell
type-specific expression patterns, and the intracellular signals that they
elicit. Additional FcgR heterogeneity is introduced by the presence of well
characterized genetic polymorphisms. Receptors for IgG play an important part
in immune complex clearance. Allelic variants of FcgR genes may influence phagocyte biologic activity,
providing a basis for inherited predisposition to autoimmune disease.
Antiphospholipid syndrome (APS), the Hughes' syndrome,
is a systemic autoimmune disorder characterized by thrombosis and recurrent
foetal loss, accompanied by thrombocytopaenia and elevated titres of
antiphospholipid antibodies (aPLs) [1] . APS was
defined originally in patients with systemic lupus erythematosus (SLE). Later
it was found that APS can be primary or secondary to other autoimmune diseases
or malignancy (reviewed in [1]). An
unusual variant of the APS, characterized predominantly by small vessel
occlusive disease affecting mainly parenchymal organs and characterized by the
fact that thrombosis occurs at multiple sites in a short space of time was defined
by Asherson and termed the Catastrophic Antiphospholipid Syndrome (CAPS) [2].
Recent
evidence suggests that certain FcgR alleles are genetic risk factors for systemic
autoimmune diseases and the development of major manifestations of these
diseases. The FcgammaRIIA-R/H131 polymorphism is an important determinant of predisposition
to APS, with different influences on SLE and APS susceptibility [3]. Besides others, FcgRIIa
polymorphisms constitute factors influencing clinical manifestations and the
disease course of SLE [4].
For atherosclerosis, we detected the
occurrence and distribution of FcgRIIa genotypes in patients with various stages of coronary artery
disease (CAD). We demonstrate that the R131 genotype predicts a higher and the
H131 genotype a lower risk for the occurrence of unstable angina pectoris
(UAP). Whatever the exact underlying pathophysiological role of FcgRIIa polymorphisms in chronic inflammatory diseases is, our data allow
clinically highly interesting risk stratification in patients with CAD. In synopsis
with the patient’s history, symptoms, ECG, and heart specific markers,
determination of the patient’s underlying FcgRIIa genotypes may allow improved risk stratification with consecutive
therapeutical consequences.
Beyond patients with known CAD, determination of FcgRIIa
genotypes may also allow risk stratification in the setting of primary
prevention. According to our results, the FcgRIIa H/H
genotype had a significantly lower frequency for acute coronary syndromes (ACS)
as compared to healthy controls. Here, early genotyping together with
stratification of classical atherogenic risk factors may improve the predictive
value. In analogy we want to examine if a certain FcgRIIa genotype predicts a higher or a lower risk for the occurrence of
SLE, APS or CAPS, respectively. Therefore, we are very much interested to
analyse DNA from patients with the CAPS. We suspect the FcgRIIa genotype may be involved in the risk to develop the catastrophic form of APS. To
perform the pilot analysis, we would need 1-5µg of DNA from approximately 25
Caucasian patients with CAPS and 25 with regular APS.
1. Marai I, Zandman-Goddard G, Shoenfeld
Y. The systemic nature of the antiphospholipid syndrome. Scand J Rheumatol
2004;33(6):365-72.
2. Asherson RA. The catastrophic
antiphospholipid syndrome, 1998. A review of the clinical features, possible
pathogenesis and treatment. Lupus 1998;7(Suppl 2):S55-62.
3. Karassa FB, Bijl M, Davies KA,
Kallenberg CG, Khamashta MA, Manger K, et al. Role of the Fcgamma receptor IIA
polymorphism in the antiphospholipid syndrome: an international meta-analysis. Arthritis Rheum 2003;48(7):1930-8.
4. Manger
K, Repp R, Jansen M, Geisselbrecht M, Wassmuth R, Westerdaal NA, et al. Fcgamma
receptor IIa, IIIa, and IIIb polymorphisms in German patients with systemic
lupus erythematosus: association with clinical symptoms. Ann Rheum Dis
2002;61(9):786-92.
For additional
information and applications, please e-mail: martin.hermann@imed3.uni-erlanger.de
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Last updated: 17 November 2005 |
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