Image: In autoimmune diseases, the immune system wrongly identifies its “enemy,” and produces antibodies that attack the patient’s own cells. One of these diseases, the anti-phospholipid antibody syndrome (APS), is still poorly understood, even though it can have serious consequences (Photo courtesy of the University of Geneva).
Using patient-derived antibodies, researchers have succeeded to identify a peptide motif in the protein B2GP1 recognized by antibodies characteristic of the autoimmune disease anti-phospholipid antibody syndrome (APLAS). This is enabling the researchers to develop a more accurate diagnostic assay for patients with this disease, and could also lead to better treatment options.
Binding of the APL antibodies circulating in the blood plasma leads to a tendency for abnormal increase in blood clot formation, which can lead to a range of vascular incidents, including venous thromboses, strokes, or repeated miscarriages. In APLAS, anti-Β2GP1 antibodies attach themselves to antigens on the surface membrane of certain cells, particularly those of the blood vessels and placenta. This generates a signal that produces pro-inflammatory and pro-thrombotic factors that cause the vascular disease events.
Diagnosis is complicated as the currently used test has a number of problems in terms of variability, specificity, and sensitivity. Now, researchers at the University of Geneva (UNIGE; Geneva, Switzerland) and the Geneva University Hospitals (HUG) have succeeded in identifying the binding motif at which the anti-Β2GP1 antibodies attach, which will enable development of a more accurate and standardized diagnostic test. The target protein is the only protein in the entire human proteome to have 5 of these motifs, which gives it multiple potential binding points for the pathogenic antibody. They also established that the APL antibodies-interacting motifs are determined by the polarity, but not by the sequence or charge, of amino acids.
On the importance of this discovery, Karim Brandt, researcher at UNIGE’s faculty of medicine, said: “The current diagnostic tests use the entire protein, which reduces its specificity and leads to standardization issues. Consequently, two tests are required at an interval of 12 weeks after a thrombotic episode or following one or more miscarriages. Our new test specifically targets this pathogenic antibody, with rapid and more accurate results.”
APLAS is usually treated with oral anticoagulants such as low-molecular-weight heparin and aspirin, long-term treatments that are not without side effects, and that must be used with caution by pregnant women. Moreover, treatment becomes very burdensome in patients suffering from the most severe form of the disease, called “catastrophic APLAS”. Dr. Brandt stressed that the researcher team is also focusing their work in this therapeutics direction: “Our breakthrough could also give rise to a targeted treatment that would neutralize specific pathogenic antibodies, reducing not just their actions but also the side effects associated with the current treatment. It would involve injecting the protein motif we have identified into a patient’s circulatory system so that it explicitly binds itself to the pathogenic antibody and prevents it from causing harm.”
The diagnostic test is being optimized for development of prototypes. To ensure validity, the researchers will reanalyze hundreds of samples already tested with the old method and compare results with the new test.
The study, by de Moerloose P et al, was published May 2017 in the journal Haematologica.
University of Geneva