Crystal-clear images reveal how pregnancy antibodies cause harm in babies
electron microscopy
Using advanced electron microscopy, researchers in Leiden have captured detailed images showing how, in the rare pregnancy disorder FNAIT, antibodies produced by the mother can cause bleeding in foetuses. The findings could help pave the way for a test that identifies during pregnancy which babies are at greatest risk.
Previous research had already shown that the severity of this condition depends on how strongly maternal antibodies interfere with the function of platelets. The new study now makes that process directly visible.
What is FNAIT?
Foetal and Neonatal Alloimmune Thrombocytopenia (FNAIT) is a condition in which a pregnant woman's immune system produces antibodies against the platelets of her unborn baby. As a result, the baby faces an increased risk of bleeding. FNAIT affects around 1 in 1,000 pregnancies.
The potential impact of the research is considerable. The results provide a basis for developing a test that could predict during pregnancy which babies may require treatment. The study also demonstrates how the latest generation of microscopes allows researchers to track disease processes at the molecular level. Leiden plays an important role in this field thanks to its expertise and investments in national research facilities.
Protein locked in place
Central to the study is the integrin αIIbβ3, a protein found on platelets that binds to fibrinogen. This blood protein enables platelets to stick together, a crucial step in blood clotting. When blood cannot clot properly, bleeding occurs. Under normal circumstances, the integrin switches between an inactive, 'bent' shape and an active, 'open' shape.
As a result, the protein remains trapped in its bent, inactive state. It can no longer open up and bind fibrinogen, an essential step in the formation of a blood clot
The researchers determined the structure of an antibody isolated from the blood of a pregnant woman whose foetus had developed bleeding complications. In the laboratory, the antibody was combined with the integrin and then examined using cryo-electron microscopy. The project involved a multidisciplinary international collaboration with research centres in Amsterdam, Spain, France and Japan.
The images show that the antibody binds precisely to a crucial region of the integrin that functions like a hinge and is required for the protein to change shape. ‘The antibodies effectively stabilise that hinge, preventing the integrin from moving,’ says researcher Coert Margadant of the Institute of Biology Leiden (IBL).
As a result, the protein remains trapped in its bent, inactive state. It can no longer open up and bind fibrinogen, an essential step in the formation of a blood clot. The consequence is that platelets cannot clump together effectively, increasing the risk of bleeding
‘That is the beauty of electron microscopy: you can literally see why that movement can no longer take place.’
Mechanism observed directly for the first time
The images confirm what researchers had long suspected: the antibody prevents the shape change required to activate the protein. ‘We already had a great deal of experimental evidence that this was the mechanism,’ says Margadant. ‘But now we can actually see it.’
‘We can now observe, at the level of individual molecular building blocks, exactly how the antibody and the integrin bind to each other,’ he says. ‘That is the beauty of electron microscopy: you can literally see why that movement can no longer take place.’
Step towards better diagnosis and treatment
The findings could help improve diagnostic testing. At present, doctors can determine whether antibodies are present, but not how dangerous they are. ‘The amount of antibodies turns out to be a surprisingly poor predictor of how severe the disease will be,’ says Margadant.
According to him, the key lies in what the antibodies actually do. In the future, it may become possible to test whether they block integrin activation. ‘You could use a blood sample from the mother to determine whether her antibodies inhibit integrin activation.’ Such a test could make it possible to identify high-risk pregnancies more accurately and provide more targeted treatment before birth.
From images to understanding
By combining patient samples, laboratory experiments and now images at atomic resolution, researchers are rapidly improving their understanding of FNAIT. What began as a medical mystery has now been reduced to a visible mechanism: a protein that can no longer move.
‘A revolution in resolution’ is how Coert Margadant describes cryo-electron microscopy, the technique that enables researchers to produce such highly detailed images. This summer, the NeCEN microscopy facility will welcome a new super-resolution electron microscope as part of the EMPower project.