The findings, available online and in a future issue of The Journal of Clinical Investigation, offer new clues into the mechanisms underlying antiphospholipid syndrome (APS).
"Patients with APS have circulating antibodies that cause exaggerated thrombosis. The longstanding mystery has been how these antibodies initiate the clotting," said Dr. Philip Shaul, professor of pediatrics and senior co-author of the study.
For the study, the researchers first examined the direct actions of APS antibodies on cultured endothelial cells, which line the inside of blood vessels.
They discovered that the thrombosis-inducing antibodies recognize a protein called Beta2-Glycoprotein I on the endothelial cell surface that then interacts with a second protein, apolipoprotein E receptor 2 (apoER2). ApoER2 ultimately inactivates the enzyme that produces the antithrombotic molecule nitric oxide. The decrease in nitric oxide causes both white blood cells and platelets to bind to the endothelium, initiating the thrombosis.
Dr. Shaul said the findings are quite promising because they identify the series of molecular events responsible for the exaggerated thrombosis.
The study also found that in contrast to normal mice, mice genetically engineered to lack apoER2 are completely protected from developing thrombosis when they are given APS antibodies collected from individuals with the syndrome.
"Patients with thrombosis often require lifelong anti-coagulation therapy," he said. "The problem with this approach is that the anti-coagulation can be ineffective, and there are multiple potential serious complications related to bleeding. It makes much more sense to develop new therapies that target the underlying disease mechanism."
Dr. Chieko Mineo, assistant professor of pediatrics and senior co-author of the study, said the findings are particularly important for pregnant women with APS because they are at high risk of miscarriage and preterm birth.
"Even if a woman with APS does carry to term, the infant is often smaller than normal and can suffer from multiple complications," Dr. Mineo said. "Our ongoing studies indicate that the mechanisms we have identified that provoke thrombosis are also operative in APS during pregnancy to adversely affect the health of both the mother and the fetus."
The next step, Dr. Shaul said, is to test in the mouse models three novel therapeutic interventions that are based on the new understanding of APS.
"If they prevent thrombosis or pregnancy complications in the mouse models, clinical trials would of course follow," Dr. Shaul said.
Other UT Southwestern researchers involved in the study include lead author Dr. Sangeetha Ramesh, former graduate research assistant in pediatrics; Dr. Cristina Tarango, former postdoctoral fellow in pediatric hematology/oncology; Ivan Yuhanna, senior research associate in pediatrics; Dr. Joachim Herz, professor of molecular genetics and neuroscience; Dr. Philip Thorpe, professor of pharmacology; and Dr. Gail Thomas, former associate professor of internal medicine. Researchers from the University of Rochester School of Medicine and Dentistry, Weill Cornell Medical College and University Medical Center Utrecht in the Netherlands also participated.
The study was supported by the National Institutes of Health, the Alliance for Lupus Research, The Lowe Foundation, the Crystal Charity Ball Center for Pediatric Critical Care Research, and the Robert L. Moore Endowment from Children's Medical Center Foundation.
Visit http://www.utsouthwestern.org/pediatrics to learn more about clinical services in pediatrics at UT Southwestern.
This news release is available on our World Wide Web home page at http://www.utsouthwestern.edu/home/news/index.html
To automatically receive news releases from UT Southwestern via e-mail, subscribe at www.utsouthwestern.edu/receivenews
Kristen Holland Shear | EurekAlert!
Scientists decipher key principle behind reaction of metalloenzymes
15.01.2018 | Rheinisch-Westfälische Technische Hochschule Aachen
New method to map miniature brain circuits
15.01.2018 | The Francis Crick Institute
For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.
Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...
At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.
No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...
Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.
Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...
The oceans are the largest global heat reservoir. As a result of man-made global warming, the temperature in the global climate system increases; around 90% of...
Scientists at Helmholtz Zentrum München have discovered a mechanism that amplifies the autoimmune reaction in an early stage of pancreatic islet autoimmunity prior to the progression to clinical type 1 diabetes. If the researchers blocked the corresponding molecules, the immune system was significantly less active. The study was conducted under the auspices of the German Center for Diabetes Research (DZD) and was published in the journal ‘Science Translational Medicine’.
Type 1 diabetes is the most common metabolic disease in childhood and adolescence. In this disease, the body's own immune system attacks and destroys the...
15.01.2018 | Event News
08.01.2018 | Event News
11.12.2017 | Event News
15.01.2018 | Physics and Astronomy
15.01.2018 | Life Sciences
15.01.2018 | Life Sciences