Hereditary swellings caused by defective blood protein
[PRESS RELEASE 20 July 2015] Hereditary angioedema type III is a rare, hereditary, and serious disorder, characterised by painful swellings in the skin and other organs. An international team of scientists have published a study in The Journal of Clinical Investigation, where they show that the disease is caused by a defective blood protein, the so-called coagulation factor XII. The results from this study may contribute to future treatment strategies for patients with the disease.
Oedema, or tissues becoming swollen due to fluid retention, is a common symptom in a number of pathologies such as allergies or kidney and heart diseases. The swelling is caused by blood vessels leaking fluid into the surrounding tissue. In hereditary angioedema (HAE), the leakage, and hence the swelling, is primarily caused by the hormone bradykinin.
HAE is a serious disease with painful episodes of swelling typically involving the skin and gastrointestinal tract. The attacks can be life-threatening since the airways may become obstructed due to the swelling. The most common variants of the disease are called HAE type I and II, and the cause of these are well known.
“HAE type III was discovered just recently. If we want to treat the disease, we must first understand the underlying mechanism”, says Dr Jenny Björkqvist at the Department of Molecular Medicine and Surgery, Karolinska Institutet, one of the researchers behind the study.
The researchers already knew that patients with HAE type III have a mutation in the blood protein factor XII – but they didn't know why this would cause swellings. In the current study, the researchers discovered that a single sugar was missing in the mutated factor XII in HAE type III patients. The mutated factor XII was found to be overactive. This caused an excess of bradykinin production, resulting in vessel leakage and swelling.
There are natural inhibitors in blood that normally prevent factor XII from becoming activated. These inhibitors can also bind to and inhibit the mutated factor XII, but this is not enough to completely stop the overactivation.
“We realised that we had to find substances that could block factor XII more effectively. We have previously made an antibody that can inhibit factor XII, and shown that this antibody blocks factor XII driven blood clot formation. In the current study, we demonstrate that the same agent prevents oedema in mice”, says Dr Thomas Renné at the Department of Molecular Medicine and Surgery, Karolinska Institutet, principal investigator of the study.
The researchers hope that the study results can be used to establish the first treatment for patients with HAE type III – with the potential for use in a broad array of other types of swelling diseases.
Participating in the study were researchers from Karolinska Institutet, Karolinska University Hospital, University Medical Center Hamburg-Eppendorf, University Medical Center Utrecht, Leibniz-Institut für Analytische Wissenschaften, Heidelberg University, University of Bonn, Univerisity Joseph Fourier, CSL Limited and CSL Behring. The research was financed with grants from the Netherlands Organization for Scientific Research (NWO), Ministerium für Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen, Bundesministerium für Bildung und Forschung, the Swedish Heart-Lung Foundation, Stockholm County Council, the Swedish Research Council, the German Research Society and the European Research Council.
Publication: ‘Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III’, Jenny Björkqvist, Steven de Maat, Urs Lewandrowski, Antonio Di Gennaro, Chris Oschatz, Kai Schönig, Markus M. Nöthen, Christian Drouet, Hal Braley, Marc W. Nolte, Albert Sickmann, Con Panousis, Coen Maas and Thomas Renné, Journal of Clinical Investigation, online 20 July 2015, doi: 10.1172/JCI77139.
For more information, please contact:
Jenny Björkqvist, PhD
Department of Molecular Medicine and Surgery
Phone: +46 (0)8 5177 3565 or +46 (0)70 827 2741
E-mail: Jenny.bjorkqvist@ki.se
Thomas Renné, PhD, Professor of Clinical Chemistry
Department of Molecular Medicine and Surgery
Phone: +46 (0)70 773 0109
E-mail: thomas.renne@ki.se
Contact the Press Office: ki.se/pressroom
Karolinska Institutet is one of the world's leading medical universities. Its vision is to significantly contribute to the improvement of human health. Karolinska Institutet accounts for over 40 per cent of the medical academic research conducted in Sweden and offers the country´s broadest range of education in medicine and health sciences. The Nobel Assembly at Karolinska Institutet selects the Nobel laureates in Physiology or Medicine.
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