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White blood cells (leukocytes) are constantly streaming through our vasculature, searching for pathogens - however, in order to trigger an immune response they need to leave the vessels and migrate into the infected tissue. In patients suffering from the hereditary disease LAD III (leukocyte adhesion deficiency) this passage is blocked. The cause of this defect has now been elucidated by collaborations between the Max-Planck-Institute of Biochemistry, the Cancer Research UK London Research Institute and the LMU Munich: The protein kindlin-3 is essential to arrest leukocytes on vessel walls of inflamed tissues - if it is lacking, transmigration of leukocytes into tissue is impossible.
White blood cells (leukocytes) are cells of the immune system defending the body against infections. By using the vasculature as transportation routes, they can - on the one hand - easily scan the entire body for pathogens in short time. On the other hand, they have to overcome a fundamental problem: Infections are localized mostly in tissues, not within vessels. Therefore leukocytes have to leave vessels at specific sites and migrate into the tissue in order to fight pathogens. While searching for pathogens, they roll along the vascular wall and establish initially only loose contact with vascular wall endothelial cells. If leukocytes get alarmed by signal molecules presented by the endothelial cells, they bind themselves firmly to the endothelial cell and transmigrate into the tissue.
The so-called integrins - a familiy of proteins expressed on the surface of almost all cells - play a central role in this process. Reinhard Fässler, the head of the department "Molecular Medicine" of the Max-Planck-Institute of Biochemistry in Martinsried and his team study these proteins. In order to migrate into the tissue, leukocytes have to "cast anchor" on the vascular endothelial cells by activating integrins as "anchor molecules". If the adhesion does not work correctly, the leukocytes will be swept away incessantly by the blood flow. "Integrin activation is vital for the adhesion of leukocytes to endothelial cells and also for the aggregation of platelets" explains Max Planck scientist Markus Moser.
Severe infections and an increased risk of bleeding are typical symptoms of the rare recessive hereditary disease LAD III (leukocyte adhesion deficiency syndrome). LAD III is caused by a gene mutation that results in defective leukocytes adhesion: Although integrins are present on the cell surface, they cannot be activated and binding to the vascular endothelial cells is impossible.
The gene defect responsible for the malfunction has so far been unclear. In order to shed light on this question, the Max Planck scientists are investigating proteins that regulate the activation of integrin. A hot candidate was the protein kindlin-3 as it directly binds to integrins. A collaboration between the scientists from the Max-Planck-Institute of Biochemistry and scientists from Cancer Research UK London Research Institute and the Ludwig-Maximilians-University Munich has now been able to prove the essential role of kindlin-3: In mice engineered to lack the kindlin-3 gene leukocytes were no longer able to adhere to the vascular walls and in addition, the mice showed a severe bleeding disorder. "Our results with the kindlin-3 mice gave the crucial hint that mutations in the kindlin-3 might be responsible for LAD III", Moser points out. This finding was then confirmed by clinical studies: In collaboration with Moser and PhD student Siegfried Ussar a team of scientists at the Cancer Research UK London Research Institute discovered that the patients' cells produced no kindlin-3 and, importantly, that their adhesion malfunction could be repaired by expressing normal kindlin-3.
http://www.biochem.mpg.de/en/rd/faessler/rg/moser - Research Group Dr. Markus Moser
http://www.biochem.mpg.de/en/rd/faessler - Department of Molecular Medicine, Prof. Dr. Reinhard Faessler
http://www.biochem.mpg.de/en/news/pressroom - Press release
http://www.nature.com/nm/journal/vaop/ncurrent/abs/nm.1921.html - Original publication Moser et.al.
http://www.nature.com/nm/journal/vaop/ncurrent/abs/nm.1931.html - Original publication Svensson et.al.
Blood vessels (green) and leukocytes (red) in infected tissue with kindlin-3 (above) and without kin ...
Source: M. Moser (MPI of Biochemistry)
Criteria of this press release:
Biology, Chemistry, Medicine
transregional, national
Research results, Scientific Publications
English
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