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.
Eva-Maria Diehl | Max-Planck-Gesellschaft
Further reports about: > Biochemistry > Cancer > LAD > Max-Planck-Institut > Molecular Target > Mouse > Mouse mutant > blood cell > endothelial cell > genetic disease > hereditary disease LAD III > immune response > leukocyte adhesion deficiency > leukocytes > protein kindlin-3 > restless legs > searching for pathogens > signal molecules > vasculature > white blood cells
Designer cells: artificial enzyme can activate a gene switch
22.05.2018 | Universität Basel
Flow of cerebrospinal fluid regulates neural stem cell division
22.05.2018 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.
At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...
There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?
At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...
A team led by Austrian experimental physicist Rainer Blatt has succeeded in characterizing the quantum entanglement of two spatially separated atoms by observing their light emission. This fundamental demonstration could lead to the development of highly sensitive optical gradiometers for the precise measurement of the gravitational field or the earth's magnetic field.
The age of quantum technology has long been heralded. Decades of research into the quantum world have led to the development of methods that make it possible...
02.05.2018 | Event News
13.04.2018 | Event News
12.04.2018 | Event News
22.05.2018 | Trade Fair News
22.05.2018 | Trade Fair News
22.05.2018 | Life Sciences