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Restless Cells

Cause of serious genetic disease discovered

Munich, 02/25/2009

White blood cells are constantly flowing through our vasculature, in search for  pathogens. In order to trigger an immune response, however, they have to leave the blood vessels and migrate into infected tissue. In patients suffering from the hereditary disease LAD III (leukocyte adhesion deficiency III), this passage is blocked. The cause of the defect has now been elucidated by collaborations between the Max Planck Institute for Biochemistry in Martinsried together with Professor Markus Sperandio of the Walter Brendel Center of Experimental Medicine at LMU Munich, and scientists of the Cancer Research UK London Research Institute: The protein kindlin-3 is essential for leukocytes to arrest on blood vessel walls. If kindling-3 is lacking, transmigration of leukocytes into tissue is dramatically impaired – in mice and in humans.

White blood cells (leukocytes) are cells of the immune system, defending the body against infections. By using the vasculature as a transportation route, they can easily scan the entire body for pathogens in a very short time. But such a rapid transport system poses a fundamental problem: Most infections are localized not within the blood vessels, but in the tissues surrounding them. The immune cells must therefore find a way to exit the vessels at exactly the right place in order to migrate into the tissue and fight the pathogens. While scouting for signs of infection, the leukocytes roll along the endothelial cells of the blood vessel wall, establishing only loose contact with them as they speed by. If they are alarmed by signal molecules, which the endothelial cells will present in the case of an infection, then they dock firmly onto the vessel wall and transmigrate into the surrounding tissue.

The so-called integrins – a family of proteins expressed on the surface of almost all cells – play a central role in this process. A group of scientists led by Professor Reinhard Fässler of the "Molecular Medicine" department of the Max Planck Institute for Biochemistry in Martinsried have been studying these proteins for some time. In order to migrate into the tissue, leukocytes first have to "cast anchor” on the vessel wall and come to a complete halt. It is the integrins that serve as their "anchor molecules". If this adhesion does not work correctly, the leukocytes will be swept away unrelentingly 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 researcher Dr. Markus Moser.

Severe infections and an increased risk of bleeding are typical symptoms of the rare, recessive hereditary disease LAD III (leukocyte adhesion deficiency III). LAD III is caused by a gene mutation that results in leukocytes failing to adhere to the blood vessel walls. Although integrins are present on the surface of leukocytes in LAD III patients, they cannot be activated. Which gene defect is responsible for the malfunction has always been unclear. In order to shed light on this question, the Max Planck researchers have been thoroughly investigating proteins that regulate the activation of integrins. One hot candidate is the protein kindlin-3, which binds to integrins directly.

When Moser and his colleagues prevented the expression of kindlin-3 in mice, the leukocytes were no longer able to adhere to the vascular walls in order to penetrate into inflamed tissue. The mice also showed excessive bleeding. “The Max Planck researchers made genetically engineered mice to perform extensive tests on the function of kindlin-3 on isolated cells,” reports Sperandio. “We then microscopically assessed the function of white blood cells in inflamed blood vessels in the mice – and detected a very serious defect in leukocyte adhesion and recruiting.” The team of researchers thereby proved that kindlin-3 is in fact pivotal in the activation of integrin: “Our results with the kindlin-3 mice gave the crucial hint that mutations in the kindlin-3 gene must be responsible for LAD III,” Moser explains. The situation is no different in humans: A team of scientists at the Cancer Research UK London Research Institute revealed in a simultaneous work published online that all LAD III patients carried mutations in the kindlin-3 gene. In collaboration with Markus Moser and PhD student Siegfried Ussar at the MPI of Biochemistry, the British researchers discovered that the patients' cells produced no kindlin-3 and, perhaps more importantly, that their adhesion malfunction could be repaired by the insertion of a normal kindlin-3 gene. (mpi/suwe)

Publication:
“Kindlin-3 is required for β2 integrin-mediated leukocyte adhesion to endothelial cells”,
M. Moser, M. Bauer, S. Schmid, R. Ruppert, S. Schmidt, M. Sixt, H.-V. Wang, M. Sperandio, R. Fässler,
Nature Medicine, advanced online publication, 22 February 2009,
doi 10.1038/nm.1921

“Leukocyte Adhesion Deficiency-III (LAD-III) is caused by mutations in the adhesion protein Kindlin-3”,
L. Svensson, K. Howarth, A. McDowall, I. Patzak, R. Evans, S. Ussar, M. Moser, A. Metin, M. Fried, I. Tomlinson, N. Hogg,
Nature Medicine, advanced online publication, 22 February 2009,
doi 10.1038/nm.1931

 

Contact:
Professor Dr. Markus Sperandio
Walter Brendel Center of Experimental Medicine of LMU Munich
Tel.: 089 / 2180 -76505
Fax: 089 / 2180 – 76532 / - 76503
E-Mail: markus.sperandio@med.uni-muenchen.de
Web: www.webex.med.uni-muenchen.de

Dr. Markus Moser
Max Planck Institute of Biochemistry
Tel.: 089 / 8578 - 2440
Fax: 089 / 8578 - 2422
E-Mail: moser@biochem.mpg.de

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