15/04/2002
Science / How the cells of the immune system "know" how to reach damaged tissue
By Marit Selvin
The process in which an immune cell migrates from the blood vessels to the damaged tissue-fig
Every minute, millions of cells of the immune system migrate through the bloodstream in order to send help to tissues in need. The cells "know" very well where they should go, according to the signs of distress that the tissue transmits. When there is an allergic reaction, for example, the immune system cells that are active in allergy situations sense the place; During an infection, other cells of the immune system that participate in the inflammatory response migrate to the site. Each cell population is recruited through signals that pass from the tissue to the blood vessels and are displayed on their inner wall.
These are unique signaling molecules that function as "stop signs". The entire mechanism is structured to ensure that the right cell goes on the right mission at the right time and in the right place.
The stop signs consist of several signals. The first signal causes the cell to get caught in the blood vessel wall and start rolling across it. Following the second signal, the cells stop and stick to the blood vessel wall. In the next step, the cells expand, become flat and stick to the blood vessel wall, and later they are pushed between the cells of the wall and infiltrate through them out of the blood vessels towards the tissue. At any stage the cells can "repent", and that is if they don't sense the next signal. In such cases they can disconnect and continue on their way.
Dr. Ronan Alon from the Department of Immunology at the Weizmann Institute studies the dynamics of cell migration from the bloodstream to the target tissues and the signals involved in this migration. In a study published in the journal "Nature Immunology" and in the National Science Foundation newsletter that appeared these days, it shows that the cells of the immune system "talk" with unique molecules called chemokines found in the cells of the tissue adjacent to the blood vessels. When there is an event that requires the intervention of the immune system, the chemokine molecules come out of the tissue cells, penetrate the blood vessel wall cells and present themselves on the cell membranes facing into the blood vessels. Alon was the first to show that the chemokine molecules are the stop signs, and the cells of the immune system moving in the bloodstream stick to them until they penetrate into the tissue. Until then, it was thought that what steers the cells of the immune system towards the tissue is the concentration cascade of the inflammatory substances secreted from it. The cells of the immune system move, so they believed, towards the high concentration.
While the cells of the immune system are busy penetrating into damaged tissue, they are exposed to the force exerted on them by the blood flow. The force of the flow threatens to detach them from their grip on the blood vessel wall and sweep them away with the current. Until recently, scientists thought that the blood flow was designed to disconnect the cells that did not bond well, thus ensuring that only the cells that were meant to migrate to the target tissue would remain.
Alon's research points to a different phenomenon. The force of the flow, he found, is an essential element in the penetration of cells from the bloodstream into the tissue. Alon, together with research student Guy Cinnamon and Dr. Vera Shinder, developed for the purpose of the study a flow chamber that simulates blood vessels, the inner surface of which is lined with endothelial cells - the same cells that line the walls of blood vessels. Using the flow chamber, the researchers simulate various conditions, such as inflammation or allergy, that the cells of the immune system encounter during their migration through the blood circulation, and study them in real time. They do this by treating the endothelial cells in the flow cell with different combinations of chemokines that represent different stop signs. "We build a sort of 'staircase' on the endothelium with different molecular compositions and test the reaction that occurs with the passage of the immune system cells, which we separated and labeled according to their function, inside the flow chamber. We accompany and record every cell of the immune system from the moment it enters the circulation cell until it penetrates the endothelial cells," says Alon.
What turned out to be surprising. "We actually wanted to check how much the blood flow interferes with the penetration of the cells into the endothelium," says Alon. "But it became clear to us that when we created the correct composition of the chemokines and let the cells pass without applying the flow force on them, we saw that the cells that entered the flow cell rolled and stopped, but not a single cell was able to penetrate the endothelial layer."
Alon photographed the path taken by the immune system cell inside the flow cell, in the presence of the chemokines that signal to it what its migration path should be. Without flow, the cells stop, adhere to chemokines, spread on the blood vessel wall, but are prevented from taking the last decisive step: they do not infiltrate through the blood vessel wall into the adjacent tissues. In this place they remain inside the blood vessels and after a short time detach and continue on their way. From the film, the researchers found that the process of threading the cells through the blood vessel wall between two endothelial cells lasted a minute and a half, preceded by a preparation phase of several minutes, in which the immune cell senses the flow while it adheres to the chemokines on the endothelial cells.
The researchers also found that the threading through the blood vessel wall occurs in a completely sealed manner that prevents blood leakage. "We think that as a result of the force exerted by the blood flow, sensors are activated in both the membranes of the immune cells and the membranes of the endothelial cells that make them flexible, and when this action is coordinated between the neighboring cells, the result is that the penetration of the cells through the wall is precise, fast, and does not allow the leakage of the blood fluids," says Alon .
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