15/04/2002
Science / How immune system cells "know" 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" well where they have to go, according to distress signals transmitted by the tissue. 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 population of cells 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 investigates 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 bulletin that appeared these days, he shows that the cells of the immune system talking" with unique molecules called chemokines found in the cells of the tissue near the blood vessels. When there is an event that requires intervention 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 immune system cells moving in the bloodstream adhere to them until they enter the blood vessels. Through the tissue Until then it was thought that what drives the immune system cells towards the tissue is the concentration cascade of the inflammatory substances secreted from it The vaccine moves, 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 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 , which the immune system cells encounter during their migration in the blood circulation, and investigate them in real time. They do this by treating the endothelial cells in the circulation chamber in different compositions of chemokines that represent different stop signs. "We build a kind 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 have separated and marked according to their function, inside the flow cell. We accompany and record every cell of the immune system from the moment it enters the flow 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 right composition of the chemokines and let the cells pass through 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 blood fluids," says Alon .
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