Time of war and time of peace

The immune system is not prepared for prolonged conflicts. She mobilizes an entire army to fight the enemies, but once the target is eliminated, she cancels the response and returns to normal 

 
Dr. Liora Kahlon and Prof. Ofer Lider. the end of the kiss
It is very easy to start a fight. Finishing it is much more complicated. Both in love quarrels and in protracted wars, the conflict can continue and get complicated, until sometimes you even forget how it started. All this is true for the relationships between people, organizations or countries. But when it comes to the wars that take place inside our bodies, the situation - fortunately for us - is completely different. The immune system is not prepared for prolonged conflicts. She mobilizes an entire army to fight the enemies, but once the target is eliminated, she cancels the response and returns to normal. Without this "shutdown" mechanism, there would be a constant inflammation in our body (a condition that means an autoimmune disease, such as type 1 diabetes, or multiple sclerosis).

How does the war end? Who gives the signal to return to normal function? Prof. Ofer Lider and Dr. Liora Kahlon from the Department of Immunology at the Weizmann Institute of Science recently discovered that the answer to this question lies in the "shutdown" system included in the mechanisms of action of the white blood cells, which are the fighters of the elite units of the immune system. It turns out that when the white blood cells are called to fight against foreign invaders, pollutants or various disease agents, they secrete substances ("chemical messengers") that promote inflammation, and then they accelerate a chain of processes, at the end of which anti-inflammatory substances are formed that turn off the immune response when it is no longer needed.

In order to reach the damaged tissue and protect it, the white blood cells - the warriors of the immune system - need to cross the blood vessel wall, and then make their way through the dense intercellular tissue. To do this, they secrete the enzyme parenase.

This enzyme breaks down sugar molecules that bind different components of the intercellular tissue, thus creating spaces through which the cells of the immune system can squeeze and pass.

In a study previously carried out by Prof. Lider and Dr. Kahlon, together with Prof. Yaron Cohen from the Department of Immunology, it became clear that the breakdown products of the sugar molecules are the chemical signal that signals the immune system to "turn off" the inflammatory response. The researchers discovered that these molecules inhibit the ability of the T cells of the immune system, and of other immune factors, to mobilize additional forces. This is how the "shutdown" system is based on a subtle strategy of negative nutrition: when the amount of broken down sugar molecules increases (a sign that enough T cells are working against the infection), the cells of the immune system produce fewer proteins that signal the recruitment of more "soldiers". And so, the same enzyme that at the beginning of the inflammatory process enables the "ignition" of the inflammation by allowing the white blood cells to reach the inflammatory site, later produces small molecules that signal the inflammatory cells to stop their work. This material will soon be tested in preliminary clinical trials.

In a follow-up study, Prof. Lider, Dr. Kahlon and (then) research student Dr. Amiram Ariel tried to create contact, in vitro, between two

Factors that play an important role in the immune system going to war: the "chemical messenger" that signals the battle call, interleukin 2, and the enzyme elastase, which is secreted by the immune cells and helps them make their way through the intercellular tissue. This is how it turned out, that the enzyme elastase breaks down interleukin 2, and that the breakdown products created in this way "turn off" the war machine of the immune system. In other words, a negative nutrition control mechanism was discovered again: the more cells of the immune system secrete more elastase, the enzyme breaks down more interleukin 2 molecules, and "turns off" the system.

Is this mechanism, which was discovered in a test tube, really active in the body? Does it actually work in wound healing or other inflammatory processes? And do malfunctions in this mechanism lead to the development of autoimmune diseases? To examine these questions, the scientists collaborated with doctors from several hospitals in Israel, including Dr. Zvi Landau from the internal medicine department at Kaplan Hospital in Rehovot. The researchers tested fluids from the bodies of people suffering from various autoimmune diseases, and isolated at least three anti-inflammatory peptides (short proteins) that are created during the immune response. To identify the peptides, the researchers compared their amino acid sequence with proteins known to be involved in inflammation. In a series of animal experiments it was found that these peptides do work against inflammation. Prof. Lider: "In fact, it became clear to us that peptides isolated from diabetic patients effectively inhibit the immune response even when the disease occurs regardless of diabetes. This finding led us to hypothesize that these peptides are anti-inflammatory in general, and therefore it seems that they could be used in a large number of medical applications."

Prof. Mati Friedkin from the Department of Organic Chemistry participated in this study, as well as research students Dalia Gilat, Iris Hecht and Hagi Shur.

facts and figures

More than 80 autoimmune diseases known to us today damage various essential components of the body, from the myelin coating that wraps the nerve fibers (multiple sclerosis), to the insulin-producing cells in the pancreas (type 1 diabetes).

Nearly 75% of patients with autoimmune diseases are women. The reasons for this are unknown, but they may be related to the hormones active in the reproductive system. In many cases, these diseases break out, or get stronger, during pregnancy or after menopause. Autoimmune diseases are the fourth leading cause of disability among women in the US.