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Corrective immune discrimination

Researchers from the Weizmann Institute have shown that the immune system knows how to mobilize a wide variety of antibodies to protect against pathogens through adhesion molecules that act as an "amplifier"

Cell T (in red) selects cell B (in blue) for the "training camp". In green - B cells lacking ICAMs. Photographed using a two-photon laser scanning microscope. Source: Weizmann Institute magazine.
Cell T (in red) chooses cell B (in blue) for the "training camp". In green - B cells lacking ICAMs. Photographed using a two-photon laser scanning microscope. Source: Weizmann Institute magazine.

The immune system not only fights pathogens (disease-causing agents) when they first attack our body, it also prepares and continuously improves itself for future attacks. Thus, cells of the immune system that produce antibodies participate in competitive "training" in order to improve their ability to eradicate harmful pathogens. New research The Weizmann Institute shows that the immune system selects the immune cells that will be allowed to enter "training camps" in order to create more effective antibodies by means of adhesion molecules that are used as an "amplifier". This strategy, according to Dr Ziv Shulman from the department of immunology, gives the body a broad and diverse protection against different strains of the same pathogen.

Antibodies are proteins produced by white blood cells called B cells. Each B cell expresses a unique antibody on its surface, so different cells will excel at identifying different invaders. When a B cell recognizes an invader, it begins to divide rapidly, and differentiate into a cell capable of secreting antibodies (plasma cell). As a result, huge amounts of antibodies are secreted from the lymph nodes and spleen (a single cell produces about 1,000 per second), and they are dispersed through the bloodstream to all parts of the body to attack and eliminate the invader. This is indeed a very effective process for attacking invaders, but the problem is that most of these primary antibodies are able to bind only weakly to the microorganisms they are fighting, so they only provide short-term protection.

"What is wonderful about antibodies," explains Dr. Shulman, "is that after the disease has passed and the pathogen has been removed from the system, the body continues to refine them through an evolutionary process (affinity maturation) that occurs in the lymph nodes. This process takes place in the framework of tiny 'training camps' created especially for this purpose, called germinal centers." B cells are the only immune cells that can rewrite their DNA sequence, thus changing and improving the antibody they produce. Within the germinal centers, B cells undergo random mutations in the genes that code for their antibodies, and as a result, the structure and quality of the binding of the antibody to the pathogen changes. The mutant cells are determined by their antibody's ability to bind the pathogen, and the winners - that is, those who have the antibodies with the highest affinity for the pathogen - become cells that secrete antibodies that will provide the body with protection for many years.

But in order to enter the competition in the "training camp" at the germinal center, B cells with different antibodies that recognized the invader need to first pass a preliminary selection. The popular belief was that the cells with the highest initial affinity for the invading pathogen were selected for the "training camp", but recent studies show that antibodies that provide the best protection against certain pathogens, such as HIV or influenza viruses, actually begin their journey when their affinity for the invader is weak is very. The potential of antibodies with weak affinity to become super-protectors is manifested only when they enter the "training camps" in the germinal centers. "If the initial selection selects the best pathogen binders, how can antibodies with weak affinity get a chance to enter the 'training camps'?" asks Dr. Shulman. "In order to answer this, we realized that it was necessary to get to the bottom of the selection process at the entrance to the germinal centers."

The judgment - both in the preliminary "selection" and in the "competition" - is in the hands of another type of immune system cells known as T cell helpers. These cells can identify the good antibodies, and they serve as "judges" in the competition. The communication between the judges and competitors is carried out "personally": these two types of cells - T and B - must actually bind to each other, for 30-60 minutes, during which they exchange messages through their outer membranes. Antibody-bearing B cells with strong affinity present T cells with "evidence": fragments of the pathogen that they have taken as "booty" in their attacks carried out by their antibody. In fact, there is a correlation between the amount of "evidence" presented to the "judges" and the effectiveness of the antibody. These "evidences" extend the duration of the engagement with the "judge" T cells for the purpose of checking the possibility of being admitted to the "training camps". But then, wonders Dr. Shulman, "how can B cells whose antibodies are weak, and as a result show less pathogenic evidence, win a ticket from the 'judge' T cells"? At this point - he explains - the researchers realized that an enhancement mechanism must be operating here which promotes cells with weak antibodies. Since the actual contact between the cells is necessary in this process, they looked for an "amplifier" of intercellular contact; Or, in other words, an adhesion molecule between cells.

From the right: Ofir Atreki, Dr. Irina Zaretsky and Dr. Ziv Shulman. Entrance ticket to the training camp. Source: Weizmann Institute magazine.
From the right: Ofir Attreki, Dr. Irina Zaretsky and Dr. Ziv Shulman. Entrance ticket to the training camp. Source: Weizmann Institute magazine.

The research team examined the possibility that intercellular adhesion molecules (ICAMs) allow B cells to improve contact and communication with T cells, thereby amplifying the signals they produce. They did some experiments. First, they tested the ability of transgenic B cells lacking ICAMs to compete with B cells possessing ICAMs. They found that B cells without ICAMs lost the "competition" upon entering the "training camp", indicating that these molecules provide a competitive advantage. Further experiments showed that B cells with low-affinity antibodies and ICAMs could prevail over high-affinity antibodies lacking ICAMs. Based on these results, the researchers concluded that the presence of the ICAMs compensated for the reduced affinity of the antibodies in the competition for the entrance ticket to the "training camp". That is, ICAMs promoted the cells with the weaker antibodies.

"The antibodies with the weak affinity are in demand due to their potential to change, and since some pathogens mutate at a rapid rate, B cells with a weak affinity today may have the strong affinity tomorrow"

How does an adhesion molecule give an advantage in the competition? To answer this question, the team used a special method, which allows them to observe, under a microscope, the dynamics of living cells within the lymph node of (anesthetized) mice. The T and B cells were labeled with fluorescent dyes, which allowed the researchers to closely monitor the contact between cells. Thus, they found that B cells with ICAMs were able to maintain contact with helper T cells for a much longer period of time than B cells lacking ICAMs. As a result, they enjoyed longer communication and were able to convey many messages, and this is what allowed them to be admitted to the "training camp" at the germinal centers. That is, the adhesion molecule prolongs the communication time between the cells, and actually allows the less good cells to receive more molecular signals and enter the "training camp".

The findings raise the question: why are cells with weak affinity desirable in the immune program at all? Dr. Shulman explains: "The antibodies with weak affinity are in demand due to their potential to change, and since some pathogens mutate at a rapid rate, B cells with weak affinity today may have strong affinity tomorrow. A wide variety of antibodies creates a wide range of protection, while a less diverse group may have too specific a specialization against one dominant target - which does not necessarily neutralize the pathogen."

These insights may help in the search for better vaccines against infectious diseases, such as malaria, HIV or influenza, where the pathogens are different in each region, in each season, and in each individual. In a vaccine against these infectious pathogens, one can try, for example, to focus on the B cells that are most likely to mutate so that they become neutralizing antibodies with a wider range of action, instead of the most effective early versions in the initial stages. The findings may also help in the use of antibodies as drugs, and may also have implications for the study of the immune system response in cancer.

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An antibody secreting cell can produce about 1,000 antibody molecules per second which are secreted from the lymph nodes and spleen and spread through the bloodstream to all parts of the body

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