Israeli researchers suggest how unwanted immune responses are prevented

The immune system is like a suit of armor for living things – a network of biological processes that protects an organism from diseases. Even bacteria have a simple immune system in the form of enzymes that protect them against virus infection.

Other basic immune mechanisms evolved in ancient plants and animals and remain in their modern descendants. These mechanisms include phagocytosisantimicrobial peptides called defensins, and the complement systemJawed vertebrates, including humans, have even more sophisticated defense mechanisms, including the ability to adapt to recognize pathogens more efficiently. 

But in mammals, the system is much more complex. 

Adaptive (or acquired) immunity creates an immunological memory leading to an enhanced response to subsequent encounters with that same pathogen. This process of acquired immunity is the basis of vaccination.

Many species have two major subsystems of the immune system. Adaptive (or acquired) immunity creates an immunological memory leading to an enhanced response to subsequent encounters with that same pathogen. This process of acquired immunity is the basis of vaccination.

The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use molecules and cells to perform their functions.

When the immune system goes “haywire,” it can cause autoimmune and inflammatory diseases and even cancerImmunodeficiency occurs when the immune system is less active than normal, resulting in recurring and life-threatening infections. In humans, immunodeficiency can be the result of a genetic disease such as severe combined immunodeficiency, acquired conditions such as HIV/AIDS or taking immunosuppressive medication

Autoimmunity results from a hyperactive immune system attacking normal tissues as if they were foreign organisms. Common autoimmune diseases, rheumatoid arthritisdiabetes type 1, and systemic lupus erythematosus

A mechanism that plays a key role in control of the immune system –

preventing it from going haywire following a false alarm – has been discovered by researchers at the Rappaport Faculty of Medicine of the Technion-Israel Institute of Technology in Haifa. The study, led by Prof. Debbie Yablonski and doctoral student Enas Hallumi, has been published in the Journal of Immunology under the title “Itk Promotes the Integration of TCR and CD28 Costimulation through Its Direct Substrates SLP-76 and Gads”  and was recommended by the journal’s editorial board as a “top read.”


Yablonski is a faculty member at the Rappaport Faculty of Medicine (preclinical staff) and of the Technion’s Russell Berrie Nanotechnology Institute. Born in the US, she completed her bachelor’s degree and Ph.D. at the Hebrew University of Jerusalem and her postdoctoral fellowship at the University of California at San Francisco.


Hallumi grew up in Kafr Manda, completed her bachelor’s degree at Ben-Gurion University and her master’s degree at the Technion, under the supervision of Yablonski, who is also Enas’s supervisor as a doctoral student.


The authors focused on the role of the adaptor protein called “Gads” in controlling the activity of T cells, which are a key part of the immune system. Their main finding was that this protein serves as a kind of gate or barrier that prevents the immune system from launching an unnecessary attack. 


T cells are the “foot soldiers of the immune system.” When the body is attacked by an infection, tumor or something else, these cells multiply rapidly, attack the invader and even mobilize other cells in the body to help them in the attack.


T cell function can be impaired in two main ways: as a result of hypoactivity or hyperactivity. As the term implies, hypoactivity causes a situation in which the body fails to attack the invader, and thus, the development of the disease will not be prevented. By contrast, hyperactivity is liable to lead to a chain reaction that is harmful to the body, for example by creating an autoimmune disease or a cytokine storm – a term that rose to prominence during the current pandemic.


The researchers found evidence that an adaptor protein called “Gads” may be able to prevent a chain reaction of this kind from being initiated. In this sense, Gads serve as a gate that prevents an immune response for as long as the T cells have not been activated. The researchers also found that when the cells are activated by an invader – a virus, tumor or something else. 


Gads is “tagged” by the addition of a certain chemical group. This occurs only when two other proteins (LAT and SLP-76) bind to Gads simultaneously to form a multimolecular complex. This binding action opens the gate and activates a T cell so that it may attack the invader. If, on the other hand, only one of the two proteins binds with Gads, the attack will not be launched. “In the present study, we discovered a mechanism that developed in the course of evolution to prevent false alarms, meaning a situation in which the body’s immune response spirals out of control and is liable to harm the organism itself by creating inflammation and other disorders,” explained Yablonski. 



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