Researchers from Sheba have discovered a new disease that damages the immune system and exposes its subjects to life-threatening infections

The research, led by Dr. Raz Somekh and his research group at the Sheba Medical Center, located a region in the genome of those patients that is common to all of them, and subsequently identified the new gene that was not known until now as the cause of the disease. Later, several changes in this gene were identified that cause a similar clinical picture. The gene participates in central processes of the body's defense against infections.

Dr. Raz Somech, Director of the North B. Children's Department at Edmond and Lili Safra Children's Hospital and his research group led by Atar Lev and Amos Simon, succeeded in discovering a new disease that damages the immune system and exposes those affected by it to life-threatening infections.

The research work is published as an article in the "New England Journal of Medicine". The work began about two years ago as an observation of a number of patients with a similar and unique clinical manifestation, different from any known disease. While collaborating with researchers from the NIH in the USA and using advanced genetic tools, a region was located in the genome of those patients that is common to all of them and subsequently the new gene that was not known until now as a disease cause was identified. Later, several changes in this gene were identified that cause a similar clinical picture. The gene participates in central processes of the body's defense against infections.
From the moment the genetic defect was detected, a long and thorough laboratory work began in Dr. Somech's laboratory in order to prove the finding. Once the biological and functional defect caused by the gene was found, the clinical symptoms of those patients could be explained. Later, attempts were made to repair the defective gene in diseased cells and induce the expression of the disease in healthy cells. A laboratory animal model was also used to demonstrate a similar clinical defect after damage to the same gene.

The animal model chosen is the "zebra" fish, which serve as a good model for imitating human genetic and biological processes. After damage to the gene that causes the disease, the damage to white blood cells could be clearly seen in the fish model, similar to what was observed in humans.
The normal process of responding to a bacterial infection that has invaded the body includes several gradual steps that lead to one another. A defect in any of the steps may lead to an inability to deal with infections and a real danger to life. First, the immune system is sent the signal about the formation of the inflammation and its location. In response, the immune system mobilizes cells from the peripheral blood and especially from the bone marrow to reach the site of infection. The process of creating cells in the bone marrow is necessary. Later, cells begin to leave the bone marrow and they move in the bloodstream towards the area of ​​inflammation. Near the site of inflammation, they will begin to slow down their movement while sticking to the blood vessel wall until a complete stop.
From here the process of the cells migrating right to the infection area will begin. When the cells reach the area of ​​contamination, they begin the process of endocytosis (cellular ingestion) of swallowing the pollutant into a small bubble called a phagosome. It is a process of absorbing material into the cell while folding the cell membrane inward, and closing the folding as a vesicle. Now the bacterium is ready for complete destruction inside the endosome. The destruction of the bacterium is carried out by oxidative processes in the wall of the bubble that cause the release of substances into the bubble cavity and cause the "digestion" of the pollutant. There are many proteins that participate in the creation of the process inside the phagosome both for the purpose of destroying the bacteria and for the "recycling" of various proteins so that they can be used again in the same process.

In the current work, the researchers were able to locate a gene belonging to the endocytosis process (VPS45) and it functions mainly in the circulation of other proteins. A genetic change in this gene resulted in the creation of a defective protein, with poor function and the inability to bind to other proteins (Rabenosym, Syntaxin). The researchers also proved the failure in the circulation of other proteins, especially the protein Integrin B1. As a result, the line of patients with life-threatening recurrent bacterial infections. In addition to this failure, the researchers identified that the VPS45 protein has a role in the production of white blood cells in the bone marrow, and apart from the functional defect, there is also a quantitative defect in the production of white blood cells. The accepted treatment is a bone marrow transplant, a procedure that requires finding a suitable donor, intensive treatment before the transplant and is accompanied by many complications after it. Now the researchers are working on another, biological treatment, which will prevent the need for a bone marrow transplant in patients with this gene.

Dr. Somech's unit at Sheba Hospital is part of an international foundation that supports centers of clinical and research excellence in the field of immunodeficiency diseases (Jeffrey Modell Foundation). The unit received the recognition about two years ago. Dr. Somech's laboratory deals with the early detection, characterization and treatment of primary immunodeficiency diseases. The laboratory is part of the cancer research center managed by Prof. Gidi Ravavi in ​​Sheba. The center has laboratory tools and technological capabilities of the first class in the world and there is an unusual combination of doctors-researchers who in practice maintain the connection between advanced science and the patient's bedside.