Immunology Advance: Understanding Immune Cell Defects in Chediak-Higashi Syndrome

Immunology Advance: Understanding Immune Cell Defects in Chediak-Higashi Syndrome


[Music] We’re studying Chediak-Higashi syndrome. This is a rare human disease that is characterized by enlarged lysosomes. Lysosomes are small vesicles inside of the cells. If they are released outside, they can be toxic to other cells. And the disease is actually a very complex disease. The patients have predisposition to bleeding, recurring infections, neurological disorders. They also develop a very serious and ultimately fatal hyperinflammatory condition due to impaired function of white blood cells known as natural killer cells, or NK cells. Normally, NK cells kill aberrant cells. But this doesn’t happen in case of Chediak-Higashi syndrome. We used a modern genome editing technology to generate a human cell model for the disease. And using this model, and a combination of super-resolution microscopy and also classic techniques, we found that the cells, they actually respond normally to different stimuli. However, they are unable to secrete their lysosomes. And the problem was that the lysosomes are simply too big. Another problem was the meshwork composed from actin protein that underlines the cell surface membrane, it’s too dense. And it doesn’t allow large lysosomes out of the cell. We also found that if we manipulate the cells, and we either shrink the size of the large granules or decrease the density of the actin meshwork, then we can restore the function. We’re hoping to find small molecules that could help with release of lysosomes. Restoration of the function of white blood cells in this disease could have a tremendous impact on the patients’ welfare. That could avert development of that lethal hyperinflammatory condition or could extend the time that the patients are waiting for bone marrow transplant, which is now the only way to prevent that hyperinflammation. If we are successful, then this could lead
to a novel therapy for the disease. [Music]

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