A team of researchers from the National Institutes of Health and University of Manchester have uncovered new insights into a rare genetic disease, with less than 500 cases of the disease on record, which devastates the lives of children.
Chediak-Higashi syndrome (CHS) is a complex disease, exhibiting very diversified symptoms, including predisposition to bleeding, a wide range of neurological issues, and dysregulated immune responses so that they are unable to fight infections which would normally be easily dealt with.
Unfortunately, in the majority of cases, people with CHS develop a severe and fatal hyperinflammatory condition. One feature of CHS patient’s is that a population of white blood cells, known as Natural Killer (NK) cells are unable to function properly.
Normally, ‘NK cells’ recognize and kill aberrant cells, like cancer cells or virus-infected cells, by secreting bags of toxic enzymes, called lytic granules, into the diseased cells. However, this does not happen in the case of CHS; people with CHS have larger-than-usual bags of these enzymes which then cannot exit the immune cell properly.
The team – which includes Professor Daniel Davis from The University of Manchester – found that the defects in in CHS immune cells are related to a mechanical barrier, the cell’s cytoskeleton, which seems to prevent the immune cells’ ability to kill diseased cells.
In order to uncover the underlying cause for the defective function of NK cells in CHS, they generated a human cell line model of the disease, using modern gene editing techniques.
With the model and super-resolution microscopy, they demonstrated that CHS NK cells have the ability to respond normally to different stimuli, but can’t secrete their lytic granules, because they are simply too big to pass through the barrier of the cell’s cytoskeleton.
Professor Davis said: “My research team and I have been using microscopes to watch how immune cells kill diseased cells for many years. From what we and others have learnt, we can now see how medicines might be able aid the process. Working with researchers at the NIH, we found that the activity of CHS NK cells could be partially restored with drugs that open up an internal barrier in cells, the cell’s cytoskeleton.