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Video: Understanding Immune Cell Defects in Chediak-Higashi Syndrome

NIAID Now | December 15, 2017

A new study by scientists from NIAID and the University of Manchester offers insights into the immune cell defects that occur in Chediak-Higashi syndrome (CHS), a rare genetic disease. Their findings also suggest a potential strategy to develop treatments for this complex syndrome, which is characterized by immune deficiency, predisposition to bleeding, recurring infections and neurological disorders. In most cases, people with the disease also develop a fatal hyperinflammatory condition.

In CHS, the function of natural killer (NK) cells, a type of immune cell, is impaired. Normally, NK cells recognize aberrant cells, like tumor cells or virus-infected cells, and kill them by releasing their lysosomes—small compartments inside the cell packed with toxic enzymes. NK cells from people with CHS contain unusually large lysosomes.

To uncover the underlying cause of defective NK cell function in CHS, the researchers generated a human cell line model of the disease. Using this model, they found that the enlarged lysosomes present in CHS NK cells are too big to be released from the cell. The protein meshwork lining the interior of the cell membrane is too dense to allow the large lysosomes out of the cell. As a result, CHS NK cells are unable to kill their target cells.

Notably, the researchers also found that reducing the lysosome size or decreasing the density of the protein meshwork restores the ability of CHS NK cells to kill target cells, suggesting a potential strategy for development of CHS treatments. The scientists next aim to identity small-molecule drugs that could help restore the impaired function of NK cells and potentially other cell types in CHS.

In a short video, NIAID’s Konrad Krzewski, Ph.D., who co-led the study, explains the new findings and their potential impact:

This video is part of the NIAID Video SNiP series. In each SNiP, a NIAID scientist explains a recent research advance and its implications in two minutes or less.

Reference: A Gil-Krzewska, MB Saeed et alAn actin cytoskeletal barrier inhibits lytic granule release from natural killer cells in Chediak-Higashi syndromeJournal of Allergy and Clinical Immunology DOI: 10.1016/j.jaci.2017.10.040 (2017)

Content last reviewed on December 15, 2017