Perforin, a pore-forming protein, is essential for cytotoxic lymphocytes to kill target cells. These immune cells use secretory granules (lysosome-like compartments) to deliver perforin and granzymes into the synapse formed with the target cell. Loss of functional perforin or failure to release it leads to severe immune dysregulation, known as familial haemophagocytic lymphohistiocytosis (FHL). Milder, often undiagnosed forms of FHL result from partial loss-of-function mutations.
Lysosomal storage diseases (LSDs), a group of over 70 genetic disorders affecting around 1 in 5,000 people, are caused by mutations in lysosomal enzyme genes. While the lysosomal system is critical for cytotoxic lymphocyte effector function, its role in LSDs has been largely overlooked due to the dominance of other severe symptoms.
Using immunological and cell biology approaches, along with patient samples where available, we examined several LSDs, including Niemann-Pick types A, C1, and C2, and Wollman disease. These disorders cause abnormal lipid accumulation, which we found disrupts cytotoxic lymphocyte function by impairing perforin pore formation. Treatment with therapeutic 2-hydroxypropyl-ß-cyclodextrin restored perforin activity and cytotoxicity in some cases by promoting lipid clearance.
Our findings suggest that lipid buildup in LSDs can compromise immune function, potentially explaining the immune dysregulation seen in patients, including haemophagocytic symptoms in Wollman disease. More broadly, this reveals a previously underappreciated link between LSDs and impaired immune surveillance.