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Charles H. Hood Foundation | Pui Lee, M.D., Ph.D. – January 2021
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Pui Lee, M.D., Ph.D.

Assistant Professor of Pediatrics

Boston Children’s Hospital

mTORC1 as a Mediator of Hemophagocytosis and Macrophage Activation Syndrome


Key Words: mTOR, Macrophage Activation Syndrome, Hemophagocytosis, Cytokine Storm Syndrome

Macrophage activation syndrome (MAS) is a life-threatening disease caused by overwhelming inflammation and activation of immune cells. MAS can affect children of any age, typically as a complication of autoimmune diseases, malignancies or infections, with a mortality rate as high as 30%. A telltale sign of MAS is the presence of hemophagocytes, which are large immune cells that ingest other blood cells through a process called hemophagocytosis. Very little is known about the origin of hemophagocytes or how they contribute to disease. Understanding the biology of hemophagocytosis may yield new insight on the treatment of MAS.

We recently established a new animal model that surprisingly links MAS with cellular metabolism. The mTOR (mechanistic target of rapamycin) pathway is normally involved in nutrient sensing and regulation of cell growth and development. We found that persistent activation of this pathway in mice leads to development of hemophagocytes, along with other MAS features including anemia, low white blood cell count, enlarged liver and spleen, and elevated levels of a serum protein called ferritin. Importantly, we found that the mTOR pathway is also highly activated in hemophagocytes from patients with MAS. Based on these findings, we hypothesize that chronic activation the mTOR pathway primes the development of hemophagocytes and contributes to the severe inflammation in MAS.

We will study why and how the mTOR pathway is activated in our new model of MAS and  perform parallel studies using samples from patients with MAS to look for metabolic signatures associated with the disease. We will address several key questions on basic biology of hemophagocytes, including how they develop from stem cells, how they “eat” other cells, and whether they are responsible for clinical features of MAS. Importantly, we will investigate the utility of available mTOR inhibitors for the treatment of MAS and explore additional therapeutic targets. Together, these studies will provide new insight on biology of hemophagocytosis and potentially uncover new approaches to treat MAS.