Defining and Testing the Hyperinflammatory Immune Synapse
Dr. Scott Canna
Children’s Hospital of Philadelphia
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Layperson Summary: Inflammation protects against infections but must also be carefully regulated to prevent collateral damage and disease. Hemophagocytic Lymphohistiocytosis (HLH) is a term often used to describe a syndrome of damaging systemic inflammation caused by T-cell hyperactivity. HLH can occur in almost any context: genetic defects, infections, cancers, rheumatic diseases, and side-effects of cancer treatments. Knowing what factors contribute to HLH, and how they contribute, is critical to making accurate and timely diagnoses, giving targeted treatments, and preventing organ damage and death.
We study two well-known HLH risk factors: perforin-deficiency and excess IL-18. IL-18 is a cytokine that activates T-cells to make other cytokines. Cytokines are inflammatory proteins our immune systems make to signal danger and activate other immune cells. Excess IL-18 is associated with a type of secondary HLH called Macrophage Activation Syndrome (MAS).
Cancerous and infected cells are “targets” for killer T-cells. When targets and killer T-cells come together, they form an Immune Synapse (IS) and stimulate each other to drive inflammation. Killer T-cells use perforin to kill target cells, ending stimulation through the IS. Perforin-deficiency causes Familial HLH type 2 (FHL2).
We suspect that factors contributing to HLH act by exaggerating the IS via 1) promoting excessive inflammation during the IS, and/or 2) allowing the IS to last too long, with IL-18 acting via the former and perforin deficiency the latter. This proposal seeks support to develop an in vitro system integrating how long the IS lasts and how much cytokine is produced to test our suspicions. Once established, we will test other HLH risk factors, alone and in combinations, for their effects on promoting a hyperinflammatory IS (hIS).
This project will generate preliminary data to support bigger projects measuring multiple factors, so we can identify the components of the IS most relevant to HLH. Establishing this system will benefit current and future HLH patients by improving how we understand known HLH contributors, and how we can identify and test new candidates.