Scott W. Canna, MD

Humans are exposed to countless microbes and other inflammatory insults throughout their lives, yet what lands one person in intensive care and another unharmed is largely unknown. Whether in hyperinflammatory disorders or less severe inflammatory states, we are broadly interested in the immunologic mechanisms of susceptibility to severe inflammation. We use genetic, biomarker, and functional insights from patients and model systems to elucidate these mechanisms in diagnostically and therapeutically meaningful ways. Patients found to have single-gene defects causing excessive innate immune activation (autoinflammatory diseases) have been particularly helpful. We’ve observed dramatic responses of many autoinflammatory patients to targeted cytokine blockade, reinforcing the translational potential of this approach.

Our focus is on the mechanisms driving hyperinflammatory diseases: Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome (HLH and MAS). We have observed independent and interacting effects of two mechanisms: 1) defective granule-mediated cytotoxicity and 2) excess of cytokines like Interleukin (IL) -18. We combine clinical insights from rheumatology and innate immunity with basic models of overwhelming systemic inflammation to define new disease subtypes and disease activity biomarkers, to flesh out mechanisms of inflammatory disease, and to test promising therapeutic strategies. 

Ongoing projects involve:

1. Comparing different inflammasomes (NLRC4, NLRP3, PYRIN, etc.)
2. Identifying the regulation and effects of cytokines in auto- and hyperinflammatory diseases (with particular attention on IL-18)
3. Understanding the interaction between IL-18 and intestinal MHC-II
4. Identifying and understanding inflammatory biomarkers
5. Increasing the number and understanding of genetic inflammatory diseases