Inflammation is a core pathogenic mechanism in virtually every disease process. For millenia, we’ve been focused on fighting microbes and viruses as the most important drivers of pathologic inflammation, and sepsis and its accompanying Systemic Inflammatory Response Syndrome (SIRS) remain major problems. But in the 21st century, we recognize that abnormal host responses to inflammatory stimuli can be just as deadly and destructive. In informing our understanding on host susceptibility to immunopathology, understanding how high-penetrance mutations cause inflammatory diseases has been incredibly instructive.

Autoinflammation is defined as systemic or organ-specific inflammation not attributable to infection, malignancy, or antigen-specific autoimmunity.

Hyperinflammation is a state of damaging immune activation that is excessive or disproportionate to what would be expected for a patient’s clinical context.

Our lab is interested in both, but particularly in the ways in which they intersect.

Most “autoinflammatory” patients have chronic organ-specific or systemic inflammation, but only rarely hyperinflammation. The dramatic response of many “autoinflammatory” patients to inhibition of the inflammasome-activated cytokine IL-1 has reinvigorated the quest for anti-inflammatory targets in SIRS and reinforced the therapeutic potential of targeting the inflammasome and related innate immune pathways.

Our group studies the intersections of hyper- and auto-inflammation. In particular, we study two related disorders, Hemophagocytic Lymphohistiocytosis (HLH) and Macrophage Activation Syndrome (MAS), because they typify the concept of hyperinflammation. Whereas the pathogenesis of HLH clearly includes the inflammatory effects of defects in granule-mediated cytotoxicity, the mechanisms at work in MAS are less clear but seem to involve abnormal production and function of the inflammasome-activated cytokine 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.