Research Interests

Beginning with a chance encounter with a patient with familial Mediterranean fever (FMF), I have spent my research career studying the genetic basis, pathophysiology, and targeted therapy of inherited disorders of inflammation. Using classical linkage analysis, my laboratory mapped the gene for FMF to chromosome 16p and subsequently identified the recessively inherited gene by positional cloning. This gene encodes what was then a novel protein (pyrin) that is the prototype for a motif found in 20 human proteins, several involved in inflammation. Prompted by an Irish patient with an FMF-like illness, we discovered that mutations in the p55 TNF receptor cause a dominantly inherited fever syndrome that we named TRAPS (the TNF receptor-associated periodic syndrome). Stimulated by other patients, we found that mutations in a pyrin domain-containing activator of interleukin-1 (IL-1) cause a devastating inflammatory disorder of the central nervous system, skin, and bones known as NOMID, that dominant mutations in a pyrin-binding protein cause a distinct syndrome of severe arthritis and skin disease, while recessive mutations in the endogenous IL-1 receptor antagonist cause a newly recognized disorder of pustulosis and osteitis. These latter three illnesses help define the role of IL-1 in human biology, and all three are clinically responsive to IL-1 inhibition. More recently we have used genome-wide association to discover that variants in the genes encoding IL-10 and the IL-23 receptor, both potential therapeutic targets, confer susceptibility to Behçet's disease. We also proposed the now widely accepted concept of autoinflammatory disease to denote disorders of innate immunity.

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Primary Section

Section 42: Medical Physiology and Metabolism

Secondary Section

Section 41: Medical Genetics, Hematology, and Oncology