Identifying the genetic causes of disease not only helps provide patients with a diagnosis, but uncovers pathways and regulatory processes that result in inflammation. We characterize these disease-causing variants in vitro, in patient samples, and in model organisms and correlate these findings with clinical manifestations in patients (Beck DB et al. NEJM 2021, Poulter JA et al. Blood 2021). Through these efforts we have discovered novel regulatory pathways critical for immune activation. Our recent efforts have focused on understanding the role of global ubiquitylation in fine tuning inflammation and cell death within immune cell subsets along with the role of specific ubiquitin chain types in cytokine production. Further characterization of such pathways, in mouse models of disease, will reveal new principles of regulation of human inflammation, which will translate to novel, more specific and effective therapeutic approaches.
