Translating pathogenic insights gained from monogenic defects that cause autoinflammatory diseases into novel
therapies has dramatically improved the lives of patients with these syndromes. The last 15 years have focused on the central role of
IL-1 in driving autoinflammatory phenotypes and on
therapies blocking
IL-1 signaling. Recent discoveries from patients unresponsive to
IL-1 blockade have highlighted other key inflammatory mediators and pathways. New genetic discoveries have confirmed unifying mechanisms of autoinflammation, including dysregulation of danger sensing, cell stress, and immune-receptor signaling. Recent gene discovery in novel diseases has demonstrated new concepts. First, several complex clinical syndromes, caused by mutations leading to chronic
type I interferon (IFN) production present with organ manifestations different from
IL-1 mediated diseases including cerebral calcifications,
myositis, and
interstitial lung disease and the frequent occurrence of
autoantibodies. These disorders introduce type I IFN's as inflammatory mediators that cause autoinflammatory phenotypes. Second, conditions associated with high
IL-18 production may provide a direct link between autoinflammation and
macrophage activation syndrome. Third, dysregulation of inflammatory and cell differentiation pathways in nonhematopoietic cells, such as aberrant calcium signaling and impaired endothelial or keratinocyte development, provide an understanding of organ specificity in autoinflammatory disorders. Many of these discoveries highlight the intricate interconnections between autoinflammation, autoimmunity, immunodeficiency, and lymphoproliferation and suggest ways in which we may better diagnose and treat autoinflammatory diseases.