IL-1 mediated autoinflammatory diseases

Abstract The genetically defined Mendelian autoinflammatory diseases are a group of immune dysregulatory conditions that present with systemic and organ-specific “sterile” inflammation with clinical features that include fever, rashes arthritis/arthralgia, serositis, meningitis, and inner ear, eye, bone, and/or gut inflammation. The pattern of organ inflammation in the various conditions often allows a specific diagnosis on clinical grounds. At the onset, autoinflammatory conditions can resemble infections or hematopoietic malignancies, warranting a careful work-up. While the genetic discovery of the initial “classic” autoinflammatory diseases was pioneered by the discovery of IL-1 mediated autoinflammatory diseases that pointed to dysregulation of the IL-1 activating inflammasomes, more recent work pointed to the dysregulation of additional innate immune pathways that regulate other pro-inflammatory cytokines, including Type-I IFN, IL-18, NFκB activation through ubiquitylation defects and IL-17 activation in keratinocytes. The subsequent chapters review many genetically defined autoinflammatory syndromes identified since the classic inflammatory disorders were described. This chapter describes the spectrum of diseases that are caused by monogenic defects that regulate the activity of 4 human IL-1β activating inflammasomes including the three “classic” hereditary periodic fever syndromes of familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), and mevalonate kinase deficiency (MKD)/hyperimmunoglobulinemia D with periodic fever syndrome (HIDS); the cryopyrin associated periodic syndromes (CAPS) that comprise the clinical continuum of neonatal-onset multisystem inflammatory disease (NOMID), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS); and diseases caused by dysregulation of other IL-1 activating inflammasomes, NLRC4-associated autoinflammatory diseases (NLRC4-AID), NLRP1-associated auto-inflammation with arthritis and dyskeratosis (NAIAD) and NLRP12-Associated Autoinflammatory Disorder (NLRP12AD).