Monogenic IL-1 mediated autoinflammatory and immunodeficiency syndromes: finding the right balance in response to danger signals.

INTRODUCTION: Interleukin-1 was the first cytokine identified and is a powerful inducer of fever and inflammation. The biologically active receptor for IL-1, shares signaling pathways with some pathogen recognition receptors, the Toll-like receptors (TLRs) which early on suggested an important role in innate immune function. DISCUSSION: The discovery that some intracellular "danger receptors", the NOD like receptors (NLRs) can assemble to form multimolecular platforms, the inflammasomes, that not only sense intracellular danger but also activate IL-1beta, has provided the molecular basis for the integration of IL-1 as an early response mediator in danger recognition. The critical role of balancing IL-1 production and signaling in human disease has recently been demonstrated in rare human monogenic diseases with mutations that affect the meticulous control of IL-1 production, release and signaling by leading to decreased or increased TLR/IL-1 signaling. In diseases of decreased TLR/IL-1 signaling (IRAK-4 and MyD88 deficiencies) patients are at risk for infections with gram positive organisms; and in diseases of increased signaling, patients develop systemic autoinflammatory diseases (cryopyrin-associated periodic syndromes (CAPS), and deficiency of the IL-1 receptor antagonist (DIRA)).
CONCLUSION: Monogenic defects in a number of rare diseases that affect the balance of TLR/IL-1 signaling have provided us with opportunities to study the systemic effects of IL-1 in human diseases. The molecular defects in CAPS and DIRA provided a therapeutic rationale for targeting IL-1 and the impressive clinical results from IL-1 blocking therapies have undoubtedly confirmed the pivotal role of IL-1 in human disease and spurred the exploration of modifying IL-1 signaling in a number of genetically complex common human diseases. Published by Elsevier Inc.