Reviews and feature article
Autoinflammation: The prominent role of IL-1 in monogenic autoinflammatory diseases and implications for common illnesses

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The discovery of the genetic causes of a rare group of immune-mediated inflammatory conditions that mimic infections and allergic conditions in their clinical presentation and the molecular understanding of the function of the mutated molecules in these diseases has led to a revolution in our understanding of the pathogenesis of systemic and local inflammation. The proteins mutated in a number of these so-called autoinflammatory diseases are part of, or regulate the activity of, intracellular molecular complexes, the inflammasomes, that sense “danger” to the body and coordinate an initial immune response. Our understanding of specific triggers of the inflammasomes, coupled with the recognition that inflammasomes are critical for activation of the proinflammatory cytokine IL-1, has provided a rational and very effective target in the treatment of a number of these rare autoinflammatory diseases. In addition, the ongoing discovery of the role of inflammasomes and IL-1 activation and secretion in a number of genetically complex disorders have fundamentally changed our view of disease pathogenesis in a growing number of disorders that were heretofore not even thought of as “immunologic” diseases.

Section snippets

The inflammasome as sensor of danger and instigator of autoinflammation

Our immune system has evolved to protect our bodies against microbial infections and cellular waste that accumulate when cells are damaged or die. Two types of immune defense systems have emerged. The recognition of exogenous and endogenous danger by the innate immune system is mediated through pattern-recognition receptors, which we inherit and are not subject to adaptation or fine tuning through gene rearrangement or somatic mutation as we get older. Receptors of the innate immune system bind

IL-1 as a prototypic “alarm” cytokine

IL-1 helps coordinate the immune system's early response to exogenous and endogenous danger, serving as a prototypic alarm cytokine.23 IL-1α and IL-1β were the first members to be described in a now 11-member family of IL-1 molecules that includes at least one IL-1 receptor antagonist (IL-1Ra) molecule.24, 25 The genes for 9 members of this family (all except IL-18 [IL-1F4] and IL-33 [IL-1F11]) are encoded in a cluster on the long arm of chromosome 2. In addition, the type I and II IL-1

Early clinical studies with IL-1Ra in sepsis and rheumatoid arthritis

Based on the observation that IL-1β blockade had attenuated the severity of disease and mortality in experimental models of shock and sepsis,30 clinical trials of the recombinant IL-1Ra anakinra were conducted in the early 1990s to asses its utility in these 2 conditions. The results of a phase II study suggested a possible benefit, with anakinra reducing 28-day all-cause mortality in a dose-dependent manner.31 However, based on a subsequent phase III trial that failed to demonstrate a

Clinical presentation

Historically, CAPS was described not as a single entity but as 3 different disorders that were not recognized as related to one another until their common genetic cause was established. These diseases are familial cold urticaria (now known as FCAS), MWS, and NOMID, which was first named CINCA syndrome. These conditions were initially not recognized as related because of striking differences in severity, multiorgan disease manifestations, and long-term morbidity and mortality, although they do

DIRA

We recently reported a series of 9 patients with a severe autoinflammatory condition with some similarity to NOMID who had homozygous mutations in IL1RN.15 Eight of the 9 patients had inactivating point mutations in IL1RN, whereas the remaining patient, a child from Puerto Rico, harbored a 175-kb genomic deletion that encompassed IL1RN and 5 other genes in the IL1 family (IL1F9, IL1F6, IL1F8, IL1F5, IL1F10, and IL1RN, from centromere to telomere). In an accompanying case report in the New

IL-1 blockade in other autoinflammatory diseases

Anakinra has also been used to prevent attacks and reduce systemic inflammation in patients with colchicine-resistant FMF,50, 51, 52 hyperimmunoglobulinemia D with periodic fever syndrome,53, 54 and TNF receptor–associated periodic syndrome,55, 56, 57 and good responses were also reported in patients with Blau syndrome58 and some with pyogenic arthritis, pyoderma gangrenosum, and acne.59 In addition to the effect in monogenic diseases, a number of presumed polygenic autoinflammatory diseases

Summary

The systemic autoinflammatory diseases are a group of illnesses characterized by episodic or sometimes chronic inflammation without evidence of high-titer autoantibodies or antigen-specific T lymphocytes. Monogenic autoinflammatory diseases are inborn errors of the phylogenetically ancient innate immune system, with its predominance of myeloid cells and germline receptors, whereas monogenic autoimmune diseases affect primarily acquired or adaptive immunity, with its predominance of lymphocytes

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    (Supported by an educational grant from Merck & Co., Inc.)

    Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, William T. Shearer, MD, PhD, and Donata Vercelli, MD

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