The spectrum of autoinflammatory diseases: recent bench to bedside observations

Abstract

Purpose of review: The autoinflammatory diseases are a group of conditions that include the hereditary fever syndromes, and result from upregulated innate immune responses. The discovery of the genetic basis for these conditions led to the description of novel intracellular receptors for infectious and noninfectious danger signals. This article focuses on recent progress in our understanding of autoinflammatory syndromes, and how insights into these conditions have triggered the exploration of the role of innate immunity in common rheumatologic diseases.

Recent findings: New models for the pathogenesis of several autoinflammatory syndromes have been proposed, including the role of pyrin and cryopyrin in regulating inflammation. Robust evidence has emerged that IL-1beta oversecretion is pivotal in cryopyrin-associated periodic syndromes, and that IL-1 inhibition ameliorates the clinical features of these syndromes. Monosodium urate crystals stimulate IL-1beta secretion via cryopyrin, which led to the addition of gout to the spectrum of autoinflammatory diseases.

Summary: Advances in our understanding of the autoinflammatory diseases have led to renewed interest in the innate immune system, and its role in the pathogenesis of more common rheumatic diseases.

Figure 1. Schematic representation of pyrin, cryopyrin and NOD2/CARD15

Pyrin (left) is composed of four domains including the pyrin domain (PYD), B-box, coiled-coil, and B30.2 (also called SPRY) domains. The B30.2 domain is postulated to interact with intracellular pathogens. Mutated pyrin results in familial Mediterranean fever. Although the role of wild-type pyrin remains unclear, one of its roles may be to inhibit the cryopyrin inflammasome. Cryopyrin (center) acts as an intracellular sensor of danger, and is composed of three domains: a pyrin domain, a central NACHT domain and a terminal domain consisting of leucine-rich repeats (LRR). The LRR domain is involved in the recognition of certain intracellular bacteria, bacterial and viral RNA, toxins and intracellular crystals. Once activated, cyropyrin forms a macromolecular complex termed the inflammasome that results in the release of the active form of the pro-inflammatory cytokine IL-1β. Cryopyrin-associated periodic syndromes are associated with mutant cryopyrin, which results in spontaneous inflammasome assembly and release of IL-1β. In patients with Blau syndrome/early-onset sarcoidosis, the NACHT domain of NOD2/CARD15 (right) is mutated. Variants of the gene encoding the LRR domain of this protein have been described in patients with Crohn's disease. The LRR domain of NOD2/CARD15 plays a role in the detection of muramyl dipeptide, a component of the cell wall of both gram-negative and gram-positive bacteria.