Autoinflammatory disease reloaded: a clinical perspective

Abstract

Our understanding of the etiology of autoinflammatory disease is growing rapidly. Recent advances offer new opportunities for therapeutic intervention and suggest that the definition of what constitutes an autoinflammatory disease should be reassessed.

Figure 1. IL-1β mediated disorders

Several mendelian autoinflammatory diseases are caused by mutations in genes encoding proteins that directly or indirectly regulate interleukin -1β (IL-1β), an important mediator of fever and inflammation. The NLRP3 inflammasome is one of the macromolecular complexes by which IL-1β is activated in monocytes, and is comprised of NLRP3, ASC, and caspase-1. Several endogenous “danger signals,” such as monosodium urate or calcium pyrophosphate dihydrate crystals, asbestos, silica, amyloid β, and ATP, as well as bacterial toxins, activate the NLRP3 inflammasome through pathways that have not been well-defined but may involve reactive oxygen species (ROS) and cathepsin B. With inflammasome activation, caspase-1 (IL-1β converting enzyme) cleaves pro-IL-1β into its biologically active form. Secreted IL-1β can act in an autocrine or paracrine fashion through the IL-1 receptor. The IL-1 receptor antagonist (IL-1Ra) is a naturally occurring antagonist of the binding of IL-1β to its receptor. Through mechanisms that have not been thoroughly elucidated, PSTPIP1 and pyrin may influence inflammasome activity (Shoham et al., 2003; Chae et al., 2006; Yu et al., 2007). Mevalonate kinase may also modulate inflammasome activity through the Rac1/PI3K/PKB pathway (Kuijk et al., 2008). Muckle-Wells syndrome is caused by activating mutations in NLRP3 itself, and manifests a hives-like skin rash. The deficiency of the IL-1 receptor antagonist (DIRA) is caused by recessive loss-of-function mutations in IL-1Ra, and presents in infancy with diffuse pustular skin lesions. Image from Aksentijevich et al. (2009) Copyright ©2009 Massachusetts Medical Society. All rights reserved. The syndrome of pyogenic arthritis with pyoderma gangrenosum and acne (PAPA) is caused by missense mutations in PSTPIP1. A typical lesion of pyoderma gangrenosum is shown. The hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) is caused by inactivating mutations in mevalonate kinase. Patients with HIDS have episodes of fever and a diffuse macular papular rash.