Inflammation has evolved as a physiologic mechanism necessary to defend our bodies from external and internal ‘danger’ triggers such as infections and waste from dying cells [1
]. Low-grade inflammation can also be a response found in ‘stressed tissues’ such as through fat deposits in obesity and the shearing stress of high blood pressure on vessel walls in hypertension [2
]. The inflammatory response has several components that include a trigger or inducer of the response such as infection, tissue damage, and tissue stress; a sensor recognizing the trigger such as Toll-like receptors and the recently discovered intracellular receptors (NOD-like receptors, NLRs); the mediators that coordinate and execute a response (such as cytokines, chemokines, and signaling pathways); and the target tissues that are affected by the inflammatory mediators [1
]. The discovery of monogenic and genetically complex auto-inflammatory diseases has led to a growing understanding of how mutations that affect the different components of an inflammatory response can lead to human diseases [3•
More than 10 years ago the discovery of mutations in MEFV
causing familial Mediterranean fever (FMF) and TNF-receptor-associated periodic syndrome (TRAPS), respectively, spurred the concept of auto-inflammation. This laid the foundation for a new class of disorders that are characterized by excessive innate immune responses to known and yet unknown triggers leading to episodic systemic and organ-specific inflammation. Mutations in the then novel gene, NLRP3
, cause the cryopyrin-associated periodic syndromes (CAPSs), and NLRP3
was the first member of a large group of intracellular sensors of danger recognition implicated in human disease. The formation of an NLRP3-containing multimolecular complex termed the ‘inflammasome’ leads to the activation of IL-1 and provides a molecular link between the recognition of danger and the activation of the pro-inflammatory cytokine IL-1 as an early ‘alarm or response’ cytokine [4
]. With the progression of the genome project, the identification of additional intracellular sensor molecules that could be activated by ‘danger signals’ such as pathogen-associated molecular patterns (PAMPs) derived from bacterial and viral pathogens and damage-associated molecular patterns (DAMPs) such as exogenous environmental noxious triggers (i.e. silica and asbestos) and endogenous signals from stressed and dying cells (i.e. ATP, uric acid and cholesterol crystals) was accomplished. The NLRP3 inflammasome is by far the best studied, and its activation has been implied in the inflammatory response in a number of genetically complex disorders in vivo
and in vitro
]. The rediscovery of IL-1 as a central cytokine in human disease was spurred by the striking clinical responses of CAPS patients to IL-1 blockade with anakinra, a daily administered recombinant IL-1 receptor antagonist.
Several advances have occurred in the study of monogenic auto-inflammatory syndromes including the recent discovery that the deficiency of the IL-1 receptor antagonist in humans leads to a severe neonatal inflammatory disease with osteolytic bone lesions and pustular skin lesions and the discovery that loss of function mutations in the IL-10 receptor leads to early-onset enterocolitis. These discoveries have expanded the clinical spectrum of IL-1-mediated disease and have demonstrated the critical role of IL-10 in the regulation of gut inflammation. The molecular targets revealed from disease-based gene discovery have stimulated research aimed at understanding the function of dysregulated inflammatory pathways that lead to end organ damage. The development of mouse models, in which a mutated TNF receptor (TNFRSF1A, the gene causing TRAPS), mutated cryopyrin (NLRP3, the gene causing CAPS) and pyrin (MEFV, the gene causing FMF) were knocked in, allows further dissection of the inflammatory mediator pathways that lead to the systemic and organ-specific disease manifestations seen in patients with these conditions.
In summary, the study of autoinflammatory disorders poses new questions regarding the molecular mechanisms that lead to organ-specific inflammation and provides us with molecular targets for rational drug design focused on the correction of the abnormal protein function on inflammatory pathways. This review describes the currently known monogenic auto-inflammatory disorders () and will focus on summarizing advances over the last 18 months in the understanding of these disorders and the implications for some polygenic diseases.