Monogenic autoinflammatory syndromes: state of the art on genetic, clinical, and therapeutic issues

Abstract

Monogenic autoinflammatory syndromes (MAISs) are caused by innate immune system dysregulation leading to aberrant inflammasome activation and episodes of fever and involvement of skin, serous membranes, eyes, joints, gastrointestinal tract, and nervous system, predominantly with a childhood onset. To date, there are twelve known MAISs: familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, familial cold urticaria syndrome, Muckle-Wells syndrome, CINCA syndrome, mevalonate kinase deficiency, NLRP12-associated autoinflammatory disorder, Blau syndrome, early-onset sarcoidosis, PAPA syndrome, Majeed syndrome, and deficiency of the interleukin-1 receptor antagonist. Each of these conditions may manifest itself with more or less severe inflammatory symptoms of variable duration and frequency, associated with findings of increased inflammatory parameters in laboratory investigation. The purpose of this paper is to describe the main genetic, clinical, and therapeutic aspects of MAISs and their most recent classification with the ultimate goal of increasing awareness of autoinflammation among various internal medicine specialists.

Figure 1

Schematic sketch showing the main pathophysiologic mechanisms of the monogenic autoinflammatory syndromes. Familial Mediterranean fever (FMF), cryopyrin-associated periodic syndromes (CAPS), mevalonate kinase deficiency (MKD), and PAPA syndrome (PAPAs) are due to mutations on pyrin (mtPYRIN), cryopyrin (mtNLRP3), mevalonate kinase enzyme (mtMK), and PSTPIP1 (mtPSTPIP1) proteins, respectively, and are associated with enhanced procaspase-1 activation, leading to increased IL-1β processing and secretion. Mutations in TNF receptors (TNFRSF1A) are responsible for tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Indeed, it is known that intracellular accumulation of mutated TNFRSF1A (mtTNFRSF1A) in the endoplasmic reticulum (ER) enhances inflammatory responses. This condition leads to the activation of ER-stress response and mitochondria (MT) release of reactive oxygen species (ROS), which in turn promotes upregulation of proinflammatory cytokines, including IL-1β, TNF-α, and IL-6. NLRP12-associated autoinflammatory disorder (NLRP12AD) and Blau syndrome (BS) are related to mutated NLRP12 protein (mtNLRP12) and mutated NOD2 protein (mtNOD2), respectively, and they bring about nuclear factor-κB (NF-κB) deregulation. Deficiency of the interleukin-1 (IL-1) receptor antagonist (DIRA) is due to mutations on the gene coding for IL-1 receptor antagonist (IL-1Ra), which lead to loss of IL-1β inhibition and unopposed inflammatory burst. TLR4: toll-like receptor-4; ASC: apoptosis-associated speck-like protein containing a caspase recruitment domain; TNF-α: tumor necrosis factor-alpha;   IL-1β: interleukin-1β; IL-1Ra: interleukin-1 receptor antagonist; IL-1RI: IL-1 receptor type I; mtIL-1Ra: mutated IL-1Ra; IL-6: interleukin-6.