The role of the inflammasome in patients with autoinflammatory diseases

Abstract

Autoinflammatory diseases are disorders of the innate immune system, characterized by systemic inflammation often driven by inflammasomes, and independent of infection and autoreactive antibodies or antigen-specific T cells. These diseases are increasingly recognized as disorders of immune dysregulation, presenting with a constellation of fevers, rashes, and mucosal symptoms in many cases, which suggests that the allergist/immunologist is the appropriate specialist for these patients. However, many practicing physicians are unaware of these disorders in their pediatric and adult patient populations, leading to substantial delays in diagnosis. Recognizing autoinflammatory disease symptom patterns, performing appropriate diagnostic tests, and instituting early effective therapy are essential to reduce morbidity and mortality in these patients. This review will focus on understanding the molecular basis of inflammasomes, recognizing the distinguishing features of the classic autoinflammatory disorders, and appreciating the treatment modalities available.

Inflammatory osteolysis: a conspiracy against bone

“…Prosthetic-wear particles activate innate immune responses, causing excessive bone resorption and, Inflammasome mutations may prompt stimulus-independent activation and are the cause of cryopyrin-associated periodic syndromes (CAPS). Neonatal-onset multisystem inflammatory disease (NOMID), the most severe CAPS, is attended by bone loss and skeletal deformation (101,(115)(116)(117)(118). IL-1-blocking agents have limited efficacy against NOMID skeletal lesions, while other symptoms related to systemic inflammation are rapidly resolved (119)(120)(121)(122).…”

Immunotherapeutic Biologic Agents to Treat Autoinflammatory Diseases

“…Following Signal 1 and 2 triggers, intracellular pattern recognition proteins, including nucleotide-binding oligomerization domain-like receptors (NOD-like receptors, NLRs such as NOD-like receptor P3 (NLRP3), and NOD-like receptor C4 (NLRC4)) and cytoplasmic DNA receptors [2], are then activated. Cytoplasmic NLRs oligomerize in response to these initial signals, forming inflammasomes that are multimeric scaffolded structures that further activate cytokines [3,4]. Inflammasomes specific to different NLR structures perpetuate cascading downstream signals.…”

“…In CAPS, spontaneous activation of cell surface TLRs and cytoplasmic sensors occurs followed by antigen unprovoked assembly of the inflammasome complex. Caspase-1 is then activated and converts both pro-IL-1ß and pro-IL-18 to operational cytokines [3,5]. Excess activity of the assembled multimolecular inflammasome results in unregulated production of IL-1ß, causing CAPS.…”

“…Loss-of-function gene mutations cause DIRA due to dysfunctional IL-1 receptor binding to this defective protein which normally would prevent dampening of IL-1 activity [3]. DIRA differs from CAPS possibly due to uninterrupted …”

“…Abnormal p55 receptors shed in TRAPS are unable to serve as naturally occurring decoys for circulating TNF [20]. These mechanisms suggest benefit of anti-TNF as well as anti-IL-1 approaches [3,[20][21][22][23][24][25].…”