Immune-mediated inflammatory diseases with chronic excess of serum interleukin-18

Abstract

Review: Interleukin-18 (IL-18) is a proinflammatory cytokine that promotes various innate immune processes related to infection, inflammation, and autoimmunity. Patients with systemic juvenile idiopathic arthritis and adult-onset Still’s disease exhibit chronic excess of serum IL-18, which is associated with a high incidence of macrophage activation syndrome (MAS), although the mechanisms of IL-18 regulation in such diseases remain largely unknown. Similar elevation of serum IL-18 and susceptibility to MAS/hemophagocytic lymphohistiocytosis (HLH) have been reported in monogenic diseases such as X-linked inhibitor of apoptosis deficiency (i.e., X-linked lymphoproliferative syndrome type 2) and NLRC4-associated autoinflammatory disease. Recent advances in molecular and cellular biology allow the identification of other genetic defects such as defects in CDC42, PSTPIP1, and WDR1 that result in high serum IL-18 levels and hyperinflammation. Among these diseases, chronic excess of serum IL-18 appears to be linked with severe hyperinflammation and/or predisposition to MAS/HLH. In this review, we focus on recent findings in inflammatory diseases associated with and probably attributable to chronic excess of serum IL-18 and describe the clinical and therapeutical relevance of understanding the pathology of this group of diseases.

High cell-free DNA is associated with disease progression, inflammasome activation and elevated levels of inflammasome-related cytokine IL-18 in patients with myelofibrosis

“…As a readout of inflammasome activation in vivo ( 45 ), we next measured IL-18 levels in patient plasma. Circulating IL-18 was elevated in this cohort, being above the reference range in 55% of MF patients ( Figure 4A ).…”

The clinical phenotype with gastrostomy and abdominal wall infection in a pediatric patient with Takenouchi-Kosaki syndrome due to a heterozygous c.191A > G (p.Tyr64Cys) variant in CDC42: a case report

“…This phenomenon reflects the clinical intersubject variability within the p.Tyr64Cys variant group and possible overlap with C-terminal variants in the CDC42 gene and highlights that the p.Tyr64Cys variant does support the hypothesis that the gene is associated with distinct diseases. The clinical phenotypes related to C-terminal variants are characterized by severe neonatal-onset dyshematopoiesis and immune dysregulation including autoinflammation, rash, and HLH (NOCARH syndrome) ( Gernez et al, 2019 ; Lam et al, 2019 ; He et al, 2020 ; Coppola et al, 2022 ) with a chronic excess of the inflammatory cytokine, IL-18 as a hallmark of these disorders ( Miyazawa and Wada, 2022 ; Shimizu et al, 2022 ). A similar phenotype distinguished by the hyperinflammatory state, full-blown HLH, and hitherto not reported, development of non-Hodgkin lymphoma has also been described by our group in the patient with a novel p.Cys81Tyr variant ( Szczawińska-Popłonyk et al, 2020 ).…”

IL-18 in Autoinflammatory Diseases: Focus on Adult Onset Still Disease and Macrophages Activation Syndrome

“…Amongst actinopathies, WDR1 disease has been recently described. It is characterized by autoinflammatory features, including recurrent stomatitis, difficult wound healing and immunodeficiency; [ 84 ] WD repeat-containing domain 1 (WDR1) is an actin regulatory protein that promotes cofilin-dependent actin filament turnover [ 85 ]. In 2015, Kim et al observed that inflammation in WDR1 patients is driven by IL-18, and this mechanism reinforces the concept that the IL-18 is induced through aberrant actin depolymerization-driven pyrin inflammasome activation [ 86 ].…”

“…Given the high mortality rate associated with the MAS condition, we believe that further clinical trials of IL-18BP and anti-IL-18 antibodies are urgently needed. Finally, the use of drug therapies that specifically focus on IL-18 inhibition, in addition to the inhibition of IL-1β, represents a new therapeutic approach and preliminarily appears to be safe and effective [ 85 , 93 ].…”