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

: 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 , , and 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.