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Serum IL-18 is a specific biomarker for Macrophage Activation Syndrome across several autoinflammatory diseases
© Canna et al. 2015
- Published: 28 September 2015
- Juvenile Idiopathic Arthritis
- Macrophage Activation Syndrome
- Systemic Juvenile Idiopathic Arthritis
- Autoinflammatory Syndrome
IL-18 is a pro-inflammatory cytokine produced by a variety of myeloid and non-hematopoietic cells. It is canonically associated with enhancing interferon gamma (IFNg) and cytotoxicity in collaboration with IL-12p70, IL-15, or type I IFN. However, in other contexts IL-18 can promote IL-17, IL-22, or allergic responses. Macrophage Activation Syndrome (MAS) is a sepsis-like syndrome that has been associated with elevated serum IL-18 in systemic Juvenile Idiopathic Arthritis, Stills disease, and XIAP-deficiency. We sought to characterize IL-18 and associated cytokines in a cohort of patients with a variety of monogenic or complex autoinflammatory syndromes.
Serum IL-18 was measured across several platforms and normalized to healthy controls run in the same batch. For many patients, IL-18 binding protein (IL-18BP) and IL-37 were measured from the same sample. Results were correlated with clinical laboratory findings, most notably acute phase reactants like C-reactive protein and erythrocyte sedimentation rate obtained on the same date.
We found three patterns of serum IL-18: 1) normal IL-18 in healthy controls, patients with STING mutations, patients with chronic non-bacterial osteomyelitis (CNO), and patients with deficiency of IL-1 receptor antagonist (DIRA); 2) Mild elevation (less than 10-fold above normal) of serum IL-18 in patients with defects in NLRP3 (Cyropyrin Associated Periodic Syndromes, CAPS) or proteasomal defects (Chronic Atypical Neutrophilic Dermatosis Lipodystrophy Elevated Temperature, CANDLE); and 3) extraordinary elevation (100 to 500 fold above normal) in patients with a history of MAS regardless of disease activity. Multiple serial IL-18 measurements were made in a patient harboring an NLRC4 mutation, as well as a patient with clinical NOMID (including severe epiphyseal overgrowth) with no detectable germ-line or somatic gene defect who had multiple severe MAS episodes. There are two endogenous antagonists of IL-18: IL-18BP and IL-37. These cytokines correlated moderately with CRP, but not with serum IL-18.
Our data suggest that extreme elevation of serum IL-18, particularly in the absence of acute inflammation, is a unique biomarker for MAS risk across many autoinflammatory phenotypes. The mechanisms by which chronic elevation of IL-18 may promote the MAS phenotype need to be further investigated.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.