Charlotte Girard1, Jürgen Rech2, Michael Brown3, Danièle Allali4, Pascale Roux-Lombard4,5, François Spertini6, Eduardo J Schiffrin7, Georg Schett2, Bernhard Manger2, Sylvette Bas1,5, Greg Del Val7, Cem Gabay8. 1. Division of Rheumatology, Department of Internal Medicine Specialties, University Hospitals of Geneva, Geneva, Switzerland. 2. Department of Internal Medicine 3, University Erlangen-Nuremberg, Erlangen, Germany. 3. Lyndin Group, Inc., Baltimore, MD, USA. 4. Division of Immunology and Allergy, University Hospitals of Geneva. 5. Department of Genetics and Laboratory Medicine, University of Geneva, Geneva. 6. Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois (CHUV). 7. AB2 Bio, Innovation Park, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. 8. Division of Rheumatology, Department of Internal Medicine Specialties, University Hospitals of Geneva, Geneva, Switzerland, cem.gabay@hcuge.ch.
Abstract
OBJECTIVE: IL-18 is a pro-inflammatory cytokine of the IL-1 family that is naturally inhibited by IL-18 binding protein (IL-18BP). High levels of IL-18 have been described in the serum of adult-onset Still's disease (AOSD) patients, but only total IL-18 levels (including inactive IL-18 bound to IL-18BP) have been measured. With a specific immunoassay, we aimed to measure free IL-18 serum levels in AOSD patients and other rheumatic diseases. METHODS: An ELISA was developed to measure free IL-18. Its sensitivity and specificity were tested by spiking recombinant IL-18 or IL-18BP in serum and PBS supplemented with 5% BSA. The binding affinity of IL-18 to IL-18BP was calculated by titration experiments using the ELISA and by Biacore analysis. Sera of 37 AOSD patients and 138 controls (40 healthy controls, 30 RA, 29 SLE, 21 AS and 18 PsA) were assayed for free IL-18, IL-18BP, total IL-18 and other cytokines. Correlations were performed between free IL-18 and markers of disease activity in AOSD patients. RESULTS: Free IL-18 serum levels were significantly higher in AOSD patients (median 8.89 pg/ml) than in healthy and disease controls (1.37 pg/ml; P < 0.01). Free IL-18 serum levels correlated with AOSD activity. The affinity of IL-18 to IL-18BP was found to be much higher than previously described, with a dissociation constant ranging from 30 to 50 pM. CONCLUSION: Free IL-18 levels are specifically elevated in AOSD compared with other inflammatory diseases, suggesting that IL-18 represents a potential target for the treatment of AOSD.
OBJECTIVE:IL-18 is a pro-inflammatory cytokine of the IL-1 family that is naturally inhibited by IL-18 binding protein (IL-18BP). High levels of IL-18 have been described in the serum of adult-onset Still's disease (AOSD) patients, but only total IL-18 levels (including inactive IL-18 bound to IL-18BP) have been measured. With a specific immunoassay, we aimed to measure free IL-18 serum levels in AOSD patients and other rheumatic diseases. METHODS: An ELISA was developed to measure free IL-18. Its sensitivity and specificity were tested by spiking recombinant IL-18 or IL-18BP in serum and PBS supplemented with 5% BSA. The binding affinity of IL-18 to IL-18BP was calculated by titration experiments using the ELISA and by Biacore analysis. Sera of 37 AOSD patients and 138 controls (40 healthy controls, 30 RA, 29 SLE, 21 AS and 18 PsA) were assayed for free IL-18, IL-18BP, total IL-18 and other cytokines. Correlations were performed between free IL-18 and markers of disease activity in AOSD patients. RESULTS: Free IL-18 serum levels were significantly higher in AOSD patients (median 8.89 pg/ml) than in healthy and disease controls (1.37 pg/ml; P < 0.01). Free IL-18 serum levels correlated with AOSD activity. The affinity of IL-18 to IL-18BP was found to be much higher than previously described, with a dissociation constant ranging from 30 to 50 pM. CONCLUSION: Free IL-18 levels are specifically elevated in AOSD compared with other inflammatory diseases, suggesting that IL-18 represents a potential target for the treatment of AOSD.
Authors: Scott W Canna; Charlotte Girard; Louise Malle; Adriana de Jesus; Neil Romberg; Judith Kelsen; Lea F Surrey; Pierre Russo; Andrew Sleight; Eduardo Schiffrin; Cem Gabay; Raphaela Goldbach-Mansky; Edward M Behrens Journal: J Allergy Clin Immunol Date: 2016-11-19 Impact factor: 10.793
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Authors: Deborah L Stone; Amanda Ombrello; Juan I Arostegui; Corinne Schneider; Vinh Dang; Adriana de Jesus; Charlotte Girard-Guyonvarc'h; Cem Gabay; Wonyong Lee; Jae Jin Chae; Ivona Aksentijevich; Raphaela T Goldbach-Mansky; Daniel L Kastner; Scott W Canna Journal: Arthritis Rheumatol Date: 2022-01-03 Impact factor: 10.995
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