Cornelia M Spies1, Paula Hoff2, Jeannine Mazuch3, Timo Gaber4, Bert Maier3, Cindy Strehl5, Martin Hahne6, Manuela Jakstadt4, Dörte Huscher5, Gerd-Rüdiger Burmester1, Jacqueline Detert1, Achim Kramer3, Frank Buttgereit1. 1. Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Germany. 2. Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, and German Arthritis Research Centre (DRFZ), Berlin, Germany. 3. Laboratory of Chronobiology, Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Germany. 4. Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin; German Arthritis Research Centre (DRFZ), Berlin; and Berlin-Brandenburg Centre for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Germany. 5. Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin; and German Arthritis Research Centre (DRFZ), Berlin, Germany. 6. Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin; German Arthritis Research Centre (DRFZ), Berlin; and Berlin-Brandenburg School for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Germany.
Abstract
OBJECTIVES: The circadian rhythm of clinical symptoms in rheumatoid arthritis (RA) has been primarily attributed to circadian variations in humoral factors and hormones. In this study, we investigated circadian rhythms of cellular immunity in RA (CiRA study). METHODS: Peripheral blood of female postmenopausal patients with active RA (DAS 28 ≥ 4.2) (n=5) and female postmenopausal non-RA controls (n=5) was collected every 2 hours for 24 hours and analysed by flow cytometry, cytokine multiplex suspension array and quantitative RT-PCR of clock gene expression in isolated CD14+ monocytes. Endogenous circadian rhythms of macrophages were investigated by BMAL1-luciferase bioluminescence. Significance of circadian rhythms was tested by Cosinor analysis. RESULTS: We found (i) circadian rhythms in the relative frequency of peripheral blood cell populations that were present in postmenopausal non-RA controls but absent in patients with active RA, (ii) circadian rhythms that were absent in non-RA controls but present in patients with RA and (iii) circadian rhythms that were present in both groups but with differences in peak phase or amplitude or amplitude/magnitude. The circadian rhythm in expression of the clock genes PER2 and PER3 in CD14+ monocytes was lost in patients with RA. The amplitude of BMAL1-luciferase bioluminescence tended to be lower in patients with RA than in non-RA controls. CONCLUSIONS: We conclude that (i) in RA some immune cell populations lose their normal circadian rhythms whereas others establish new 'inflammatory' circadian rhythms and (ii) these findings provide a good basis for further identifying pathophysiological aspects of RA chronobiology with potential therapeutic implications.
OBJECTIVES: The circadian rhythm of clinical symptoms in rheumatoid arthritis (RA) has been primarily attributed to circadian variations in humoral factors and hormones. In this study, we investigated circadian rhythms of cellular immunity in RA (CiRA study). METHODS: Peripheral blood of female postmenopausal patients with active RA (DAS 28 ≥ 4.2) (n=5) and female postmenopausal non-RA controls (n=5) was collected every 2 hours for 24 hours and analysed by flow cytometry, cytokine multiplex suspension array and quantitative RT-PCR of clock gene expression in isolated CD14+ monocytes. Endogenous circadian rhythms of macrophages were investigated by BMAL1-luciferase bioluminescence. Significance of circadian rhythms was tested by Cosinor analysis. RESULTS: We found (i) circadian rhythms in the relative frequency of peripheral blood cell populations that were present in postmenopausal non-RA controls but absent in patients with active RA, (ii) circadian rhythms that were absent in non-RA controls but present in patients with RA and (iii) circadian rhythms that were present in both groups but with differences in peak phase or amplitude or amplitude/magnitude. The circadian rhythm in expression of the clock genes PER2 and PER3 in CD14+ monocytes was lost in patients with RA. The amplitude of BMAL1-luciferase bioluminescence tended to be lower in patients with RA than in non-RA controls. CONCLUSIONS: We conclude that (i) in RA some immune cell populations lose their normal circadian rhythms whereas others establish new 'inflammatory' circadian rhythms and (ii) these findings provide a good basis for further identifying pathophysiological aspects of RA chronobiology with potential therapeutic implications.
Authors: G Esther A Habers; Annette H M van der Helm-van Mil; Dieuwke S Veldhuijzen; Cornelia F Allaart; Erno Vreugdenhil; Daniëlle E J Starreveld; Tom W J Huizinga; Andrea W M Evers Journal: Clin Rheumatol Date: 2021-01-16 Impact factor: 2.980