Article
Circadian rhythms of immune cells in healthy individuals and patients with rheumatoid arthritis
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Authors
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Siska Wilantri
- Charité – Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Berlin
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Cindy Strehl
- Charité – Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Berlin
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Dimas Abdirama
- Charité – Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Berlin
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Timo Gaber
- Charité – Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Berlin
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Frank Buttgereit
- Charité – Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Berlin
| Published: | February 5, 2019 |
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Outline
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Background: Clinical symptoms of rheumatoid arthritis (RA), such as join stiffness, swelling and pain, manifest in circadian pattern with the highest intensity occurs at early dawn. This is known to correlate with the circadian expression of IL-6, which peaks before the onset of the symptom. Despite this finding, the circadian behavior of immune system in cellular and molecular level in RA patients has not yet been extensively investigated. Our previous study suggested that immunological circadian rhythms in patients with RA were altered when compared to the healthy individuals. We have performed 24-hours studies involving RA patients and healthy individuals to further monitor the dynamic occurrence of diverse immune cells in the periphery.
Methods: Thirteen eligible RA patients aged 45-75 years and twelve eligible healthy controls were recruited to join the study. On the study day, the blood was drawn in two hours interval throughout 24 hours. The participants were provided with regular meal, allowed to eat snacks ad libitum and carry passive activities. The absolute number of circulating immune cells was determined using TruCount. RNA were isolated from CD14+ monocytes and analyzed by real-time PCR.
Results: The major populations of immune cells in the periphery of healthy controls, including CD4 T cells, CD8 T cells, regulatory T cells, B cells and monocytes, displayed circadian rhythm that peaks during the rest phase. The rhythms are in general shifted a few hours later in the RA patients. Noteworthy, CD14 monocyte, which is one of the major sources of IL-6 in RA, showed a more pronounced rhythm with higher amplitude in RA patients compared to healthy individuals. Furthermore, the following clock genes are rhythmically expressed in CD14 monocytes of both groups: Rorα, Per1, Per2, Per3 and DBP. The peak of Rorα, Per1, Per3 DBP and CRY1 is shifted a few hours later in RA patients. Interestingly, circadian variation is not observed in the expression of RevErbα in healthy individuals, while in the RA patients a rhythm is established.
Conclusion: In general, circadian rhythm of immune system in cellular and molecular level in RA patients appears to undergo phase shift and peaks a few hours later in comparison to healthy individuals. New established rhythms were also observed in cellular and molecular level in RA patients. Considering our data, we will continue to investigate circadian rhythms in expanded immune cell population using mass cytometry, flow cytometry, immunoassay and microarray. Identification of immunological circadian rhythms in patients with RA and healthy individuals will help us to expand our knowledge in autoimmunity and provide an outlook on potential future implications.
Acknowledgements: We thank our clinical study team; Robert Biesen, Kim-Nikola Zeiner, Desiree Freier, Edgar Wiebe, Manuela Jakstadt, Lisa Ehlers, Annamarie Lang, Moritz Pfeiffenberger, Alexandra Damerau, Piere-Louis Krauß, JustynaPienczykowski, Marius Ibach, Franziska Heinsohn and Antonia Brinkman; for their help, support and contribution during the 24-H study days.
Affiliation: Deutsches Rheuma Forschungzentrum Berlin
Funding: BMBF-KMUi
