Regulatory T cells confer a circadian signature on inflammatory arthritis

Hand, Laura E.; Gray, Kathryn J.; Dickson, Suzanna; Simpkins, Devin Amanda; Ray, David; Konkel, Joanne E.; Hepworth, Matthew R.; Gibbs, Julie

doi:10.1038/s41467-020-15525-0

Cited by 27 publications

(34 citation statements)

References 70 publications

(99 reference statements)

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“…From the perspective of biorhythm, moderate elevation of body temperature at night in ICU patients may be a positive embodiment of immune protection. This is consistent with the normal body temperature regulation, indicating that the patient has better immune regulation function [23][24][25][26][27]. Therefore, BTCRR could be used as a reliable risk factor for ICU mortality.…”

Section: Discussionsupporting

confidence: 78%

The Circadian Temperature Trajectory Predicts the Severity and Prognosis in Critically Ill Patients

Deng¹,

Yu²,

Lin³

et al. 2021

Preprint

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Background: Disrupted circadian temperature is commonly observed in patients in the intensive care unit (ICU). The aim of this study is to examine the association between body temperature (BT) circadian rhythm and mortality critically in patients receiving ICU admission for at least 24h.Method: Adult patients with a complete record of temperature during the first 24 hours of ICU stay in the Multi-parameter Intelligent Monitoring in Intensive Care III (MIMIC-III) database were included in this retrospective cohort study. Body temperature circadian rhythm ratio (BTCRR) was calculated according to the value of mean nighttime divided by daytime mean temperature. All patients were divided into the nocturnal BT rising (NBTR) group (BTCRR >1) and the non-NBTR group (BTCRR≤1). Five subgroups were also built according to different quantile of BTCRR (5%, 10%, 30%, 50%). The associations of NBTR, subgroup, and BTCRR with 28-day mortality were assessed separately using Cox proportional hazards model.Findings: The overall cohort comprised 32419 patients. The non-NBTR group (n=20148) had higher 28-day mortality than the NBTR group (n=12271). After adjusting for covariates, the analysis showed that NBTR was significantly associated with mortality at 28 days (hazard ratio: 0.923; 95% CI, 0.888–0.960, P<0.05). All results of subgroup analysis showed obvious statistical significance, and similar results persisted in the patients with different groups. The % BTCRR had a significant non-linear (p < 0.05) association with 28d-mortality after adjusting for other variables (p < 0.05). Increasing the percentage up to 101% resulted in a hazard ratio (HR) to reduced mortality (HR: 0.96; 95%, 0.941–0.972, P<0.001), while increases above 101 % didn’t make a significant suggestion in mortality.Conclusions: The findings of this study suggest that both low and high BTCRR indicates a poor outcome, such that having a BTCRR of 101% had a survival advantage. BTCRR may aid in the early identification of critically ill patients at high risk of 28-day mortality. These findings may provide a basis for future randomized controlled trials comparing temperature control of ICU patients.

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Section: Discussionsupporting

confidence: 78%

The Circadian Temperature Trajectory Predicts the Severity and Prognosis in Critically Ill Patients

Deng¹,

Yu²,

Lin³

et al. 2021

Preprint

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“…Indeed, 24-h rhythms in bioluminescence have been observed from CD4 + T cells isolated from spleen and thymus of PER2::luciferase mice stimulated with phorbol 12-myristate 13-acetate (PMA) [7]. Furthermore, it has been shown that anti-CD3e/anti-CD28 stimulation can induce PER2 bioluminescence, indicating direct coupling of core clock genes to extrinsic T cell stimulation [11]. Despite lack of conclusive evidence of a functional clock within naïve CD4 + T cells, it is well recognised that genetic deletion of Bmal1 in CD4 + cells dampens the rhythmic function of these cells and impacts on temporal gating of adaptive immune function [10] (see 'Lymphocyte trafficking' section).…”

Section: Cd4 + T Cellsmentioning

confidence: 99%

“…For example, studies in human tissue have shown perturbations of clock genes and proteins within the synovial membrane [71] and specifically FLS [72] in RA patients. A mouse model of inflammatory arthritis additional shows clear evidence of down-regulation of core clock genes in inflammatory cells recruited to the joints, including macrophages and neutrophils [11]. Similarly, there is evidence for dampened clock gene expression within both the site of inflammation [41,73,74] and within the periphery [74,75] in colitis and within the spinal cord in EAE [36].…”

Section: Chronic Inflammation Affects the Molecular Clockmentioning

confidence: 99%

Adaptive immunity, chronic inflammation and the clock

Gray

Gibbs

2022

Semin Immunopathol

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The adaptive arm of the immune system facilitates recognition of specific foreign pathogens and, via the action of T and B lymphocytes, induces a fine-tuned response to target the pathogen and develop immunological memory. The functionality of the adaptive immune system exhibits daily 24-h variation both in homeostatic processes (such as lymphocyte trafficking and development of T lymphocyte subsets) and in responses to challenge. Here, we discuss how the circadian clock exerts influence over the function of the adaptive immune system, considering the roles of cell intrinsic clockwork machinery and cell extrinsic rhythmic signals. Inappropriate or misguided actions of the adaptive immune system can lead to development of autoimmune diseases such as rheumatoid arthritis, ulcerative colitis and multiple sclerosis. Growing evidence indicates that disturbance of the circadian clock has negative impact on development and progression of these chronic inflammatory diseases and we examine current understanding of clock-immune interactions in the setting of these inflammatory conditions. A greater appreciation of circadian control of adaptive immunity will facilitate further understanding of mechanisms driving daily variation in disease states and drive improvements in the diagnosis and treatment of chronic inflammatory diseases.

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“…IL-2, IFNγ) from CD4 + T cells follows diurnal rhythms 113 . However, Treg cells do not seem to have a functional circadian machinery 124 . The general idea is that the circadian machinery may significantly impair the adaptive anti-tumor immune responses through the attenuation of T cell homing to the lymph nodes and the reduction of APC-T cell interaction with consequent reduction in T cell activation, an event essential for killing cancer cells.…”

Section: Circadian Disruption: Implication For Human Health and Diseasesmentioning

confidence: 99%

Molecular regulations of circadian rhythm and implications for physiology and diseases

Fagiani

Marino

Romagnoli

et al. 2022

Sig Transduct Target Ther

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The term “circadian rhythms” describes endogenous oscillations with ca. 24-h period associated with the earth’s daily rotation and light/dark cycle. Such rhythms reflect the existence of an intrinsic circadian clock that temporally orchestrates physiological processes to adapt the internal environment with the external cues. At the molecular level, the circadian clock consists of multiple sets of transcription factors resulting in autoregulatory transcription-translation feedback loops. Notably, in addition to their primary role as generator of circadian rhythm, the biological clock plays a key role in controlling physiological functions of almost all tissues and organs. It regulates several intracellular signaling pathways, ranging from cell proliferation, DNA damage repair and response, angiogenesis, metabolic and redox homeostasis, to inflammatory and immune response. In this review, we summarize findings showing the crosstalk between the circadian molecular clock and some key intracellular pathways, describing a scenario wherein their reciprocal regulation impinges upon several aspects of mammalian physiology. Moreover, based on evidence indicating that circadian rhythms can be challenged by environmental factors, social behaviors, as well as pre-existing pathological conditions, we discuss implications of circadian misalignment in human pathologies, such as cancer and inflammatory diseases. Accordingly, disruption of circadian rhythm has been reported to affect several physiological processes that are relevant to human diseases. Expanding our understanding of this field represents an intriguing and transversal medicine challenge in order to establish a circadian precision medicine.

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Regulatory T cells confer a circadian signature on inflammatory arthritis

Cited by 27 publications

References 70 publications

The Circadian Temperature Trajectory Predicts the Severity and Prognosis in Critically Ill Patients

The Circadian Temperature Trajectory Predicts the Severity and Prognosis in Critically Ill Patients

Adaptive immunity, chronic inflammation and the clock

Molecular regulations of circadian rhythm and implications for physiology and diseases

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